Prof. M.C.Bansal MBBS,MS,MICOG,FICOG Professor OBGY Ex-Principal & Controller Jhalawar Medical College & HospitalMahatma Gandhi Medical College, Jaipur.
The number of cells in a normal tissue is tightly regulated by a balance between cell proliferation and death. The final common pathway for cell division involves distinct molecular switches that control cell cycle progression from G1 to S phase of DNA synthesis. Dysregulation of cellular proliferation is the main hallmark of cancer. There may be increased activity of genes involved in cellular proliferation(oncogenes) or loss of growth inhibitory(tumor suppressor) genes or both.
Cancer is a complex disease that arises because of genetic and epigenetic alterations that disrupt cellular proliferation, senscence & death The malignant phenotype is also characterized by its ability to invade surrounding tissues and metastasize.
Hippocrates was the first to use the word “cancer” to describe tumors Cancer is derived from the Greek word “karkinos” which means crab It is thought Hippocrates was referring to the appearance of tumors. The main portion of the tumor being the crabs body and the various extensions of the tumor appear as the legs and claws of the crab.
Changes to the DNA of a cell (mutations) lead to cellular damage Mutations enable cancer cells to divide continuously, without the need for normal signals In some cancers the unchecked growth results in a mass, called a tumor Cancerous cells may invade other parts of the body interfering with normal body functions
Although cancer is often referred to as if it were a single disease, it is really a diverse group of diseases that affects many different organs and cell types The likelihood of developing any particular cancer depends on an individual’s genetics, environment, and lifestyle. The occurrence of some cancers may be prevented/reduced by wise lifestyle choices.
Cancer arises from one cell, Transformation from a normal cell to multistage process, typically progression from a pre cancerous lesion to malignant tumor. The changes are the result of interaction between a person’s genetic factors and the environmental factor and carcinogenic agents. This unguarded tissue growth is responsible for high morbidity and mortality.
Atleast three different pathways of cell death have been characterized, including apoptosis, necrosis, autophagy All three pathways may be ongoing simultaneously within a tumor.
The apoptosis derives from Greek and alludes to a process akin to leaves dying and falling off a tree. Apoptosis is a active energy dependent process that involves cleavage of DNA by endonucleases and proteins by proteases called CASPASES.
Morphologically apoptosis is characterized by condensation of chromatin, nuclear and cytoplasmic blebbing & cellular shrinkage. The molecular signals that affect apoptosis in response to various stimuli are complex and have only been partially elucidated, but several reliable markers of apoptosis have been discovered including ANNEXIN V, CASPASE 3 ACTIVATION, and DNA FRAGMANTATION.
The intrinsic apoptosis pathway is regulated by a complex interaction of pro and anti apoptotic proteins in mitochondrial membranes that affects its permeability. The TP53 tumor suppressor gene is a critical regulator of cell cycle arrest and apoptosis in response to DNA damage.
Necrosis is a process that is distinct from apoptosis and is a result of bioenergetic compromise. Necrosis is less well regulated process that leads to spillage of protein contents, and this may incite a brisk immune response. This is in contrast to silent elimination of cells by apoptosis, which typically elicits a minimal immune response.
Thereis evidence that some drugs may enhance necrotic death in tumors, and this may stimulate beneficial antitumor immune response.
Atophagy is a potentially reversible process in which a cell that is stressed EATS itself. Atophagy is characterized by the formation of cytoplasmic AUTOPHAGIC VESCICLES into which cellular protein and organelles are sequestered. Several cancer therapeutic agents have been shown to induce autophagy, while targeted disruption of genes such as ATG5 that are involved in autopaghy can inhibit cell death.
Normal cells are only capable of undergoing division a finite number of times before becoming senescent. Cellular sescence is regulated by a biological clock related to progressive shortening of repetitive DNA sequence(TTAGGG) called telomers that cap the end of each chromosome.
Telomers are thought to be involved in chromosome stabilization and preventing recombination during mitosis. At birth chromosomes have long telomeric sequence( 150,000 bases) that become shorter by 50- 200 bases each time the cell divides. Telomeric shortening is a biological clock that triggers senescence.
Telomeric activity is detectable in a high fraction of many cancers, including ovarian(8,9), cervical(10,11), and endometrial cancers(12). It has been suggested that deletion of telomerase might be useful for early diagnosis of cancer, but lack of specificity is a significant issue.
Human cancers arise because of series of genetic and epigenetic alterations that leads to disruption of normal of normal mechanism that govern cell growth, death and senescence. Genetic damage may be inherited or arise after birth as a result of either exposure to exogenous carcinogens or endogenous mutagenic process within the cell.
Itis thought that at least 3-6 alterations are required to fully transform the cell. Most cancer cells are genetically unstable and leading to an accumulation of substantial number of secondary changes that play a role in evolution of malignant phenotype with respect to growth, invasion, metastasis and response to therapy amongst characterstics
Genetic instability also result in evolution of heterogeneous clones within a tumor. There is some evidence that progenitor cells(stem cell) exist within a tumor that may be relatively resistant to therapy.
Although most cancers arise sporadically in the population because of acquired genetic damage, inherited mutations in cancer susceptibility genes are responsible for some cases. Families with these mutations exhibit a high incidence of specific type of cancers The age of cancer onset is younger in these families and it is not unusual for a person to be affected with multiple primary cancers.
Many of the genes involved in hereditary cancer syndrome have been identified. The most common forms of hereditary cancers syndrome predispose to breast or ovarian(BRAC1,BRAC2) and colon or endometrial(HNPCC genes) cancers. Tumor suppressor genes have been implicated most frequently in hereditary cancer syndromes, followed by DNA repair genes.
The familial cancer syndrome described above result from rare mutation that occur in 1% of the population. In addition low penetranc common genetic polymorphism may also affect cancer susceptibility, albeit less dramatically. There are more than 10 million polymorphic genetic loci in human genome. Many of these polymorphism are common, with rarer allele occurring in more than 5% of individuals.
