This study examined the association between genetic polymorphisms in glutathione S-transferase M1 (GSTM1) and T1 (GSTT1) and N-acetyltransferase 2 (NAT2) genes and the risk of developing asbestos-related pulmonary disorders in Finnish construction workers with high asbestos exposure. The risk of developing malignant mesothelioma or nonmalignant pulmonary disorders was not significantly associated with GSTM1 or GSTT1 genotypes. However, individuals with the NAT2 slow acetylator genotype had over a two-fold increased risk of developing asbestos-related pulmonary disorders compared to those with the fast acetylator genotype. Those with both the GSTM1 null genotype and NAT2 slow acetyl
Whiteman et al-1998-international_journal_of_cancerSilvina Verna
This study investigated the relationship between p53 expression and risk factors for cutaneous melanoma using a case-control study design. Tissue samples from 121 melanoma cases were analyzed for p53 expression using immunohistochemistry. Abnormal p53 expression was detected in 22 samples (18%). Risk factors for p53-positive melanoma included an inability to tan and history of non-melanoma skin cancer. Risk factors for p53-negative melanoma included high nevus count and heavy freckling. The results suggest there may be two pathways in melanoma pathogenesis characterized by p53 overexpression related to chronic sun exposure and pigment cell instability.
Three key points:
1) The study identified a group of myeloma patients with an "ultra-high risk" of early relapse and poor survival outcomes based on having both high-risk genetic lesions and a high-risk gene expression profile.
2) In two large clinical trials, these ultra-high risk patients had a median progression-free survival of 13.4 months and median overall survival of 26.1 months, significantly worse than other patient groups.
3) Validation in an independent patient group confirmed ultra-high risk patients defined by both genetic and gene expression risk factors experienced particularly poor outcomes, with all progressing within 2 years and no survivors beyond 4 years.
This study aims to evaluate the gene expression profile of FOXE1 mRNA in paired thyroid tumor and non-tumor tissue samples. Preliminary results from the first 10 paired samples show variation in FOXE1 gene expression levels between tumor and non-tumor tissues, with non-tumor tissue appearing to have higher FOXE1 expression compared to tumor tissue. Analysis of more sample pairs is ongoing, and FOXE1 expression levels will be compared to patient clinical data and tumor pathological characteristics. The results so far indicate there may be a profile of FOXE1 expression in thyroid cancer.
1) The study analyzed the radiation survival of 533 human cancer cell lines across 26 cancer types using a high-throughput profiling platform. It found significant variation in survival both across and within lineages, on the order of 5- to 7-fold difference within lineages.
2) The profiling platform was validated against standard clonogenic survival assays, showing a high correlation between results. Sensitivity to radiation was found to have a normal distribution within most lineages studied.
3) Analyzing genomic features, the study found that higher levels of somatic copy number alterations (SCNAs) in a tumor's genome correlated with increased survival after radiation exposure, possibly by enabling more error-prone DNA repair mechanisms. Certain gene mutations and
Multicentric and multifocal versus unifocal breast cancer: differences in the...Enrique Moreno Gonzalez
This study compared the expression of E-cadherin, β-catenin, and MUC1 in multicentric/multifocal breast cancers versus unifocal breast cancers of identical tumor size and grade. The study found significantly downregulated expression of E-cadherin in multicentric/multifocal cancers compared to unifocal cancers. In contrast, no significant differences were seen in β-catenin expression between the two groups. Within the unifocal group, E-cadherin and β-catenin expression were positively correlated, but this was not seen in the multicentric/multifocal group. The results suggest multicentric/multifocal and unifocal breast cancers differ in E-
Differences in microRNA expression during tumor development in the transition...Enrique Moreno Gonzalez
The prostate is divided into three glandular zones, the peripheral zone (PZ), the transition zone (TZ), and the central zone. Most prostate tumors arise in the peripheral zone (70-75%) and in the transition zone (20-25%) while only 10% arise in the central zone. The aim of this study was to investigate if differences in miRNA expression could be a possible explanation for the difference in propensity of tumors in the zones of the prostate.
Clinical and experimental studies regarding the expression and diagnostic val...Enrique Moreno Gonzalez
Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is a multifunctional Ig-like cell adhesion molecule that has a wide range of biological functions. According to previous reports, serum CEACAM1 is dysregulated in different malignant tumours and associated with tumour progression. However, the serum CEACAM1 expression in nonsmall-cell lung carcinomas (NSCLC) is unclear. The different expression ratio of CEACAM1-S and CEACAM1-L isoform has seldom been investigated in NSCLC. This research is intended to study the serum CEACAM1 and the ratio of CEACAM1-S/L isoforms in NSCLC.
This document discusses vitamin D and its potential relationship to ovarian cancer risk. It notes that vitamin D receptor (VDR) expression is higher in ovarian cancer cells than normal ovarian cells. Studies have found that vitamin D administration can inhibit growth and induce apoptosis in ovarian cancer cell lines. The document reviews several studies that found associations between the VDR Fok1 polymorphism and increased ovarian cancer risk. In particular, there is evidence that women with the CT and TT genotypes may have higher risk. Based on these findings, the document calls for larger studies to further evaluate the relationship between the VDR Fok1 polymorphism and epithelial ovarian cancer risk, as well as measuring serum vitamin D levels in ovarian cancer patients.
Whiteman et al-1998-international_journal_of_cancerSilvina Verna
This study investigated the relationship between p53 expression and risk factors for cutaneous melanoma using a case-control study design. Tissue samples from 121 melanoma cases were analyzed for p53 expression using immunohistochemistry. Abnormal p53 expression was detected in 22 samples (18%). Risk factors for p53-positive melanoma included an inability to tan and history of non-melanoma skin cancer. Risk factors for p53-negative melanoma included high nevus count and heavy freckling. The results suggest there may be two pathways in melanoma pathogenesis characterized by p53 overexpression related to chronic sun exposure and pigment cell instability.
Three key points:
1) The study identified a group of myeloma patients with an "ultra-high risk" of early relapse and poor survival outcomes based on having both high-risk genetic lesions and a high-risk gene expression profile.
2) In two large clinical trials, these ultra-high risk patients had a median progression-free survival of 13.4 months and median overall survival of 26.1 months, significantly worse than other patient groups.
3) Validation in an independent patient group confirmed ultra-high risk patients defined by both genetic and gene expression risk factors experienced particularly poor outcomes, with all progressing within 2 years and no survivors beyond 4 years.
This study aims to evaluate the gene expression profile of FOXE1 mRNA in paired thyroid tumor and non-tumor tissue samples. Preliminary results from the first 10 paired samples show variation in FOXE1 gene expression levels between tumor and non-tumor tissues, with non-tumor tissue appearing to have higher FOXE1 expression compared to tumor tissue. Analysis of more sample pairs is ongoing, and FOXE1 expression levels will be compared to patient clinical data and tumor pathological characteristics. The results so far indicate there may be a profile of FOXE1 expression in thyroid cancer.
1) The study analyzed the radiation survival of 533 human cancer cell lines across 26 cancer types using a high-throughput profiling platform. It found significant variation in survival both across and within lineages, on the order of 5- to 7-fold difference within lineages.
2) The profiling platform was validated against standard clonogenic survival assays, showing a high correlation between results. Sensitivity to radiation was found to have a normal distribution within most lineages studied.
3) Analyzing genomic features, the study found that higher levels of somatic copy number alterations (SCNAs) in a tumor's genome correlated with increased survival after radiation exposure, possibly by enabling more error-prone DNA repair mechanisms. Certain gene mutations and
Multicentric and multifocal versus unifocal breast cancer: differences in the...Enrique Moreno Gonzalez
This study compared the expression of E-cadherin, β-catenin, and MUC1 in multicentric/multifocal breast cancers versus unifocal breast cancers of identical tumor size and grade. The study found significantly downregulated expression of E-cadherin in multicentric/multifocal cancers compared to unifocal cancers. In contrast, no significant differences were seen in β-catenin expression between the two groups. Within the unifocal group, E-cadherin and β-catenin expression were positively correlated, but this was not seen in the multicentric/multifocal group. The results suggest multicentric/multifocal and unifocal breast cancers differ in E-
Differences in microRNA expression during tumor development in the transition...Enrique Moreno Gonzalez
The prostate is divided into three glandular zones, the peripheral zone (PZ), the transition zone (TZ), and the central zone. Most prostate tumors arise in the peripheral zone (70-75%) and in the transition zone (20-25%) while only 10% arise in the central zone. The aim of this study was to investigate if differences in miRNA expression could be a possible explanation for the difference in propensity of tumors in the zones of the prostate.
