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5th Annual Early Age Onset Colorectal Cancer - Session V: Part II

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5th Annual Early Age Onset Colorectal Cancer - Session V: Part II

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5th Annual Early Age Onset Colorectal Cancer - Session V: Part II

  1. 1. Obesity, Sedentary Behaviors, and Early-Onset CRC Yin Cao, MPH, ScD Assistant Professor, Division of Public Health Sciences Department of Surgery Siteman Cancer Center Washington University in St. Louis May 2nd, 2019
  2. 2. Obesity and risk of CRC CUP, 2017 (WCRF-AICR) Murphy et al, Nat Rev Gastroenterol Hepatol, 2018
  3. 3. • Ongoing prospective follow-up cohort study • Enrolled in 1989, 116,430 female nurses aged from 25 to 42 • Lifestyle factors, medications, medical diagnoses were updated every 2 years; validated food frequency questionnaire (FFQ) every 4 years Follow-up rates > 90% in each 2-year cycle for the cohort Nurses’ Health Study II
  4. 4. Current BMI and risk of early-onset CRC NHS II 1989-2011 1 (ref) 1.33 1.37 1.93 0.5 1 2 4 < 23 (n=29) 23-25 (n=20) 25-30 (n=30) ≥ 30 (n=35) P for trend = 0.01 RR=1.20(1.05-1.38) per 5kg/m2 Multivariablerelativerisk Body Mass Index (kg/m2) Liu et al, JAMA Oncology, 2018
  5. 5. Current BMI and risk of CRC diagnosed after age 50 NHS II 1989-2011 1 (ref) 1.37 0.93 0.94 0.5 1 2 4 < 23 (n=34) 23-25 (n=33) 25-30 (n=43) ≥ 30 (n=45) P for trend = 0.38 Multivariablerelativerisk Body Mass Index (kg/m2) Liu et al, JAMA Oncology, 2018
  6. 6. BMI at age 18 and risk of early-onset CRC NHS II 1989-2011 1.05 1(ref) 1.32 1.63 0.5 1 2 4 < 18.5 (n=13) 18.5-21 (n=39) 21-23 (n=27) ≥ 23 (n=35) Multivariablerelativerisk Body Mass Index (kg/m2) Liu et al, JAMA Oncology, 2018
  7. 7. Weight change since 18 and risk of early-onset CRC NHS II 1989-2011 1 (ref) 0.86 1.65 2.15 0.5 1 2 4 8 <5 (n=27) 5-19 (n=42) 20-39 (n=34) ≥40 (n=11) P for trend = 0.007 Multivariablerelativerisk Weight Change Since 18 Years of Age (kg) Liu et al, JAMA Oncology, 2018
  8. 8. Hu et al, JAMA, 2003 Prolonged sedentary TV watching time increases risk of obesity and type 2 diabetes
  9. 9. Sedentary behaviors and all-cause and cancer-specific mortality Patterson et al, Eur J Epidemiol., 2018
  10. 10. Dramatic increase in TV watching since 1965 Aguiar et al, The Quarterly Journal of Economics, 2007
  11. 11. Trends in sitting watching TV/video since 2001 NHANES 2001-2016 Yang et al, JAMA, 2019
  12. 12. Sitting watching TV/video and risk of early-onset CRC NHSII 1991-2011 1 (ref) 1.11 1.67 0.5 1 2 4 0-7 (n=53) 8-14 (n=33) ≥15 (n=33) P for trend = 0.03 Multivariablerelativerisk Hours per week Nguyen et al, JNCI Cancer Spectrum, 2018
  13. 13. 1 (ref) 0.88 1.45 0.5 1 2 4 8 0-7(n=40) 8-14(n=20) ≥15(n=22) P for trend = 0.24 Multivariablerelativerisk 1 (ref) 1.90 2.47 0.5 1 2 4 8 0-7(n=12) 8-14(n=13) ≥15(n=11) P for trend = 0.03 Hours per week Multivariablerelativerisk Sitting watching TV/video and risk of early-onset CRC by anatomic site NHS II 1991-2011 Rectal CancerColon Cancer Nguyen et al, JNCI Cancer Spectrum, 2018 Hours per week
  14. 14. Potential mechanisms linking prolonged sitting and early- onset CRC • Lower energy use, higher caloric intake, and less healthy diet • Unbroken sitting in the absence of social or occupational cues • Extends exposure to fecal carcinogens, such as secondary bile acids • Impairs glucose homeostasis and decreases vitamin D levels • Linked to gut dysbiosis and enrichment for cancer associated microbes • Occurs in lieu of standing and other light activities that improve blood flow, muscle contraction, glucose regulation, and endothelial function
  15. 15. Summary • Current obesity, obesity in early adulthood and weight change since early adulthood are associated with increased risk of early-onset CRC • Prolonged time spent sitting watching TV, is associated with increased risk of early-onset CRC • Obesity and sedentary behaviors may contribute to the rising burden of early-onset CRC • Validations are needed