Althoughgenetic polymorphism would not be expected to increase the risk sufficiently to produce familial cancer clustering, they could account for significant fraction of cancers currently classified as sporadic because of there high prevalence
The etiology of acquired genetic damage seen in cancers also has been elucidated to some extent. For ex. Strong casual link exists between cigarette smoke and cancers of airodigestive tract and between ultraviolet radiation and skin cancers. For many common forms of cancers (colon, breast, endometrium, ovary) a strong association with specific carcinogens doesn’t exists.
Several families of highly effective DNA damage surveillance and repair genes exist, but some mutations may elude them The efficiency of these DNA damage- response systems varies between individuals because of genetic and other factors and may affect susceptibility to cancers.
Epigenetic changes are heritable changes that do not result from alteration in DNA sequence. Methylation of cytosines residues that reside next to guanine residues is the primary mechanism of epigenetic regulation, and this process is regulated by a family of DNA methyl transferases. Most cancers have globally reduced DNA methylation, which may contribute to genomic instability.
Conversely, selective hypermethylation of cytosines in the promoter regions of tumor suppressor genes may lead to their inactivation, and this may contribute to carcinogenesis. There is a family of imprinted genes in which either the maternal or paternal copy is normally completely silenced because of methylation. Loss of imprinting in the genes that stimulate proliferation, such as insulin-like growth factor 2, may provide an oncogenic stimulus by increasing proliferation
Acetylation and methylation of the histon protein that coat DNA represent another level of epigenetic regulation that is altered in cancer.
Alteration in genes that stimulate cellular growth(oncogenes) can cause malignant transformation. Many genes that are involved in normal growth regulatory pathwayscan elicit transformation to overactive form when altered to overactive forms via amplification, mutation, or translocation.
Peptide growth factors- such as those of epidermal growth factor, platlet growth factor, and fibroblast growth factor families stimulate a cascade of molecular events that leads to proliferation by binding to cell membrane receptors. Growth factors in the extracellular space can stimulate a cascade of molecular events that leads to proliferation by binding to celll membrane receptors.
There is little evidence to suggest that overproduction of growth factors is a precipitating event in development of most cancers. Cell membrane receptors that bind peptide growth factors are composed of an extracellular ligand binding domain, a membrane spanning region, and a cytoplasmic tyrosine kinase domain.
Binding of growth factor to extracellular domain results in aggregation and conformational shifts in receptor and activation of inner tyrosine kinase. This kinase phosphorylate tyrosine residue both on the growth factor receptor itself (autophosphorylation) and on molecular targets in the cell interior , leading to activation of secondary signals.
Growth of some cancers is driven by overexpression of receptor tyrosine kinase receptors. Therapeutic strategies that target receptor tyrosine kinase have been an active area of investigation. Trastuzumab is a monoclonal antibody that blocks the HER-2/neu receptor, and it is widely used in the treatment of breast cancers that overexpress this tyrosine kinase (20).
Cetuximab is a monoclonal antibody that targets the epidermal growth factor receptor (EGFR), whereas gefitinib is a direct inhibitor of the EGFR tyrosine kinase (21). Lapatinib is a dual EGFR/HER-2 kinase inhibitor. Imatinib antagonizes the activity of the BCR-ABL, c-kit, and PDGF receptor tyrosine kinases and has proven effective in treatment of chronic myelogenous leukemias and gastrointestinal stromal tumors.
Following the interaction of peptide growth factors and their receptors, secondary molecular signals are generated to transmit the growth stimulus to the nucleus . This function is served by a multitude of complex and overlapping signal transduction pathways that occur in the inner cell membrane and cytoplasm. Many of these signals involve phosphorylation of proteins by enzymes known as nonreceptor kinases (22). These kinases transfer a phosphate group from ATP to specific amino acid residues of target proteins.
The kinases that are involved in growth regulation are of two types: those that are phosphorylate tyrosine residues on proteins, including those of the SRC family (23); and others that are specific for serine or threonine residues such as AKT (24). The activity of kinases is regulated by phosphatases such as PTEN
Guanosine-triphosphate-binding proteins (G proteins) represent another class of molecules involved in transmission of growth signals . They are located on the inner aspect of the cell membrane and have intrinsic GTPase activity that catalyzes the exchange of guaninetriphosphate (GTP) for guanine- diphosphate (GDP). In their active GTP-bound form, G proteins interact with kinases that are involved in relaying the mitogenic signal, such as those of the MAP kinase family.
Conversely, hydrolysis of GTP to GDP, which is stimulated by GTPase-activating proteins (GAPs), leads to inactivation of G proteins. The ras family of G proteins is among the most frequently mutated oncogenes in human cancers. BRAF mutations occur in many cancers that lack ras mutations, and most of these mutations involve codon 599 in the kinase domain .
Therapeutic approaches to interfering with ras signaling are being developed, including farnesyltransferase inhibitors that block attachment of ras to the inner cell membrane, antisense oligonucleotides, and RNA interference.
If proliferation is to occur in response to signals generated in the cell membrane and cytoplasm, these events must lead to activation of nuclear transcription factors and other genetic products responsible for stimulating DNA replication and cell division. Expression of several genes that encode nuclear proteins increases dramatically within minutes of treatment of cells with peptide growth factors. Once induced, the products of these genes bind to specific DNA regulatory elements and induce transcription of genes involved in DNA synthesis and cell division.
Examples include the fos and jun oncogenes, which dimerize to form the activator protein 1 (AP1) transcription complex. When inappropriately overexpressed, however, these transcription factors can act as oncogenes. Among the nuclear transcription factors involved in stimulating proliferation, amplification or overexpression of members of the myc family has most often been implicated in the development of human cancers (27). Many of the nuclear regulatory genes such as myc that control proliferation also affect the threshold for apoptosis.