Clinical and experimental studies regarding the expression and diagnostic val...Enrique Moreno Gonzalez
Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is a multifunctional Ig-like cell adhesion molecule that has a wide range of biological functions. According to previous reports, serum CEACAM1 is dysregulated in different malignant tumours and associated with tumour progression. However, the serum CEACAM1 expression in nonsmall-cell lung carcinomas (NSCLC) is unclear. The different expression ratio of CEACAM1-S and CEACAM1-L isoform has seldom been investigated in NSCLC. This research is intended to study the serum CEACAM1 and the ratio of CEACAM1-S/L isoforms in NSCLC.
This document discusses vitamin D and its potential relationship to ovarian cancer risk. It notes that vitamin D receptor (VDR) expression is higher in ovarian cancer cells than normal ovarian cells. Studies have found that vitamin D administration can inhibit growth and induce apoptosis in ovarian cancer cell lines. The document reviews several studies that found associations between the VDR Fok1 polymorphism and increased ovarian cancer risk. In particular, there is evidence that women with the CT and TT genotypes may have higher risk. Based on these findings, the document calls for larger studies to further evaluate the relationship between the VDR Fok1 polymorphism and epithelial ovarian cancer risk, as well as measuring serum vitamin D levels in ovarian cancer patients.
1. The document analyzes the pathogenesis of lung adenocarcinoma in relation to current treatment guidelines and future developments. It finds that genomic analysis has identified recurrent dysregulation of the MAPK and PI3K/mTOR pathways, which drive cell cycle progression and pathogenesis.
2. Current targeted therapies against EGFR and PD-L1 have improved survival rates compared to non-targeted therapies, but an underappreciation of copy number alterations may be limiting progress. Future treatments are exploring targets like HER-2, KRAS, and CDK4/6 inhibitors.
3. While progress has been made, rapid further advances are still needed due to poor survival rates and a lack of defined patient cohorts
This document is a curriculum vitae for Dr. Phyllis Joanne Cornbleet that summarizes her academic and professional background. It includes the following information in 3 sentences:
Dr. Cornbleet received her MD and PhD from Washington University and the University of Missouri, respectively, and completed her residency in clinical pathology at the University of California, San Diego. She worked at Stanford University Medical Center for over 25 years, serving as the Director of several hematology programs. The CV lists her extensive publications, honors, committee work, and areas of expertise in hematopathology, laboratory hematology, and clinical pathology.
Overexpression of YAP 1 contributes to progressive features and poor prognosi...Enrique Moreno Gonzalez
Yes-associated protein 1 (YAP 1), the nuclear effector of the Hippo pathway, is a key regulator of organ size and a candidate human oncogene in multiple tumors. However, the expression dynamics of YAP 1 in urothelial carcinoma of the bladder (UCB) and its clinical/prognostic significance are unclear.
Acute myeloid leukemia (AML) is a hematopoietic malignancy with a dismal outcome in the majority of cases. A detailed understanding of the genetic alterations and gene expression changes that contribute to its pathogenesis is important to improve prognostication, disease monitoring, and therapy. In this context, leukemia-associated misexpression of microRNAs (miRNAs) has been studied, but no coherent picture has emerged yet, thus warranting further investigations.
hMSH2 Gly322Asp (rs4987188) Single nucleotide polymorphism and the risk of br...Agriculture Journal IJOEAR
Aim: Breast cancer is the most common cancer in women both in the developed and less developed world. The reported study was designed to explore associations between hMSH2 - Gly322Asp (1032G>A, rs4987188) single nucleotide polymorphism (SNP) and the risk of breast carcinoma in the Polish women.
Material and methods: Blood samples were obtained from women with breast cancer (n=225), treated at the Department of Oncological Surgery and Breast Diseases, Polish Mother’s Memorial Hospital – Research Institute between the years 2005 and 2012. A control group included 220 cancer-free women. Genomic DNA was isolated and the SNP Gly322Asp of hMSH2 was determined by High-Resolution Melter method. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for each genotype and allele.
Results: This study revealed that single nucleotide polymorphism Gly322Asp of hMSH2 is associated with both breast cancer risk and grading. Moreover, it can be linked with breast carcinoma tumor size and lymph node status. The Asp allele in patients may be a risk factor for breast carcinoma (OR 5.12; 95% CI 3.77 –6.97, p<.0001).
Conclusions: Gly322Asp single nucleotide polymorphism of hMSH2 may be a risk factor of breast cancer in the Polish women.
Stratification of TCGA melanoma patients according to Tumor Infiltrative CD8...Antonio Ahn
The tumour microenvironment, namely the interaction between immune cells and tumour cells plays a crucial role in the treatment outcome of immunotherapy.
In order to predict patient responses to immunotherapy a tumour stratification framework has been proposed based on PD-L1 expression and presence of CD8 Tumour Infiltrative Lymphocytes (TIL).
Advances in genomic technologies and computational tools now allow to determine compositions of different immune cell infiltrates in bulk tumors with increasing accuracy and resolution. Our aim here was to use RNA-seq and methylation 450k data to stratify 469 melanoma patients in TCGA dataset according to the presence of CD8 Tumour Infiltrative Lymphocytes (TIL) and PD-L1 mRNA expression.
Ong et al._Translational utility of next-generation sequencing_2013_GenomicsFrank Ong, MD, CPI
Next-generation sequencing (NGS) has made DNA sequencing rapid, cost-effective and highly accurate. NGS has translational utility in several areas: 1) It can detect genetic variations associated with disease risk and treatment response; 2) It enables non-invasive prenatal testing for fetal abnormalities; 3) Cancer genome sequencing can improve diagnosis, prognosis and treatment by deciphering a cancer's genetic makeup. NGS also has utility in rare genetic disease diagnosis and in precision medicine by matching patients to targeted therapies.
This document discusses how the Cancer Genome Atlas (TCGA) project, which aimed to sequence tumors to identify genetic changes and develop treatments, is now at a crossroads due to the confounding factor of intratumoral heterogeneity. Sequencing more tumors with single biopsies cannot capture heterogeneity between tumor parts or over time. Obtaining multiple biopsies presents logistical challenges. Recent studies reveal significant genetic differences within individual tumors in space and time. This challenges the utility of TCGA's approach and whether its data can guide treatment. Better methods are needed to address tumor heterogeneity.
This document discusses how exome sequencing is revolutionizing the identification of genes that cause Mendelian diseases. It provides three main points:
1) Exome sequencing has identified over 30 new disease genes since 2009, improving clinical diagnosis, genotype-phenotype correlations, and understanding of rare genetic variation.
2) Our view of Mendelian diseases is changing as exome sequencing is less biased than previous methods and is identifying disease genes in cases where the genetic cause was unclear.
3) Exome sequencing is now the primary tool for studying Mendelian diseases as it can sequence hundreds of patient exomes per year more efficiently than whole genome sequencing.
Recently, a phase II clinical trial in hepatocellular carcinoma (HCC) has suggested that the combination of sorafenib and 5-fluorouracil (5-FU) is feasible and side effects are manageable. However, preclinical experimental data explaining the interaction mechanism(s) are lacking. Our objective is to investigate the anticancer efficacy and mechanism of combined sorafenib and 5-FU therapy in vitro in HCC cell lines MHCC97H and SMMC-7721.
Exploring chemo-resistance in NSCLC - Dr Martin BarrHannahMcCarthy31
Dr Martin Barr is a Clinical Scientist at St James's Hospital and Adjunct Assistant Professor at Trinity College Dublin. Dr Barr's research interests are chemotherapy resistance in Non-Small Cell Lung Cancer (NSCLC), in vivo and in vitro models, Liquid Biopsy and EGFR-mutant NSCLC.