Thus, there is overlap in the molecular pathways that regulate the opposing processes of proliferation and apoptosis. Genes involved in chromatin remodeling also that have been implicated as oncogenes, but primarily in hematologic malignancies rather than solid tumors. Finally, as discussed previously, genes encoding nuclear proteins that inhibit apoptosis (e.g., bcl-2) can act as oncogenes when altered to constituitively active forms.
Loss of tumor suppressor gene function also plays a role in the development of most cancers. This usually involves a two-step process in which both copies of a tumor suppressor gene are inactivated. In most cases, there is mutation of one copy of a tumor suppressor gene and loss of the other copy because of deletion of a segment of the chromosome where the gene resides. There is also evidence that some tumor suppressor genes may be inactivated because of methylation of the promoter region of the gene .
The promoter is an area proximal to the coding sequence that regulates whether the gene is transcribed from DNA into RNA. When the promoter is methylated, it is resistant to activation, and the gene is essentially silenced despite remaining structurally intact. This two-hit paradigm is relevant to both hereditary cancer syndromes, in which one mutation is inherited and the second acquired, and sporadic cancers, in which both hits are acquired.
The retinoblastoma gene was the first tumor suppressor gene discovered. The Rb gene plays a key role in the regulation of cell cycle progression. Mutations in the Rb gene have been noted primarily in retinoblastomas and sarcomas.
Beyond simply inhibiting proliferation, normal p53 is thought to play a role in preventing cancer by stimulating apoptosis of cells that have undergone excessive genetic damage. In this regard, p53 has been described as the ―guardian of the genome‖.
Although many tumor suppressor genes— including TP53, Rb, and p16—encode nuclear proteins, some extranuclear tumor suppressors have been identified. Inactivation of APC leads to malignant transformation, and inherited mutations in this gene are responsible for familial adenomatous polyposis syndrome. The transforming growth factor-beta (TGF-β) family of peptide growth factors inhibit proliferation of normal epithelial cells and serve as a tumor suppressive pathway.
Prominent intracellular targets include a class of molecules called Smads that translocate to the nucleus and act as transcriptional regulators. In addition to primary disregulation of oncogenes and tumor suppressor genes, altered expression of microRNAs that regulate the expression of these genes occurs in many cancers . MicroRNA genes consist of a single RNA strand of approximately 21 to 23 nucleotides that does not encode proteins.
Theybind to messenger RNAs that contain complementary sequences and can block protein translation.
Metastasis is a process by which cancer cells spread from the primary tumor to distant sites . It is now appreciated at a molecular level that metastasis is dependent on a balance between stimulating factors from both the tumor and host cells versus inhibitory signals. To produce metastasis, the balance must be weighted toward the stimulatory signals.
Cancer progression is a product of an evolving crosstalk between different cell types within the tumor and its surrounding supporting tissue, the tumor stroma . The tumor stroma contains a specific extracellular matrix as well as cellular components such as fibroblasts, immune and inflammatory cells, and blood-vessel cells. The interactive signaling between tumor and stroma contributes to the formation of a complex multicellular organ..
The organ microenvironment can markedly change the gene-expression patterns of cancer cells and therefore their behavior and growth potential . Recent studies regarding chemokines and their receptors provide important clues regarding why some cancers metastasize to specific organs. For example, breast cancer cells frequently express chemokine receptors CXCR4 and CCR7 at high levels.
The specific ligands for these receptors, CXCL12 and CCL 21, are found at high levels in lymph nodes, lung, liver, and bone marrow, which are common sites for breast cancer metastasis.
Angiogenesis occurs as a result of a shift in balance toward proangiogenic factors within the tumor microenvironment along with down regulation of antiangiogenic influences. One of the primary mediators of angiogenesis is vascular endothelial growth factor A (VEGF-A), which increases vascular permeability, stimulates endothelial cell proliferation and migration, and promotes endothelial cell survival.
Other mediators of angiogenesis include tumor-derived factors and host stromal factors including interleukin-8, alpha v-beta 3 integrin, the tyrosine kinase receptor EphA2, and matrix metalloproteinases. Antiangiogenesis therapies such as Bevicizumab that target the VEGF pathway are showing promise in ovarian cancer and have already entered phase III clinical trials.
A critical first step in metastasis, and the primary feature that defines malignancy, is invasion through the basement membrane. This requires interplay between cancer cells and a permissive underlying stroma . Invasion of malignant cells through the basement membrane and endothelial cell migration for angiogenesis require degradation of the extracellular matrix.
Thisprocess is facilitated by a group of enzymes called matrix metalloproteinases (MMPs), which are a family of zinc- dependent endopeptidases that digest collagen and other extracellular matrix components. They also stimulate proliferation and induce release of VEGF. Ovarian tumors overexpress MMP-2 and MMP-9, and this increased expression correlates with aggressive clinical features .
Tumor cell adhesion to the extracellular matrix within tissues greatly influences the ability of a malignant cell to invade and metastasize. Given the shedding nature of ovarian cancer, adhesion molecules such as focal adhesion kinase, integrins, and E-cadherin have been evaluated for their role in peritoneal metastasis.
Cadherins are another group of cell-cell adhesion molecules that are involved in development and maintenance of solid tissues. E-cadherin is uniformly expressed in ovarian cancer, in low-malignant-potential tumors, in benign neoplasms, and—notably—in inclusion cysts of normal ovaries, but not in the normal surface epithelium.
The cytoplasmic tails of cadherins exist as a macromolecular complex with β-catenin, which is involved in the wnt signaling pathways that regulate both adhesion and growth. Regulation of β-catenin activity also depends on the APC gene product and others in the wnt pathway. Mutations in the APC gene that abrogate its ability to inhibit β-catenin activity are common in both the hereditary adenomatous polyposis coli syndrome and sporadic colon cancers. Likewise, mutations in the β-catenin gene that result in
Within the tumor microenvironment, other cell types also play a critical role in tumor growth and progression. For example, recent studies indicate that certain types of inflammatory cells, including macrophages and mast cells, and their associated cytokines confer an unfavorable prognosis and increased tumor growth. Conversely, the presence of an adaptive immune response characterized by cytotoxic T cells is associated with improved clinical outcome.