This systematic review and meta-analysis examined the risk of early and late cardiotoxicity from anthracycline agents used to treat cancers like breast cancer and lymphoma. The analysis included 55 randomized controlled trials. It found that anthracycline regimens carried a significantly higher risk of clinical cardiotoxicity compared to non-anthracycline regimens or mitoxantrone. Risk was lower for epirubicin vs doxorubicin, liposomal doxorubicin vs non-liposomal doxorubicin, and when cardioprotective agents were used. A similar pattern was seen for subclinical cardiotoxicity. However, evidence was not deemed sufficiently robust to support clear recommendations or routine use of protective measures due
Cancer testis antigens and NY-BR-1 expression in primary breast cancer: prog...Enrique Moreno Gonzalez
Cancer–testis antigens (CTA) comprise a family of proteins, which are physiologically expressed in adult human tissues solely in testicular germ cells and occasionally placenta. However, CTA expression has been reported in various malignancies. CTAs have been identified by their ability to elicit autologous cellular and or serological immune responses, and are considered potential targets for cancer immunotherapy. The breast differentiation antigen NY-BR-1, expressed specifically in normal and malignant breast tissue, has also immunogenic properties. Here we evaluated the expression patterns of CTAs and NY-BR-1 in breast cancer in correlation to clinico-pathological parameters in order to determine their possible impact as prognostic factors.
Targeted sequencing of 99 colorectal cancer samples identified frequent mutations in TP53 (65%), APC (36%), KRAS (35%), PIK3CA (19%), and other genes. EGFR mutations were associated with younger age of onset. EGFR or PIK3CA mutations were markers of poor disease-specific survival, and KRAS or PIK3CA mutations were associated with poor survival in TP53 wild-type cases. The findings provide novel prognostic insights and could help clinical decision-making for colorectal cancer patients in Saudi Arabia.
The treatment for sarcoma cancer is done only through the surgical methods in which the bone and soft-tissue of limb of the patient is saved from extremity tumour cases.
Giant cell arteritis (GCA) is a common type of vasculitis that affects elderly individuals. The study assessed whether three single nucleotide polymorphisms (SNPs) in the BANK1 gene are associated with susceptibility to biopsy-proven GCA. Genotyping of 222 GCA patients and 534 controls found no significant differences in genotype frequencies between the two groups for the three BANK1 SNPs. There was a trend toward a decreased risk of GCA in individuals carrying a specific genotype. However, the results do not support a major role for these BANK1 gene variants in susceptibility to GCA.
We describe a comprehensive genomic characterization of 91 adrenocortical carcinoma specimens. Analysis identified several new ACC driver genes including PRKAR1A, RPL22, TERF2, CCNE1, and NF1. Genome-wide analysis revealed frequent occurrence of massive DNA loss followed by whole-genome doubling (WGD), associated with aggressive disease. WGD was identified as a hallmark of ACC progression, supported by increased TERT expression, decreased telomere length, and cell-cycle activation. Integrated molecular subtyping identified three ACC subtypes with distinct clinical outcomes and alterations, which could be captured by a 68-CpG DNA-methylation signature for clinical stratification.
Ultrasound Technology as a Novel Treatment Strategy in Pancreatic Cancer_Crim...CrimsonpublishersCancer
Adenocarcinoma of the pancreas (PDAC) accounts for 2.4% of all cancers diagnosed and is the fourth leading cause of cancer death, with almost equal rates of incidence and mortality [1]. By 2030, pancreatic cancer is projected to be the second leading cause of cancer-related death [2], surpassing breast, prostate and colorectal cancer. The overall survival at 5 years of around 7.2% as the majority of patients present with advanced disease at diagnosis. Patients with localized disease are treated with surgery, with or without neoadjuvant chemotherapy/ radiotherapy, followed by adjuvant chemotherapy. The majority (around 80%) of patients are treated only with chemotherapy as they have an advanced disease. Patients are treated in the first line with gemcitabine-abraxane or Folfirinox and with Naliri plus 5FU in the second line. There have been few clinical advances in PDAC treatment over the last 20 years and chemotherapy is the only treatment option available for the majority of patients. These tumours are also resistant to many targeted therapies such as anti-EGFR therapy like cetuximab [3] due to the presence of a KRAS mutation in the majority of primary tumors. Personalized medicine strategies have not yet been established in pancreatic cancer as in other more common tumour types. Thus, novel anti-tumour strategies are an important clinical need in order to improve survival rates.
1. The document provides information about a presentation on prostate cancer given by Mwebaza Victor, a 6th year medical student at Kampala International University.
2. Key details include symptoms of prostate cancer like difficulty urinating and blood in the urine. Common risk factors include older age and family history.
3. Treatment options discussed are active surveillance, surgery, radiation therapy, hormone therapy, and chemotherapy.
Personalized medicine in radiation oncology aims to individualize radiotherapy treatment through better imaging, genetics, and biomarkers. Newer radiotherapy techniques like IMRT and IGRT allow for more precise targeting of tumors while minimizing dose to normal tissues. Biomarkers can help characterize tumor hypoxia, proliferation, and a patient's inherent radiosensitivity at the genetic level. Radiogenomics research seeks genetic polymorphisms associated with radiation response and side effects. The goal is to predict treatment outcomes and tailor radiotherapy for each patient's unique biology and genetics.
1. The document analyzes the pathogenesis of lung adenocarcinoma in relation to current treatment guidelines and future developments. It finds that genomic analysis has identified recurrent dysregulation of the MAPK and PI3K/mTOR pathways, which drive cell cycle progression and pathogenesis.
2. Current targeted therapies against EGFR and PD-L1 have improved survival rates compared to non-targeted therapies, but an underappreciation of copy number alterations may be limiting progress. Future treatments are exploring targets like HER-2, KRAS, and CDK4/6 inhibitors.
3. While progress has been made, rapid further advances are still needed due to poor survival rates and a lack of defined patient cohorts
This document is a curriculum vitae for Dr. Phyllis Joanne Cornbleet that summarizes her academic and professional background. It includes the following information in 3 sentences:
Dr. Cornbleet received her MD and PhD from Washington University and the University of Missouri, respectively, and completed her residency in clinical pathology at the University of California, San Diego. She worked at Stanford University Medical Center for over 25 years, serving as the Director of several hematology programs. The CV lists her extensive publications, honors, committee work, and areas of expertise in hematopathology, laboratory hematology, and clinical pathology.
Overexpression of YAP 1 contributes to progressive features and poor prognosi...Enrique Moreno Gonzalez
Yes-associated protein 1 (YAP 1), the nuclear effector of the Hippo pathway, is a key regulator of organ size and a candidate human oncogene in multiple tumors. However, the expression dynamics of YAP 1 in urothelial carcinoma of the bladder (UCB) and its clinical/prognostic significance are unclear.
Acute myeloid leukemia (AML) is a hematopoietic malignancy with a dismal outcome in the majority of cases. A detailed understanding of the genetic alterations and gene expression changes that contribute to its pathogenesis is important to improve prognostication, disease monitoring, and therapy. In this context, leukemia-associated misexpression of microRNAs (miRNAs) has been studied, but no coherent picture has emerged yet, thus warranting further investigations.
hMSH2 Gly322Asp (rs4987188) Single nucleotide polymorphism and the risk of br...Agriculture Journal IJOEAR
Aim: Breast cancer is the most common cancer in women both in the developed and less developed world. The reported study was designed to explore associations between hMSH2 - Gly322Asp (1032G>A, rs4987188) single nucleotide polymorphism (SNP) and the risk of breast carcinoma in the Polish women.
Material and methods: Blood samples were obtained from women with breast cancer (n=225), treated at the Department of Oncological Surgery and Breast Diseases, Polish Mother’s Memorial Hospital – Research Institute between the years 2005 and 2012. A control group included 220 cancer-free women. Genomic DNA was isolated and the SNP Gly322Asp of hMSH2 was determined by High-Resolution Melter method. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for each genotype and allele.
Results: This study revealed that single nucleotide polymorphism Gly322Asp of hMSH2 is associated with both breast cancer risk and grading. Moreover, it can be linked with breast carcinoma tumor size and lymph node status. The Asp allele in patients may be a risk factor for breast carcinoma (OR 5.12; 95% CI 3.77 –6.97, p<.0001).
Conclusions: Gly322Asp single nucleotide polymorphism of hMSH2 may be a risk factor of breast cancer in the Polish women.
Stratification of TCGA melanoma patients according to Tumor Infiltrative CD8...Antonio Ahn
The tumour microenvironment, namely the interaction between immune cells and tumour cells plays a crucial role in the treatment outcome of immunotherapy.
In order to predict patient responses to immunotherapy a tumour stratification framework has been proposed based on PD-L1 expression and presence of CD8 Tumour Infiltrative Lymphocytes (TIL).
Advances in genomic technologies and computational tools now allow to determine compositions of different immune cell infiltrates in bulk tumors with increasing accuracy and resolution. Our aim here was to use RNA-seq and methylation 450k data to stratify 469 melanoma patients in TCGA dataset according to the presence of CD8 Tumour Infiltrative Lymphocytes (TIL) and PD-L1 mRNA expression.
Ong et al._Translational utility of next-generation sequencing_2013_GenomicsFrank Ong, MD, CPI
Next-generation sequencing (NGS) has made DNA sequencing rapid, cost-effective and highly accurate. NGS has translational utility in several areas: 1) It can detect genetic variations associated with disease risk and treatment response; 2) It enables non-invasive prenatal testing for fetal abnormalities; 3) Cancer genome sequencing can improve diagnosis, prognosis and treatment by deciphering a cancer's genetic makeup. NGS also has utility in rare genetic disease diagnosis and in precision medicine by matching patients to targeted therapies.
This document discusses how the Cancer Genome Atlas (TCGA) project, which aimed to sequence tumors to identify genetic changes and develop treatments, is now at a crossroads due to the confounding factor of intratumoral heterogeneity. Sequencing more tumors with single biopsies cannot capture heterogeneity between tumor parts or over time. Obtaining multiple biopsies presents logistical challenges. Recent studies reveal significant genetic differences within individual tumors in space and time. This challenges the utility of TCGA's approach and whether its data can guide treatment. Better methods are needed to address tumor heterogeneity.
This document discusses how exome sequencing is revolutionizing the identification of genes that cause Mendelian diseases. It provides three main points:
1) Exome sequencing has identified over 30 new disease genes since 2009, improving clinical diagnosis, genotype-phenotype correlations, and understanding of rare genetic variation.
2) Our view of Mendelian diseases is changing as exome sequencing is less biased than previous methods and is identifying disease genes in cases where the genetic cause was unclear.
3) Exome sequencing is now the primary tool for studying Mendelian diseases as it can sequence hundreds of patient exomes per year more efficiently than whole genome sequencing.
Recently, a phase II clinical trial in hepatocellular carcinoma (HCC) has suggested that the combination of sorafenib and 5-fluorouracil (5-FU) is feasible and side effects are manageable. However, preclinical experimental data explaining the interaction mechanism(s) are lacking. Our objective is to investigate the anticancer efficacy and mechanism of combined sorafenib and 5-FU therapy in vitro in HCC cell lines MHCC97H and SMMC-7721.
Exploring chemo-resistance in NSCLC - Dr Martin BarrHannahMcCarthy31
Dr Martin Barr is a Clinical Scientist at St James's Hospital and Adjunct Assistant Professor at Trinity College Dublin. Dr Barr's research interests are chemotherapy resistance in Non-Small Cell Lung Cancer (NSCLC), in vivo and in vitro models, Liquid Biopsy and EGFR-mutant NSCLC.
This systematic review and meta-analysis examined the risk of early and late cardiotoxicity from anthracycline agents used to treat cancers like breast cancer and lymphoma. The analysis included 55 randomized controlled trials. It found that anthracycline regimens carried a significantly higher risk of clinical cardiotoxicity compared to non-anthracycline regimens or mitoxantrone. Risk was lower for epirubicin vs doxorubicin, liposomal doxorubicin vs non-liposomal doxorubicin, and when cardioprotective agents were used. A similar pattern was seen for subclinical cardiotoxicity. However, evidence was not deemed sufficiently robust to support clear recommendations or routine use of protective measures due
Cancer testis antigens and NY-BR-1 expression in primary breast cancer: prog...Enrique Moreno Gonzalez
Cancer–testis antigens (CTA) comprise a family of proteins, which are physiologically expressed in adult human tissues solely in testicular germ cells and occasionally placenta. However, CTA expression has been reported in various malignancies. CTAs have been identified by their ability to elicit autologous cellular and or serological immune responses, and are considered potential targets for cancer immunotherapy. The breast differentiation antigen NY-BR-1, expressed specifically in normal and malignant breast tissue, has also immunogenic properties. Here we evaluated the expression patterns of CTAs and NY-BR-1 in breast cancer in correlation to clinico-pathological parameters in order to determine their possible impact as prognostic factors.
Targeted sequencing of 99 colorectal cancer samples identified frequent mutations in TP53 (65%), APC (36%), KRAS (35%), PIK3CA (19%), and other genes. EGFR mutations were associated with younger age of onset. EGFR or PIK3CA mutations were markers of poor disease-specific survival, and KRAS or PIK3CA mutations were associated with poor survival in TP53 wild-type cases. The findings provide novel prognostic insights and could help clinical decision-making for colorectal cancer patients in Saudi Arabia.
The treatment for sarcoma cancer is done only through the surgical methods in which the bone and soft-tissue of limb of the patient is saved from extremity tumour cases.
Giant cell arteritis (GCA) is a common type of vasculitis that affects elderly individuals. The study assessed whether three single nucleotide polymorphisms (SNPs) in the BANK1 gene are associated with susceptibility to biopsy-proven GCA. Genotyping of 222 GCA patients and 534 controls found no significant differences in genotype frequencies between the two groups for the three BANK1 SNPs. There was a trend toward a decreased risk of GCA in individuals carrying a specific genotype. However, the results do not support a major role for these BANK1 gene variants in susceptibility to GCA.
We describe a comprehensive genomic characterization of 91 adrenocortical carcinoma specimens. Analysis identified several new ACC driver genes including PRKAR1A, RPL22, TERF2, CCNE1, and NF1. Genome-wide analysis revealed frequent occurrence of massive DNA loss followed by whole-genome doubling (WGD), associated with aggressive disease. WGD was identified as a hallmark of ACC progression, supported by increased TERT expression, decreased telomere length, and cell-cycle activation. Integrated molecular subtyping identified three ACC subtypes with distinct clinical outcomes and alterations, which could be captured by a 68-CpG DNA-methylation signature for clinical stratification.
Ultrasound Technology as a Novel Treatment Strategy in Pancreatic Cancer_Crim...CrimsonpublishersCancer
Adenocarcinoma of the pancreas (PDAC) accounts for 2.4% of all cancers diagnosed and is the fourth leading cause of cancer death, with almost equal rates of incidence and mortality [1]. By 2030, pancreatic cancer is projected to be the second leading cause of cancer-related death [2], surpassing breast, prostate and colorectal cancer. The overall survival at 5 years of around 7.2% as the majority of patients present with advanced disease at diagnosis. Patients with localized disease are treated with surgery, with or without neoadjuvant chemotherapy/ radiotherapy, followed by adjuvant chemotherapy. The majority (around 80%) of patients are treated only with chemotherapy as they have an advanced disease. Patients are treated in the first line with gemcitabine-abraxane or Folfirinox and with Naliri plus 5FU in the second line. There have been few clinical advances in PDAC treatment over the last 20 years and chemotherapy is the only treatment option available for the majority of patients. These tumours are also resistant to many targeted therapies such as anti-EGFR therapy like cetuximab [3] due to the presence of a KRAS mutation in the majority of primary tumors. Personalized medicine strategies have not yet been established in pancreatic cancer as in other more common tumour types. Thus, novel anti-tumour strategies are an important clinical need in order to improve survival rates.
1. The document provides information about a presentation on prostate cancer given by Mwebaza Victor, a 6th year medical student at Kampala International University.