In addition, cancer cells may evade immune recognition and destruction by various means, such as Fas ligand production to induce lymphocytice apoptosis and HLA-G secretion to inhibit natural-killer cell activity. Moreover, cytokine production by cancer cells promotes growth and inhibits apoptosis.
Themechanistic relationships between the microenvironment and tumor growth remain only partially understood, but immunomodulating strategies that target the cancer-promoting properties of both innate and adaptive immune cell populations are being developed.
Cancer is leading causes of death worldwide. It accounts for 7.4 million deaths e.g. 13% of all deaths worldwide in 2004. The Common types of Cancer in general population are- Lung - 1.3 million deaths per year Stomach - 803000 deaths per year Colorectal- 639000 deaths per year Liver - 610000 deaths per year Breast - 519000 deaths per year Female Genital Tract - 467000 deaths per year (Source – WHO-2008 Burden of disease 2004 update)
Cancer Cerebro vascular diseases Motor vehicle Accidents Chronic Obstructive lung diseases Diabetes Pneumonia and influenza
Breast – 20.27 per lac population Female Genital Cancer – 22.42 per lac population Colorectal – 6.74 lac population Lungs – 6.62 per lac population Liver – 4.55 per lac population (ICMR 2004 – Assessment of burden of non communicable diseases)
Lungs and Bronchus – 25% Breast Cancer – 16% Colorectal Cancer – 11% Ovarian Cancer – 5% Cancer Cervix - 4%
• Lungs and Bronchus – 6.45 per lac Population• Breast Cancer – 5.52 per lac population• Colorectal Cancer – 6.83 per lac population• Female Genital Tract – 4.94 per lac population• Liver – 13.49 per lac population (ICMR – 2004)
Cancer Cervix – 75-80% Cancer Endometrium – 15-20% Cancer Ovary – 5% Vulval Cancers – 3.5% Chorio-carcinoma - 1:20000- 14000 Pregnancy
Gynecologic cancers vary with respect to grade, histology, stage, response to treatment, and survival. It is now appreciated that this clinical heterogeneity is attributable to differences in underlying molecular pathogenesis. Some cancers arise in a setting of inherited mutations in cancer susceptibility genes, but most occur sporadically in the absence of a strong hereditary predisposition.
The spectrum of genes that are mutated varies between cancer types. There also is significant variety with respect to the spectrum of genetic changes within a given type of cancer The molecular profile may prove valuable in predicting clinical behavior and response to treatment.
Epidemiologic and clinical studies of endometrial cancer have suggested that there are two distinct types of endometrial cancer . Type I cases are associated with unopposed estrogen stimulation and often develop in a background of endometrial hyperplasia. Obesity is the most common cause of unopposed estrogen and is part of a metabolic syndrome that also includes insulin resistance and overexpression of insulin-like growth factors that may also play a role in carcinogenesis.. r
Type I cancers are well differentiated, endometrioid, early stage lesions and have a favorable outcome. In contrast, type II cancers are poorly differentiated or nonendometrioid (or both) and are more virulent. They often present at an advanced stage, and survival is relatively poor. A small minority of endometrial cancers occur in women with a strong hereditary predisposition because of germ-line mutations in DNA repair genes in the context of HNPCC syndrome
A higher rate of proliferation in response to estrogens may lead to an increased frequency of spontaneous mutations. Progestins oppose the action of estrogens by both down regulating estrogen receptor levels and decreasing proliferation and increasing apoptosis.
Approximately 3% to 5% of endometrial cancers arise because of inherited mutations in DNA repair genes in the context of hereditary nonpolyposis colon cancer (HNPCC) syndrome. HNPCC typically manifests as familial clustering of early onset colon cancer.
The identification of the DNA mismatch repair genes responsible for HNPCC has facilitated the development of genetic testing . Most HNPCC cases result from alterations in MSH2 and MLH1. MSH6 mutations also are associated with an increased incidence of endometrial cancer . PMS1 and PMS2 have been implicated in a small number of these cancers as well.
Loss of mismatch repair leads to a ―mutator phenotype‖ in which genetic mutations accumulate throughout the genome, particularly in repetitive DNA sequences called microsatellites. Examples of microsatellite sequences include mono-, di-, and trinucleotide repeats (AAAA, CACACACA, and CAGCAGCAGCAG). The propensity to accumulate mutations in microsatellite sequences is referred to as microsatellite instability (MSI).
Analysis of cancers for microsatellite instability has been proposed as a genetic screening test for HNPCC. Among families with germ-line mutations in mismatch repair genes, MSI is seen in greater than 90% of colon cancers and approximately 75% of endometrial cancers . Another screening approach for HNPCC is immunohistochemical staining of tumors to determine where there has been a loss of MSH2 or MLH1 protein . Currently, mutational analysis of the responsible genes remains the gold standard for diagnosis of HNPCC.
Endometrial cancer is the most common extracolonic malignancy is women with HNPCC. The risk of a woman developing endometrial cancer has ranged from 20% to 60%. The most striking clinical feature of HNPCC- related cancers is early onset, typically at least ten years earlier than sporadic cases. Transvaginal ultrasound has been proposed as a screening test for endometrial and ovarian cancer, but it appears to be relatively ineffective .
There is no evidence that CA125 or other blood markers facilitate early detection of endometrial cancer, but CA125 can be justified as a means of screening for HNPCC-associated ovarian cancer. Endometrial biopsy may be the only screening test with sufficient sensitivity. prophylactic hysterectomy demonstrated that there were no cases of endometrial cancer in 61 HNPCC carriers who underwent prophylactic hysterectomy, whereas endometrial cancer developed in 69 of 210 (33%) who did not undergo surgery.