2. Key details include symptoms of prostate cancer like difficulty urinating and blood in the urine. Common risk factors include older age and family history.
3. Treatment options discussed are active surveillance, surgery, radiation therapy, hormone therapy, and chemotherapy.
Personalized medicine in radiation oncology aims to individualize radiotherapy treatment through better imaging, genetics, and biomarkers. Newer radiotherapy techniques like IMRT and IGRT allow for more precise targeting of tumors while minimizing dose to normal tissues. Biomarkers can help characterize tumor hypoxia, proliferation, and a patient's inherent radiosensitivity at the genetic level. Radiogenomics research seeks genetic polymorphisms associated with radiation response and side effects. The goal is to predict treatment outcomes and tailor radiotherapy for each patient's unique biology and genetics.
The KRAS-Variant and miRNA Expression in RTOG Endometrial Cancer Clinical Tri...UCLA
The KRAS-variant may be a genetic marker of risk for type 2 endometrial cancers. In addition, tumor miRNA expression appears to be associated with patient age, lymphovascular invasion and the KRAS-variant, supporting the hypothesis that altered tumor biology can be measured by miRNA expression, and that the KRAS-variant likely impacts endometrial tumor biology.
This document summarizes information about small cell lung cancer (SCLC), including its incidence, risk factors, staging, prognosis, diagnostic workup, and treatment approaches. Some key points:
- SCLC accounts for 15-20% of lung cancer cases and has a median age of diagnosis of 64. Most patients are smokers.
- Limited stage SCLC is confined to one lung and nearby lymph nodes, while extensive stage has spread further. Median survival is 25 months for limited vs 9 months for extensive disease.
- Workup includes imaging, biopsy, and brain MRI due to the risk of brain metastases. PET-CT helps determine extent of disease.
- Historically, surgery and chemotherapy alone did
Gene expression signatures in tuberculosis have greater overlap with autoimmune diseases than infectious diseases. The analysis identified 2,468 differentially expressed genes in tuberculosis, 8,134 in infection, and 11,348 in autoimmune disorders. There was more overlap between the tuberculosis and autoimmune signatures, with 810 shared genes, compared to only 96 shared with infection. Additionally, pathways analysis showed the predominant involvement of type I interferon signaling, which is important in autoimmunity. This supports the hypothesis that an autoimmune process contributes to pathology in pulmonary tuberculosis.
1) The study analyzed dermatoglyphic patterns such as digital patterns, ATD angles, ridge counts, and triradii on the hands of 30 prostate cancer patients and 30 normal subjects in Nigeria.
2) Significant differences were found between the two groups in terms of higher mean A-B and B-C ridge counts, and lower mean ATD angles, in the prostate cancer patients compared to normal subjects.
3) These characteristic dermatoglyphic patterns associated with prostate cancer could potentially provide a tool for early diagnosis of prostate cancer among Nigerians.
This document summarizes evidence from 16 studies on the association between physical activity and mortality among breast cancer survivors and 7 studies among colorectal cancer survivors. The studies involved a total of 49,095 cancer survivors, including 8,129 deaths from any cause and 4,826 deaths from cancer. The studies found that higher levels of physical activity before or after breast cancer diagnosis were associated with lower risks of total mortality and breast cancer mortality. Higher levels of physical activity before or after colorectal cancer diagnosis were also associated with lower risks of total mortality and colorectal cancer mortality. Increasing physical activity levels from before to after cancer diagnosis was associated with lower total mortality risk compared to those who did not change activity levels.
The document summarizes a study that aimed to predict clinical failure in patients with metastatic prostate cancer by identifying genes related to prostate cancer. Researchers analyzed gene expression levels of androgen receptor, estrogen receptor, and stem cell markers in cancer and stromal cells collected via laser capture microdissection from biopsy samples of 76 patients. Logistic regression analysis showed that expression of Sox2, Her2, and CRP in cancer cells and AR and ER in stromal cells highly predicted prostate-specific antigen recurrence. Ten factors were identified as prognostic for cancer-specific survival, including expression of Oct1, TRIM36, Sox2, c-Myc, AR, Klf4, ER, and clinical parameters. Patients were divided into risk
The document summarizes a study that aimed to predict clinical failure in patients with metastatic prostate cancer by identifying genes related to prostate cancer. Researchers analyzed gene expression levels of androgen receptor, estrogen receptor, and stem cell markers in cancer and stromal cells collected via laser capture microdissection from biopsy samples of 76 patients. Logistic regression analysis showed that expression of Sox2, Her2, and CRP in cancer cells and AR and ER in stromal cells highly predicted prostate-specific antigen recurrence. Ten factors were identified as prognostic for cancer-specific survival, including expression of Oct1, TRIM36, Sox2, c-Myc, AR, Klf4, ER, as well as PSA, Gleason score
This document discusses thyroid cancer guidelines from ESMO. It covers:
1) Incidence and epidemiology of the main types of thyroid cancer, including higher rates in women and certain races.
2) Diagnosis using ultrasound and fine needle aspiration biopsy to evaluate nodules, with molecular testing also showing promise.
3) Treatment for differentiated thyroid cancer typically involving total thyroidectomy followed by staging and risk assessment to guide further treatment and follow-up.
This document summarizes evidence from prospective studies on the association between physical activity and mortality among breast and colorectal cancer survivors. It conducted a systematic review and meta-analysis of 16 studies on breast cancer survivors and 7 studies on colorectal cancer survivors, including over 49,000 total cancer survivors and over 8,000 cases of total mortality. The analysis found that higher levels of physical activity before and after cancer diagnosis were associated with significantly reduced risks of total and cancer-specific mortality for both breast and colorectal cancer survivors. Specifically, the highest levels of pre-diagnosis and post-diagnosis physical activity were associated with 23-28% lower risks of total mortality.
This document outlines a research protocol to study neutrophil lymphocyte ratio (NLR) and platelet lymphocyte ratio (PLR) as predictors of systemic inflammation and chronic illness in pre-surgery patients. The study will retrospectively analyze data from 1000 patients who attended a preadmission clinic between January and April 2013. Medical history, exam findings, and blood test results will be collected to calculate NLR and PLR ratios and examine their relationship to inflammation and health conditions. The goal is to determine the prevalence of elevated ratios and their ability to predict surgical risk factors.
This document describes the characterization of a new head and neck squamous cell carcinoma (HNSCC) cell line called USC-HN2. USC-HN2 was established from a patient with recurrent oral cavity cancer. Characterization showed USC-HN2 has properties typical of aggressive oral HNSCC, including expression of markers like EGFR, CD44v6, and FABP5. Testing revealed USC-HN2 strongly induces regulatory T cells and myeloid-derived suppressor cells in vitro, suggesting an immunosuppressive phenotype. Comparison to another HNSCC cell line, SCCL-MT1, showed both lines have robust cytokine production and immune cell induction, making them useful models for
Sex-Based Difference in Gene Alterations and Biomarkers in Anal Squamous Cell...semualkaira
anal squamous cell carcinoma (ASCC) is a relatively rare malignancy ac-counting for about 2-3% of all the gastrointestinal tumors. The standard of treatment for localized disease is chemoradiotherapy
Sex-Based Difference in Gene Alterations and Biomarkers in Anal Squamous Cell...semualkaira
anal squamous cell carcinoma (ASCC) is a relatively rare malignancy ac-counting for about 2-3% of all the gastrointestinal tumors. The standard of treatment for localized disease is chemoradiotherapy. Several studies reported a sex disparity
in ASCC prognosis showing a better survival for female compared
to men. Methods: we examined 1,380 patients with ASCC who received comprehensive genomic profiling as part of routine clinical
care and present key
Sarcoma is one of the leading cancer centers in Washington DC providing the best musculoskeletal cancer surgery. Dr. Martin Malawer is a highly specialized surgeon who had pioneered in the field of limb-sparing surgery.
Biomedical Informatics 706: Precision Medicine with exposuresChirag Patel
This document discusses the need for a more comprehensive approach to understanding disease etiology by investigating environmental exposures, or the "exposome", in addition to genetic factors. It notes that genome-wide association studies have been successful in identifying genetic risk factors, but genetics alone explains only a portion of disease risk. Large studies like the National Health and Nutrition Examination Survey collect extensive exposure and health data that could be leveraged to discover environmental risk factors through an "exposome-wide association study" approach analogous to GWAS. Characterizing both genetic and environmental contributions is crucial for advancing precision medicine.