Some women in HNPCC families elect to undergo prophylactic colectomy. In view of the increased risk of ovarian cancer in HNPCC syndrome, concomitant prophylactic salpingo-oophorectomy should be strongly considered. Postmenopausal estrogen-replacement therapy in the general population substantially decreases colon cancer risk.
Approximately 80% of endometrial cancers have a normal diploid DNA content as measured by ploidy analysis. Aneuploidy occurs in 20% and is associated with advanced stage, poor grade, nonendometrioid histology and poor survival (87). The frequency of aneuploidy (20%) is relatively low in endometrial cancers relative to ovarian cancers (80%). Finally, patterns of genetic expression have been described using microarrays that distinguish between normal and malignant endometrium and between various histologic types of cancer.
Inactivation of the TP53 tumor suppressor gene is among the most frequent genetic events in endometrial cancers . Overexpression of mutant p53 protein occurs in approximately 20% of endometrial adenocarcinomas and is associated with several known prognostic factors, including advanced stage, poor grade, and nonendometrioid histology . Overexpression occurs in some 10% of stages I and II and 40% of stages III and IV cancers.
Numerous studies have confirmed the strong association between p53 overexpression and poor prognostic factors and decreased survival. In some of these studies, p53 overexpression has been associated with worse survival even after controlling for stage. This suggests that loss of p53 tumor suppressor function confers a particularly virulent phenotype
Mutations in the PTEN tumor suppressor gene occur in approximately 30% to 50% of endometrial cancers , and this represents the most frequent genetic alteration described thus far in these cancers. Deletion of the second copy of the gene is also a frequent event, which results in complete loss of PTEN function. Most of these mutations are deletions, insertions, and nonsense mutations that lead to truncated protein products, whereas only about 15% are missense mutations that change a single amino acid in the critical phosphatase domain.
The PTEN gene encodes a phosphatase that opposes the activity of cellular kinases. For example, it has been shown that loss of PTEN in endometrial cancers is associated with increased activity of the PI3 kinase with resultant phosphorylation of its downstream substrate Akt. Mutations in the PTEN gene are associated with endometrioid histology, early stage and favorable clinical behavior . Well differentiated, noninvasive cases have the highest frequency of mutations.
Inaddition, PTEN mutations have been observed in 20% of endometrial hyperplasias, suggesting that this is an early event in the development of some endometrioid type I endometrial cancers. Synchronous endometrioid cancers are sometimes encountered in the endometrium and ovary that are indistinguishable microscopically. Endometrial cancer is the second most common malignancy observed in women with HNPCC.
Cancers that arise in these women with HNPCC syndrome are characterized by mutations in multiple microsatellite repeat sequences throughout the genome. This microsatellite instability also has been seen in approximately 20% of sporadic endometrial cancers . Endometrial cancers that exhibit microsatellite instability tend to be type I cancers. Loss of mismatch repair in these cases usually results from silencing of the MLH1 gene by promoter methylation .
Methylation of the MLH1 promoter also has been noted in endometrial hyperplasias and normal endometrium adjacent to cancers, suggesting that this is an early event in the development of some of these cancers . Several other tumor suppressor genes may play a role in the development of some endometrial cancers. The Par-4 gene is a proapoptotic factor, and loss of expression of this gene occurs in some human cancers. Reduced expression occurs in approximately 40% of endometrial cancers and may be attributable to methylation of the promoter region of the gene.
The Cables gene is a putative tumor suppressor involved in regulating phosphorylation of cyclin- dependent kinase 2 in a manner that restrains cell cycle progression. Cables mutant mice develop endometrial hyperplasia at an early age, and exposure to low levels of estrogen causes endometrial cancer. Cables expression is up regulated by estrogen and decreases following progestin treatment. Loss of Cables expression also occurs in human endometrial hyperplasias and cancers.
Finally, mutations in the CDC4 gene, which is involved in regulating cyclin E expression during cell cycle progression, have been noted in 16% of endometrial cancers.
Alterations in oncogenes have been demonstrated in endometrial cancers, but these occur less frequently than inactivation of tumor suppressor genes . Increased expression of the HER-2/neu receptor tyrosine kinase initially was noted in only 10% of endometrial cancers and was associated with advanced stage and poor outcome. Recently, it has been suggested that HER-2/neu overexpression may be more prevalent in patients with papillary serous endometrial cancers.
These data also suggest that therapies that target HER-2/neu may have a role in the treatment of papillary serous endometrial carcinomas. The fms oncogene encodes a tyrosine kinase that serves as a receptor for macrophage- colony stimulating factor (M-CSF). Expression of fms in endometrial cancers was found to correlate with advanced stage, poor grade, and deep myometrial invasion.
The ras oncogenes undergo point mutations in codons 12, 13, or 61 that result in constitutively activated molecules in many types of cancers. K-ras mutations also have been identified in some endometrial hyperplasias, which suggests that this may be a relatively early event in the development of some type I cancers. The PTEN tumor suppressor gene, which normally acts to restrain PI3K activity, is frequently inactivated in type I endometrial cancers. Conversely, the PIK3CA gene is oncogenically activated in some cases.
Studies confirm that PIK3CA activating mutations are common in endometrial cancers. Both inactivation of PTEN or unrestrained PIK3CA can lead to activation of AKT, which in turn leads to up regulation of the mammalian target of rapamycin (mTOR). Recent studies have suggested that mTOR inhibitors may have a role in the in the management of progesterone refractory hyperplasia and treatment of type I endometrial cancer.
Alterations in the wnt pathway involving E- cadherin, APC, and β-catenin, the product of the CTNNB1 gene, have been noted in some endometrial cancers. E-cadherin is a transmembrane glycoprotein involved in cell-cell adhesion, and decreased expression in cancer cells is associated with increased invasiveness and metastatic potential. APC mutations have not been described in endometrial cancers β-catenin gene is considered an oncogene.
β-catenin mutations have been observed in several types of cancers, including hepatocellular, prostate, and endometrial cancers. Mutation of β-catenin occurs in approximately 10% to 15% of endometrial cancers. Mutations have also been observed in the fibroblast growth factor receptor 2 (FGFR2) gene in approximately 10% of endometrial cancers.
Several studies have suggested that myc may be amplified in a fraction of endometrial cancers.
Approximately 10% of ovarian cancers arise in women who carry germ-line mutations in cancer susceptibility genes—predominantly BRCA1 or BRCA2. Reproductive events that decrease lifetime ovulatory cycles (e.g., pregnancy and birth control pills) are protective against ovarian cancer . Five years of oral contraceptive use provides a 50% risk reduction while only decreasing total years of ovulation by less than 20%. Epithelial ovarian cancers are heterogeneous with respect to behavior (borderline versus invasive) and histologic type (serous, mucinous, endometrioid, clear cell). Many endometrioid and clear cell cancers likely develop in deposits of endometriosis.
Low-grade tumors are generally confined to the ovary at diagnosis and include low-grade serous carcinoma, mucinous, endometrioid, and clear cell carcinomas. They are genetically stable and characterized by mutations in a number of genes including K-ras, BRAF, PTEN, and β-catenin. High-grade cancers typically present at an advanced stage and are predominantly serous but also include carcinosarcoma and undifferentiated cancers. This group of tumors has a high level of genetic instability and is characterized by mutation of TP53.
It had long been suspected based on epidemiologic and family studies that approximately 10% of epithelial ovarian cancers are attributable to inheritance of mutations in high-penetrance cancer susceptibility genes. The BRCA1 gene was identified on chromosome 17q in 1994, and BRCA2 was identified on chromosome 13q in 1995. Inherited mutations in these two breast and ovarian cancer susceptibility genes are responsible for approximately 6% and 3% of ovarian cancers, respectively.
BRCA mutations were found in 28% and 17% of women with fallopian tube cancer. Likewise, germ-line BRCA mutations have been reported in some studies in approximately onethird of those with primary peritoneal cancer. In some studies, survival of BRCA carriers with ovarian cancer was better than that of sporadic. BRCA1 and BRCA2 mutations are associated with 60% to 90% lifetime risks of breast cancer, and this begins to manifest before age 30. BRCA2 also increases the risk of breast cancer in men.
The lifetime risk of ovarian cancer ranges from 20% to 40% in BRCA1 carriers and 10% to 20% in BRCA2 carriers, but this increased risk is not manifest until the late 30s. The median age of sporadic epithelial ovarian cancer is in the early to mid-60s, compared to the mid-40s and early 50s for BRCA1- and BRCA2- associated cases. The most common founder mutations described thus far are the BRCA1 185delAG and BRCA2 6174delT mutations that occur in approximately 1.0% and 1.4% of Ashkenazi Jews, respectively
the most reliable method of detecting mutations is complete gene sequencing. Testing generally has been advocated when the family history suggests at least a 5% probability of finding a mutation. In practical terms, this translates into two first- or second-degree relatives with either ovarian cancer at any age or breast cancer before age 50. When a specific mutation is identified in an affected individual, others in the family can be tested much more rapidly and inexpensively for that specific mutation.
Failure to identify a BRCA1 or BRCA2 mutation in a family may be reassuring, but it must be tempered by the realization that BRCA mutational analysis may miss some mutations and that other undiscovered hereditary ovarian cancer genes may exist. Because BRCA testing is now widely accepted and insurance companies generally cover the costs, results should be acknowledged in the medical record. The value of screening for early stage ovarian cancer with CA125 or ultrasound is unproven but seems reasonable until controlled studies are available. Use of birth control pills as a chemopreventive also has been advocated .
Because ovarian cancer has a 70% mortality rate, prophylactic bilateral salpinoophorectomy (BSO) should be discussed with all women who carry germ- line BRCA1 or BRCA2 mutations. The therapeutic benefit of BSO in women with breast cancer has long been appreciated, and more recent studies support the contention that this intervention significantly reduces breast cancer risk in BRCA carriers.
Many patients elect to have the uterus removed as part of the surgical procedure because they have completed their family. Furthermore, the likelihood of future exposure to tamoxifen, which increases endometrial cancer risk two- to threefold, in the context of breast cancer prevention or treatment, also argues for concomitant hysterectomy. The more problematic issue in performing prophylactic BSO is whether the risk of malignant transformation is increased solely in the ovaries and fallopian tubes or in the entire field of mullerian-derived epithelia.
Peritoneal papillary serous carcinoma that is indistinguishable histologically or macroscopically from ovarian cancer has been described in rare instances following prophylactic salpingo-oophorectomy. Careful examination of prophylactic salpingo- oophorectomy specimens has led to the identification of occult cancers in as many as 12% of women in some series. there is some evidence to suggest that the tubal fimbria rather than the ovarian epithelium may be the preferred site of cancer development in BRCA1 and BRCA2 mutation carriers.
Among 259 women who had undergone prophylactic oophorectomy, 2.3% were found to have stage I ovarian cancer at the time of the procedure, and two women subsequently developed papillary serous peritoneal carcinoma. an international registry study of more than 1,800 subjects with median follow-up of 3.5 years found that prophylactic BSO reduced ovarian, tubal, and peritoneal cancer risk by only 80%, partly because of an estimated 6% residual lifetime risk of primary peritoneal cancer.
Invasive epithelial ovarian carcinoma generally is a monoclonal disease that develops as a clonal expansion of a single transformed cell in the ovary. advanced stage, poorly differentiated cancers have a higher number of genetic changes than early stage, low-grade cases. microarrays have demonstrated patterns of gene expression that distinguish between histologic types, borderline and invasive cases and between early and advanced stage disease .
Alteration of the TP53 tumor suppressor gene is the most frequent genetic event described thus far in ovarian cancers. approximately two-thirds of early stage serous ovarian cancers were found to have TP53 mutations compared to only 21% of nonserous cases. Overall, some 70% of advanced ovarian cancers have either missense or truncation mutations in the TP53 gene.