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The document provides a conflict analysis of Egypt, summarizing the key conflict dynamics, triggers, actors and causes of conflict according to recent literature. It finds that conflict in Egypt manifests as popular unrest and terrorist attacks, with proximate drivers including repressive politics, military control over the judiciary, and migration issues. Structural causes include economic challenges and environmental factors. Key actors fueling conflict are the Egyptian military, trade unions, Salafist parties like the Muslim Brotherhood, and extremist groups operating in different regions.
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AHMR is an interdisciplinary peer-reviewed online journal created to encourage and facilitate the study of all aspects (socio-economic, political, legislative and developmental) of Human Mobility in Africa. Through the publication of original research, policy discussions and evidence research papers AHMR provides a comprehensive forum devoted exclusively to the analysis of contemporaneous trends, migration patterns and some of the most important migration-related issues.
Indira awas yojana housing scheme renamed as PMAYnarinav14
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UN WOD 2024 will take us on a journey of discovery through the ocean's vastness, tapping into the wisdom and expertise of global policy-makers, scientists, managers, thought leaders, and artists to awaken new depths of understanding, compassion, collaboration and commitment for the ocean and all it sustains. The program will expand our perspectives and appreciation for our blue planet, build new foundations for our relationship to the ocean, and ignite a wave of action toward necessary change.
Awaken new depths - World Ocean Day 2024, June 8th.
88 24-1853 051.812.955.17 folder to Tax Return
1. medical irradiation. Acta Radiol (Nippon)
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(16) Weiss HA, Darby SC, Doll R. Cancer mor-
tality following x-ray treatment for ankylosing
spondylitis. Int J Cancer 1994^9:327-38.
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V, Kunz E. Radon exposure and cancers other
than lung cancer among uranium miners in
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LA, Brown R, Choi NW, et al. Second cancers
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955-75.
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Pedersen D, Storm HH. Incidence of second
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Notes
The following investigators compose the Skin
Cancer Prevention Study Group: E. R. Greenberg, J.
A. Baron, M. R. Karagas, M. M. Stevens, T. A.
Stukel, S. Spencer, D. Nierenberg (Dartmouth
Medical School); N. Lowe, R. Haile (The Univer-
sity of California, Los Angeles); P. Elias, V.
Emster, N. Lapins (The University of California,
San Francisco); J. Mandel, J. C. Vance, G. Bayrd
(The University of Minnesota).
Supported by Public Health Service grants
CA32934, CA23108, and CA57494 from the Na-
tional Cancer Institute, National Institutes of Health,
Department of Health and Human Services, and
ACS SIG-17 from the American Cancer Society.
We thank Leila Mott for her contribution to the
data analysis and Nicole Danforth for assisting with
the literature review.
Manuscript received April 12, 1996; revised
August 16, 1996; accepted September 13, 1996.
Glutathione 5-Transferase and
/V-Acetyltransferase Genotypes
and Asbestos-Associated
Pulmonary Disorders
Ari Hirvonen, Sirkku T.
Saarikaski, Kaija Linnainmaa,
Kari Koskinen, Kirsti
Husgafvel-Pursiainen, Karin
Mattson, Harri Vainio*
Background: Humans vary in their
ability to metabolize endogenous and
exogenous compounds. Glutathione S-
transferases (GSTs) and N-acetyltrans-
ferases (NATs) are enzymes involved in
the detoxification of hazardous agents.
The GSTM1 and GSTT1 genes exhibit
null (i.e., deletion) polymorphisms; in
specific individuals, homozygous dele-
tion (i.e., both copies lost) of these
genes can be detected. Polymorphism
of the NAT2 gene results in slow and
fast acetylators of potentially toxic sub-
stances. The GSTMl-null and the
NAT2 slow-acetylator genotypes have
been associated with increased risks for
the development of environmentally in-
duced cancers. Purpose: We assessed
whether homozygous GSTMl-null or
GSTTl-null genotypes or the NAT2
slow-acetylator genotype were asso-
ciated with increased risks for the
development of malignant and non-
malignant asbestos-related pulmonary
disorders in a cohort of Finnish con-
struction workers. Methods: The study
population consisted of 145 asbestos in-
sulators who were classified as having
been exposed to high levels of asbestos;
69 of these individuals had no pul-
monary disorders (control subjects),
and 76 had either malignant meso-
thelioma (n = 24) or nonmalignant pul-
monary disorders, such as asbestosis
and/or pleural plaques (n = 52). Lym-
phocyte DNA and the polymerase
chain reaction were used to determine
the GSTM1, GSTT1, and NAT2 geno-
types of the study subjects. Odds ratios
(ORs) and 95% confidence intervals
(CIs) estimating the relative risks of
disease associated with specific geno-
types were calculated from 2 x 2 tables
by use of Fisher's exact method.
Results: Risks for the development of
asbestos-related pulmonary disorders
were not affected significantly by
homozygous deletion of the GSTM1 or
GSTT1 genes. However, the risk of
developing both malignant and non-
malignant pulmonary disorders for in-
dividuals with a NAT2 slow-acetylator
genotype was more than twice that ob-
served for those with a NAT2 fast-
acetylator genotype (OR = 2.3; 95% CI
= 1.1-4.7); the risk of developing malig-
nant mesothelioma for NAT2 slow
acetylators was increased almost four-
fold (OR = 3.8; 95% CI = 1.2-143). In-
dividuals who lacked the GSTM1 gene
and possessed a NAT2 slow-acetylator
genotype had a risk of developing ma-
lignant and nonmalignant pulmonary
disorders that was approximately
fivefold greater than that observed for
those who had the GSTM1 gene and a
NAT2 fast-acetylator genotype (OR =
5.1; 95% CI = 1.6-17.6); these in-
dividuals had a fourfold increased risk
of developing nonmalignant pulmonary
disorders (OR = 4.1; 95% CI = 1.1-
17.2) and an eightfold increased risk of
developing malignant mesothelioma
(OR = 7.8; 95% CI = 1.4-78.7) when
compared with the same reference
group. Conclusions: Individuals with
homozygous deletion of the GSTM1
gene and a NAT2 slow-acetylator
genotype who are exposed to high
levels of asbestos appear to have en-
hanced susceptibility to asbestos-re-
lated pulmonary disorders. [J Natl
Cancer Inst 1996;88:1853-6]
Inhalation of asbestos fibers has been
shown to cause lung cancer, diffuse inter-
stitial pulmonary fibrosis (asbestosis),
*Afftlialions of authors: A. Hirvonen, K. Husgaf-
vel-Pursiainen, K. Linnainmaa, S. T. Saarikoski, H.
Vainio (Department of Industrial Hygiene and
Toxicology), K. Koskinen (Uusimaa Regional In-
stitute), Finnish Institute of Occupational Health,
Helsinki, Finland; K. Mattson, Department of Inter-
nal Medicine, Helsinki University Central Hospital,
Finland.
Correspondence to: Ari Hirvonen, Ph.D., Depart-
ment of Industrial Hygiene and Toxicology,
Molecular Epidemiology Group, Finnish Institute of
Occupational Health, FIN-00250 Helsinki, Finland.
See "Notes" section following "References."
Journal of the National Cancer Institute, Vol. 88, No. 24, December 18, 1996 REPORTS 1853
2. malignant mesothelioma of the pleura and
peritoneum, and several other pleura! dis-
eases such as pleural plaques (7). Since
the causal relationship between asbestos
exposure and pulmonary diseases was es-
tablished, much work has been under-
taken to understand the mechanisms of
fiber-induced pathogenesis. According to
present knowledge, both direct and in-
direct cellular effects of fibers may con-
tribute to disease outcome. These effects
include the generation of reactive free
radicals, which result from interactions of
fibers and target cells or are generated
following the phagocytosis of fibers by
inflammatory cells (2). The other factors
(e.g., individual susceptibility) that could
contribute to the development of asbes-
tos-related diseases have not yet been
identified.