Ithas been suggested that loss of functional p53 might confer a chemoresistant phenotype because of its role in chemotherapy-induced apoptosis. TP53 mutational status was not concordant between the original borderline tumor and the subsequent invasive cancer. The cyclin-dependent kinase (cdk) inhibitors act as tumor suppressors.
In approximately 15% of ovarian cancers, p16 undergoes homozygous deletions . There is evidence to suggest that p16 , CDKN2B (p15) , and some other tumor suppressor genes such as BRCA1 may be inactivated via transcriptional silencing because of promoter methylation rather than mutation or deletion. Likewise, decreased expression of the p21 cdk inhibitor has been noted in a significant fraction of ovarian cancers despite the absence of inactivating mutations .
Loss of CDKN1B (p27) also may occur and correlates with poor survival in some studies. It has been suggested that abberant expression of p27 in the cytoplasm may be most associated with poor outcome . Normal ovarian epithelial cells are inhibited by the growth inhibitory peptide TGF-β. Thus far, it has not been convincingly demonstrated that derangement of the TGF- β pathway plays a role in the development of ovarian cancers.
Ovarian cancers produce and are capable of responding to various peptide growth factors. For example, epidermal growth factor and transforming growth factoralpha (TGF-α) are produced by some ovarian cancers that also express the receptor that binds these peptides (EGF receptor) . Some cancers produce insulin-like growth factor- 1 (IGF-1), IGF-1 binding protein, and express type 1 IGF receptor. Plateletderived growth factor also is expressed by many types of epithelial cells, including human ovarian cancer cell lines, but these cells usually are not responsive to PDGF .
In addition, ovarian cancers produce basic fibroblast growth factor and its receptor, and basic FGF acts as a mitogen in some ovarian cancers . Ovarian cancers produce macrophagecolony stimulating factor, and serum levels of M-CSF are elevated in some patients . Because the M-CSF receptor (fms) is expressed by many ovarian cancers. it is possible that growth factors may primarily act as ―necessary but not sufficient‖ cofactors that support growth and metastasis following malignant transformation.
The HER-2/neu tyrosine kinase is a member of a family of related transmembrane receptors that includes the EGF receptor. Expression of HER-2/neu is increased in a fraction of ovarian cancers and overexpression has been associated with poor survival in some studies , but not all. only 11% of ovarian cancers exhibit significant HER-2/neu overexpression . The response rate to single-agent trastuzumab therapy was disappointingly low (7%).
In contrast, K-ras mutations are common in borderline serous ovarian tumors, occurring in approximately 25% to 50% of cases. In addition, mutations in BRAF occur in some 20% of serous borderline cases lacking K-ras mutations . Mutations in K-ras and BRAF have also been noted in cystadenoma epithelium adjacent to serous borderline tumors, suggesting that this is an early event in their development . K-ras mutations have been noted in approximately 50% of mucinous ovarian cancers, but BRAF mutations have not been found .
Similar to endometrial cancers, activation of the PIK3CA and AKT2 oncogenes occurs in some ovarian cancers. The region of chromosome 3p26 that includes the phosphatidylinositol 3-kinase (PIK3CA) is amplified in some ovarian cancers . In addition, activating mutations in PIK3CA occur in about 10% of ovarian cancers, and are much more common in endometrioid and clear cell cancers (20%) as compared to serous cancers (2%). PTEN phosphatase, and this tumor suppressor gene also is inactivated in about 20% of endometrioid ovarian cancers.
Mutations in the β-catenin gene are a feature of some endometrial cancers. Similarly, β- catenin mutations are present in some 30% of endometrioid ovarian cancers. cyclin E overexpression has been was shown to be associated with serous and clear cell histology, advanced stage, and poor outcome.
One of the most preventable and curable malignancies More than 75% cases belong to developing countries. Incidence falling by about 7% per annum in developed countries due to operational screening programs Cancer cervix is twice common among Africo- Americans as compared to white Americans probably due to high prevalence of HPV, STD, HIV infections, drug abuses and Smoking.
Young women (<35 yrs.) have lower survival rate then older women within the same ca cx – staging. Ca cx in situ or early stage I-A is detected more frequently in develop country as compare to under developed (II, III stage) 5% cases of ca cx report in stage IV in India while majority >80% in stage II & III.
Cervical cancer is a slow developing cancer that starts in the interior lining of the cervix. Almost all cases begin with changes caused by the human papillomavirus (HPV), a sexually transmitted infection. Over time the changes caused by HPV build up and a pre- cancerous condition called cervical intraepithelial neoplasia (CIN) develops. CIN can progress to cervical cancer, but this is not always the case.
Abnormal Vaginal bleeding Menstrual bleeding is longer and heavier than usual Bleeding after menopause or increased vaginal discharge Bleeding following intercourse or pelvic exam Pain during intercourseSource: American Cancer Society
About 80% of Women will be infected with HPV in their lifetime
ABOUT 9-25 PER 100,000 WOMEN IN INDIAWILL DEVELOPE CERVICAL CANCER.
Procedure by which cancer can be detected in precancerous/ early stage to make the treatment effective. According to WHO cervical cancer is the only preventable cancer of female genital tract as the precancerous changes of cervix can be diagnosed way before the development of cancer by the screening methods.
Littleunderstanding of cervical cancer Limited understanding of female reproductive organs and associated diseases Lack of access to services Shame and fear of a vaginal exam Fear of death from cancer Lack of trust in health care system Lack of community and family support Concept of ―preventive care‖ is foreign
Visualinspection of cervix Pap smear Conventional Liquid based cytology Viraltyping for high risk HPV subtypes Combination of Pap smear and HPV Colposcopy
Cancer is leading cause of death worldwide : it accounted for 7.4 million deaths all deaths) in 2004. The most frequent types of cancer differ between men and women More than 30% of cancer deaths can be prevented HPV is the single most important risk factor in causation of ca cx. Cancer arises from a change in one single cell. The change may be started by ext and inherited genetic factors. Ca cx is detectable in Pre Cancerous stage by screening methods. Ca cx cost effectively preventable cancer
Cervical cancer is the most common gynecologic malignancy worldwide and accounts for more than 400,000 cases annually. Molecular and epidemiologic studies have demonstrated that sexually transmitted human papilloma virus (HPV) infections play a role in almost all cervical dysplasias and cancers . Although HPV plays a major role in the development of most cervical cancers, only a small minority of women who are infected develop invasive cervical cancer.
Thissuggests that other genetic or environmental factors also are involved in cervical carcinogenesis. For example, individuals who are immunosuppressed because of either HIV infection or immunosuppressive drugs are more likely to develop dysplasia and invasive cervical cancer following HPV infection.
There are more than 100 HPV subtypes, but not all infect the lower genital tract. HPV 16 and 18 are the most common types associated with cervical cancer and are found in more than 80% of cases. Types 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, and 82 should be considered high-risk types, and types 26, 53, and 66 should be considered probably carcinogenic. Low-risk types that may cause dysplasias or condyloma in the lower genital tract, but rarely cause cancers, include types 6, 11, 40, 42, 43, 44, 54, 61, 70, 72, and 81. The advent of HPV typing now allows assessment of whether patients carry high-risk or low-risk HPV types, and this has proven clinically useful in the management of patients with low-grade Pap smear abnormalities.
The HPV DNA sequence consists of 7,800 nucleotides divided into ―early‖ and ―late‖ open reading frames (ORFs). Early ORFs are within the first 4,200 nucleotides of the genome and encode proteins (E1-E8) that are important in viral replication and cellular transformation. Late ORFs (L1 and L2) are found within the latter half of the sequence and encode structural proteins of the virion. In oncogenic subtypes such as HPV 16 and 18, transformation may be accompanied by integration of episomal HPV DNA into the host genome.
Opening of the episomal viral genome usually occurs in the E1-E2 region, resulting in a linear fragment for insertion. The location of the opening may be significant because E2 acts as a repressor of the E6-E7 promoter, and disruption of E2 can lead to unregulated expression of the E6/E7 transforming genes. HPV 16 DNA may be found in its episomal form in some cervical cancers, however, and unregulated E6-E7 transcription may occur independently of viral DNA integration into the cellular genome.
The E6 and E7 oncoproteins are the main transforming genes of oncogenic strains of HPV. Transfection of these genes in vitro results in immortalization and transformation of some cell lines. The HPV E7 protein acts primarily by binding to and inactivating the Rb tumor suppressor gene product. E7 contains two domains, one of which mediates binding to Rb while the other serves as a substrate for casein kinase II (CKII) phosphorylation.
Variations in oncogenic potential between HPV subtypes may be related to differences in the binding efficacy of E7 to Rb. High-risk HPV types contain E7 oncoproteins that bind Rb with more affinity than E7 from low-risk types. The transforming activity of E7 may be increased by CKII mutation, implying a role for this binding site in the development of HPV-mediated neoplasias. The E6 proteins of oncogenic HPV subtypes bind to and inactivate the TP53 tumor suppressor gene product .
HPV-negative cervical cancers are uncommon but have been reported to exhibit overexpression of mutant p53 protein. This suggests that inactivation of the p53 tumor suppressor gene either by HPV E6 or by mutation is a requisite event in cervical carcinogenesis. In some studies, the levels of E6 and E7 in invasive cervical cancers have been found to predict outcome, whereas HPV viral load does not .
Comparative genomic hybridization techniques have been used to identify chromosomal loci that are either increased or decreased in copy number in cervical cancers. A strikingly consistent finding of various studies is the high frequency of gains on chromosome 3q in both squamous cell cancers and adenocarcinomas . Other chromosomes that exhibit frequent gains include 1q and 11q. The most common areas of chromosomal loss include chromosomes 3p and 2q
For the most part, with the exception of the fragile histidine triad (FHIT) gene on chromosome 3p, it has not been proven that these genomic gains and losses result in the recruitment of specific oncogenes and tumor suppressor genes in the process of malignant transformation. It is conceivable that these chromosomal alterations may be frequent sequelae of infection with oncogenic HPVs while playing no significant role in the pathogenesis of cervical cancers. Abnormalities seen in invasive cancers using comparative genomic hybridization also have been identified in high-grade dysplasias, however, suggesting that these are early events in cervical carcinogenesis .
Only a small fraction of HPV-infected women develop cervical cancer. This suggests that additional genetic alterations are requisite for progression to high-grade dysplasia and cancer. the cyclindependent kinase inhibitor p16 is up regulated in almost all cervical dysplasias and cancers. Mutant ras genes are capable of cooperating with HPV in transforming cells in vitro.
Alterations in ras genes have not been seen in cervical intraepithelial neoplasia, suggesting that mutation of ras is a late event in the pathogenesis of some cervical cancers. In contrast, c-myc amplification and overexpression may be an early event in the development of some cervical cancers. The fragile histidine triad gene localized within human chromosomal band 3p14.2 is frequently deleted in many different cancers, including cervical cancer.
it is thought that gene silencing resulting from promoter hypermethylation also may play a role in cervical carcinogenesis. Hypermethylation of genes associated with programmed cell death (apoptosis) or tumor suppressor genes have also been described in association with cervical cancer. Likewise, hypermethylation of HPV DNA that has been integrated into the host genome may also play a role in suppressing the transformation associated with viral oncogenes until other molecular alterations overcome this method of epigenetic silencing .
The most prominent feature of these tumors is an imbalance of parental chromosomes. In the case of partial moles, this involves an extra haploid copy of one set of paternal chromosomes, while complete moles generally are characterized by two complete haploid sets of paternal chromosomes and an absence of maternal chromosomes. Thus far, there is no convincing evidence that damage to specific tumor suppressor genes or oncogenes contributes to the development of gestational trophoblastic disease.
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