Humans vary in their ability to metabo-
lize exogenous and endogenous com-
pounds, and individuals with a genetically
determined reduced capacity to detoxify
hazardous compounds may be at in-
creased risk of adverse health effects
compared with those with unaltered meta-
bolic capacity (3). In this respect, con-
jugation of electrophilic compounds to
glutathione, mediated by glutathione S-
transferases (GSTs), may be of great im-
portance (4). The GST Ml and Tl genes
are polymorphic in humans, and a pheno-
typic absence of enzyme activity results
from the homozygous deletion of the re-
spective genes (i.e., the null genotypes)
(5,6). About 50% of Caucasians have the
GSTMl-null genotype, which has been
suggested in several studies (7-70) to
pose an increased risk for the develop-
ment of environmentally induced cancers.
To date, there are no studies on the as-
sociation between the GSTTl-null geno-
type, which putatively has a frequency of
10%-25% in Caucasians, and individual
cancer risk. However, lack of the GSTT1
gene was recently associated with an en-
hanced susceptibility to myelodysplastic
syndromes, which are clonal proliferative
disorders of bone marrow that often
progress to acute myeloid leukemia (77).
In addition to glutathione conjugation,
acetylation by N-acetyltransferase 2
(NAT2) is an important detoxification
pathway in humans (J). Consequently,
the slow-acetylation-associated NAT2
genotypes, which have a frequency of
about 50% among Caucasians, have been
suggested to modulate individual risk for
the development of, for example, en-
vironmentally induced bladder and colon
cancers (5).
We previously found an association be-
tween the occurrence of malignant meso-
thelioma and GSTM1 and NAT2
genotypes among workers who were
highly exposed to asbestos (70). How-
ever, only a population-based control
group without occupational exposure data
was available, and mesothelioma was the
sole asbestos-related pulmonary disorder
studied. We therefore substituted the
population-based control subjects with a
carefully characterized group of workers
who had a history of high asbestos ex-
posure but no pulmonary disorders, and
we extended the study to cover workers
with two other asbestos-caused disorders,
asbestosis and pleural plaques. We also
assessed the recently described GSTT1
gene polymorphism (<5) to clarify further
the potential role of GST genes in asbes-
tos-associated pulmonary disorders.
Subjects and Methods
Study Subjects
The study subjects were selected from a cohort
of approximately 1500 construction workers who
were recruited for a health-screening survey carried
out at the Finnish Institute of Occupational Health.
All of the workers were interviewed for detailed oc-
cupational and smoking histories by a physician
who was specialized in occupational medicine. The
degree of asbestos exposure, on the basis of all
available data (e.g., personal interview and measure-
ments of lung fiber burden from some of the patients
with mesothelioma), was classified as 1) definite or
probable, 2) possible, and 3) unlikely/unknown. On
the basis of the data, individuals were classified to
high, moderate, or low asbestos-exposure groups. A
subcohort of asbestos insulators who were classified
to the high asbestos-exposure group comprised the
present study population consisting of 145 workers,
69 of whom had no pulmonary disorders detectable
in thorax x rays (mean subject age, 52.8 years
[standard deviation, 9.0 years]) and 76 of whom had
developed either malignant mesothelioma (n = 24)
or nonmalignant pulmonary disorders (asbestosis
and/or pleural plaques) (n = 52) (mean subject age,
55.7 years [standard deviation, 9.3 years]). The dis-
tribution of years of known asbestos exposure was
as follows: 1-9 years (n = 29); 10-19 years (n = 17);
20-29 years (n = 54); and 30 years or more (n = 45).
A minority of the study subjects were never
smokers, both among the healthy workers (25 of 76
[33%]) and among the workers with pulmonary dis-
orders (16 of 69 [23%]). The rest were either ex-
smokers (23 of 76 [30%] and 33 of 69 [48%],
respectively) or current smokers (28 of 76 [37%]
and 20 of 69 [29%], respectively), with mean
cumulative tobacco smoke doses of 28 (standard
deviation, 20) pack-years and 27 (standard devia-
tion, 18) pack-years in the two groups, respectively.
The more specific tobacco smoke dose distribution
for the study population was as follows: 0 pack-
years (n = 41); 1-19 pack-years (n = 36); 20-39
pack-years (n = 48); and 40 or more pack-years (n =
20).
All of the patients with mesothelioma had been
admitted to the Department of Pulmonary Medicine
at the Helsinki University Central Hospital between
1985 and 1993 and were subsequently diagnosed as
having malignant mesothelioma. The tumors were
classified as having epithelial, mixed, or fibroma-
tous histology. The diagnoses were confirmed by
both the Finnish National Mesothelioma Panel and
the European Organization for Research and Treat-
ment of Cancer Mesothelioma Panel. The diagnoses
of asbestosis and pleural plaques were determined
first by conventional chest x rays, using the Interna-
tional Labour Office classification of Radiographs
of Pneumoconiosis. The diagnoses of asbestosis
were subsequently confirmed by the Finnish Nation-
al Panel of Pneumoconiosis by use of high-resolu-
tion central tomography.
Determination of Genetic
Polymorphisms
Genomic DNA was extracted from lymphocytes
by the use of standard techniques. A multiplex
polymerase chain reaction (PCR) method was used
to detect the presence or absence of the GSTM1 and
GSTT1 genes as described by Chen et al. (//). This
modified PCR method (5,6,9,12) had both GST-
specific pnmer pairs in the same amplification mix-
ture and included a third primer pair for f5-globin.
The PCR mixture was composed of 100 ng genomic
DNA template, 30 pmol of each GST primer (G5-
5'GAA CTC CCT GAA AAG CTA AAG C3' and
G6-5'GTT GGG CTC AAA TAT ACG GTG G3',
for amplifying GSTM1; gsttF-5TTC CTT ACT
GGT CCT CAC ATC TC3' and gsttR-5TCA CCG
GAT CAT GGC CAG CA3', for amplifying GSTT1
[primers synthesized by the Institute of Biotechnol-
ogy, Helsinki, Finland]), 10 pmol p-globin gene
primers (BG1-5'CAA CTT CAT CCA CGT TCA
CC3' and BG2-5'GAA GAG CCA AGG ACA GGT
AC3' [primers synthesized by the Institute of
Biotechnology]), 200 ujnol deoxynucleoside tri-
phosphates (dNTPs) (Boehnnger Mannheim GmbH,
Federal Republic of Germany), 1 U Taq polymerase
(Promega Corp., Madison, WI), and 3.3 mM MgCl2
(stock solution, 25 mM; Promega Corp.) in a final
volume of 30 uL with the PCR buffer (final con-
centrations: 16.6 mA/ [NH4]2SO4, 50 mM fJ-mercap-
toethanol, 6.8 |lM EDTA, 67 mM Tris [pH 8.8], and
80 (ig/mL bovine serum albumin). The reaction
mixture was assembled at 85 "C, placed in a Perkin-
Elmer 9600 thermal cycler (Perkin-Elmer Cetus,
Norwalk, CT) for 3 minutes at 94 "C, and then sub-
jected to 30 cycles of 94 "C for 10 seconds, 60 'C
for 20 seconds, and 72 'C for 45 seconds. The ther-
mal cycling program was followed by a final step at
72 "C for 5 minutes. The GSTT1 (480 base pair
[bp]), P-globin (268 bp), and GSTM1 (215 bp)
amplification products were resolved in an ethidium
bromide-stained 4% 3:1 NuSieve/agarose gel (FMC
Corp., Rockland, ME). The absence of the GSTM1-
1854 REPORTS Journal of the National Cancer Institute, Vol. 88, No. 24, December 18, 1996
3. Table 1. Distribution of glutathione 5-transferase (GST) and A'-acetyltransferase (NAT) genotypes in workers exposed to asbestos in relation to
pulmonary disorders*
End point
No pulmonary disorders
Pulmonary disorders (all)
Nonmalignant
Malignantt
No. of
patients
69
76
52
24
GSTM1 genotype
%null
46
61
58
67
OR (95% CI)
1.0
1.8(0.3-3.4)
1.5(0.8-3.3)
2.3(0.8-7.1)
No. of
patients
69
76
52
24
GSTT1 genotype
% null
10
8
8
8
OR (95% CI)
1.0
0.8 (0.2-2.8)
0 7(0.2-3.1)
0.8(0.1-4.7)
No. of
patients
68
75
51
24
NAT2 genotype
%slow
50
69
65
79
OR(95%CI)
1.0
2.3(1.1-4.7)
1.8(0.8-4.2)
3.8(1.2-14.3)
*OR = odds ratio; CI = confidence interval; null = absence of the gene; slow = slow acetylator.
tMalignant mesothelioma.
or the GSTT1-specific fragment indicated the cor-
responding null genotype, whereas the p^-globin-
specific fragment confirmed the presence of
amplifiable DNA in die reaction mixture (//). To
verify the GSTTl-null genotype further and to en-
sure that DNA degradation did not influence the
results, a second PCR was performed that yielded a
112-bp fragment (data not shown).
The NAT2 allele corresponding to the fast-
acetylator phenotype and the four slow-acetylator
phenotype-associated alleles were distinguished by
use of pnmers specific for the NAT2 gene in a PCR
reaction and restriction enzyme digestion of the
resulting amplification product as described by Bell
et al. (13). A single PCR was earned out using 50
pmol of the primers (N5-5'GGA ACA AAT TGG
ACT TGG3' and N4-5TCT AGC ATG AAT CAC
TCT GC3' [synthesized by Institute of Biotechnol-
ogy]), 200 umol dNTPs (Boehringer Mannheim
GmbH), 1 U Taq polymerase (Promega Corp.), and
2.0 nW MgCl2 (Promega Corp.) in a volume of 50
uL with the above-described PCR buffer. After
PCR, which was performed as indicated for the GST
analyses, except that an annealing temperature of
57 'C was used, 7.5-|iL aliquots were removed and
subjected to restriction digestion with Kpn I (for the
M1 allele), Taq I (for the M2 allele), BamHl (for the
M3 allele), or Msp UAlu I (for the M4 allele). (The
restriction enzymes were from New England
Biolabs, Inc., Beverly, MA.) The digests were sub-
jected to electrophoresis in 4% agarose gels. The ab-
sence of a restriction site indicated the presence of a
defective NAT2 allele, and the presence of two
defective alleles identified the slow acetylators (13)
Statistical Methods
The odds ratio (OR) is an estimate of the rela-
tive risk of disease associated with specific
genotypes and is defined as the odds of a case
patient having the at-risk genotype divided by the
odds of a control subject having the same
genotype. ORs and 95% confidence intervals (CIs)
were calculated from 2 x 2 tables with the Fisher's
exact model, and Pearson coefficients of correla-
tion were calculated between determinants and
potential confounders (14).
Results and Discussion
When the three genes were studied
separately (Table 1), no statistically sig-
nificant differences were observed for the
GST genotypes, although the frequency
of the GSTM 1-null genotype was clearly
higher among the patients with malignant
mesothelioma (67%) and somewhat
higher among the asbestos workers with
nonmalignant pulmonary disorders (58%)
than among workers who lacked evidence
of these disorders (46%). In contrast, the
NAT2 slow-acetylator genotypes were
significantly more prevalent among the
workers with pulmonary disorders (69%)
than among those lacking them (50%)
(OR = 2.3; 95% CI = 1.1-4.7). The fre-
quency of NAT2 slow-acetylator geno-
types was highest among the patients with
malignant mesothelioma (79%) (OR =
3.8; 95% CI = 1.2-14.3). Moreover, the
slow acetylators lacking the GSTM 1 gene
had nearly an eightfold higher risk of
mesothelioma (OR = 7.8; 95% CI = 1.4-
78.7) compared with those who had the
gene and the NAT2 fast-acetylator
genotype (Table 2). They were also at a
fourfold higher risk of nonmalignant pul-
monary disorders (OR = 4.1; 95% CI =
1.1-17.2) and, consequently, at about a
fivefold higher risk overall (OR = 5.1;
95% CI = 1.6-17.6) of developing one of
the pulmonary disorders studied. As ex-
pected, correlations between the geno-
types and age, pack-years of cigarette
smoking, duration of smoking, and dura-
tion of asbestos exposure were negligible,
with correlation coefficients ranging from
-0.05 to 0.12. Therefore, no adjustment
of the ORs by these factors was needed.
In contrast to the effects shown by com-
binations of GSTM1 and NAT2 geno-
types, other combinations of the studied
genotypes showed no additive effects.
Table 2. Combinations of GSTM 1 and NAT2 genotypes in workers exposed to asbestos in relation to pulmonary disorders*
End point
NAT2 slow acetylators NAT2 fast acetylators
GSTM 1-null
No. of
patients %
GSTM 1-positive
No. of
patients %
GSTM I-null
No. of
patients %
GSTM 1-positive
No. of
patients % ORt 95% CI*
No pulmonary disorders
Pulmonary disorders (all)
Nonmalignant
Malignant§
15
30
17
13
22
40
33
54
19
22
16
6
28
29
31
25
16
16
13
3
24
21
26
13
18
7
5
2
27
9
10
8
1.0
5.1
4.1
7.8
1.6-17.6
1.1-17.2
1.4-78.7
•Null = absence of the gene; positive = presence of the gene.
tOR = odds ratio. OR shown is for the NAT2 slow-acetylator and GSTM 1 -null genotype combination compared with the NAT2 fast-acetylator and GSTM 1 -posi-
tive genotype combination; reference group consists of subjects with no pulmonary disorders.
pZl = confidence interval.
§Malignant mesothelioma.
Journal of the National Cancer Institute, Vol. 88, No. 24, December 18, 1996 REPORTS 1855
4. The lack of effect of smoking in this
study stands in contrast to previous
analyses of the GSTM1 gene and cancer
susceptibility, where the risk associated
with the GSTM 1-null genotype was
mostly attributable to smoking (7-9). In
the previous analyses, the associations
appeared, however, to be heavily influ-
enced by the asbestos exposure levels, in
agreement with two more recent studies.
An association was reported between the
GSTM 1-null genotype and the risk of
developing asbestosis among highly ex-
posed asbestos workers (15), whereas no
association was found between radiograph-
ic or lung function changes and GSTM1
genotype in a group of asbestos workers
with mostly low or moderate exposure
levels (16).
Certain GST isoenzymes are con-
sidered to be part of a system required for
the repair of free-radical-induced lipid
peroxidation (4), which is considered to
be one possible mechanism in the multi-
step process of asbestos carcinogenesis
(2). Therefore, the observed association
between the GSTM 1-null genotype and
asbestos-associated pulmonary disorders
was not surprising, whereas the remark-
able impact of the NAT2 genotype ob-
served both in this study and in our
previous study (10) was rather unex-
pected. However, asbestos fibers are able
to induce ornithine decarboxylase en-
zyme activity, resulting in increased cell
proliferation as a consequence of en-
hanced polyamine synthesis (17). Since
an acetylation step is known to be in-
volved in the catabolism of polyamines
(18), the slow NAT2 acetylators may ac-
cumulate greater amounts of polyamines
than the fast acetylators. This could ex-
plain, in part, the modulating effect of
NAT2 polymorphism in individual re-
sponses to asbestos exposure.
In conclusion, we found that, among
workers with high levels of asbestos ex-
posure, individuals concurrently having a
NAT2 slow-acetylator genotype and
homozygous deletion of the GSTM 1 gene
showed a marked excess of asbestos-as-
sociated pulmonary disorders. Even if the
present study size is relatively small, the
high prevalence of these potential at-risk
genotypes indicates that our observations
may have important implications for
public health.
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Notes
Supported in part by the Finnish Academy of
Sciences grants 8566 and 29456 and by the Finnish
Work Environment Fund grant 93384.
We thank Drs. Antti Karjalainen and Timo Par-
tanen for helping in the statistical analyses and
Maria Reinikainen for her skillful technical assis-
tance.
Manuscript received April 18, 1996; revised July
23, 1996; accepted September 25, 1996.
1856 REPORTS Journal of the National Cancer Institute, Vol. 88, No. 24, December 18, 1996