  16. 16. Acknowledgement Andrew T. Chan, MD Chief, Clinical and Translational Epidemiology Unit MGH Edward Giovannucci, ScD Professor epts of Nutrition and Epidemiology Harvard Chan Walter Willett, DrPH Professor Dept of Nutrition Harvard Chan Ulrike Peters, PhD Research Professor GECCO Consortium Fred Hutch Ann Zauber, PhD Member Attending Biostatistician MSKCC Charles Matthews Senior investigator NCI Curtis Huttenhower, PhD Professor Dept of Biostatistics Harvard Chan Graham A. Colditz, MD Chief, Professor Division of Public Health Sciences, Wash U Li Ding, PhD Associate Professor Division of Oncology McDonnell Genome Institute, Wash U Nicholas O. Davidson Chief Professor Division of Gastroenterology, Wash U
  17. 17. Acknowledgement • Cao Lab @ Wash U • Xiaobin Zheng • Chao Cao • Xiaoyu Zong • Cong Wang • Alex Kanemaru • Hanyu Chen • Catherine Shi • Xiao Li • Clinical & Translational Epi Unit @ MGH GI • Stuart Liu (@southwestern) • Long Nguyen • Dana Farber • Shuji Ogino • Kimmie Ng • Harvard Chan • Kana Wu • Alberta Health Services • Lin Yang • Participants of NHSII
  18. 18. Semir Beyaz Cold Spring Harbor Laboratory 05-02-19 Diet, Microbiome, Immunity and Cancer Risk
  19. 19. Are you really what you eat? Identify causal molecular and cellular mechanisms that links nutrition to health and disease states such as cancer
  20. 20. Obesity epidemic in the US Modified from Center for Disease ControlSummary of data collected since 1980s
  21. 21. The link between obesity and cancer risk NCI Obesity Fact Sheet
  22. 22. Paradigms for obesity-associated cancers Obesity Cancer A complicated problem with lots of variables and lack of causality in associations! ? ? Diet (?)
  23. 23. A High Fat Diet (HFD)-induced obesity augments spontaneous intestinal carcinoma incidence percentofspontaneoustumorincidence 9-12 months long-term lard-based HFD Beyaz et al. Nature, 2016
  24. 24. Stem cells maintain the intestinal epithelium and are the cell of origin for intestinal tumors
  25. 25. A HFD-induced obesity leads to abnormal stem cell activity and increases cancer risk in the intestine Beyaz et al. Nature, 2016 Tumor Tumor • A causal mechanism that links HFD-induced obesity to intestinal cancer • Targeting PPAR-d for the treatment of obesity associated cancers? Pascual et al., Nature 2017, Chen et al., Nature Genetics 2018
  26. 26. A step back, a step forward…
  27. 27. Tumor MHC-I MHC-II CD4 TCR CD8 TCR cytokines cytotoxic molecules cytotoxic molecules cytokines myeloid cells B cells Immune recognition mechanisms that contribute to anti-tumor immunity Kreiter et al., Nature 2015 Hirschhorn-Cymerman et al., JEM 2012 Haabeth et al., Leukemia 2016 Tarafdar et al., Blood 2017 Tran et al., Science 2014 Spitzer et al., Cell 2017 Hung et al., JEM 1998 Janssen et al., Nature 2003
  28. 28. ISCs express high levels of MHC-II, which is significantly downregulated upon HFD-induced obesity Test whether dampening MHC-II on tumor-initiating cells increase risk of cancer? Cerf-Bensussan et al., Journal of Immunology 1984 Hershberg et al., PNAS 1997 Telega et al., Gastroenterology 2000 Biton et al., Cell 2018
  29. 29. MHC-II- APC-null stem cells give rise to increased numbers of tumors compared to MHC-II+ counterparts in vivo * Immune competent hosts
  30. 30. …but not in immune deficient hosts!
  31. 31. A HFD leads to reduced microbial diversity in the intestine Ley et al. PNAS 2005, Schulz et al. Nature 2014
  32. 32. Germ-free mice exhibit reduced MHC-II expression in ISCs Bacteria MHC-II expression Cytokine signaling PRR signaling
  33. 33. Tumor-initiating stem cell MHC-II TCR immune cells T immune response Control Diet High Fat Diet T immune cells impaired immune recognition Recognition of tumor cells by the immune system is an important mechanism in controlling intestinal tumorigenicity Tumor “Healthy” Microbiome “Altered” Microbiome Diet-induced alterations in intestinal microbiome regulate immune recognition mechanisms and tumor formation in the intestine
  34. 34. Integrating modules influencing cancer risk
  35. 35. COMMON GENETIC RISK VARIANTS AND SUSCEPTIBILITY TO EARLY-ONSET COLORECTAL CANCER Richard B. Hayes, DDS, PhD Department of Population Health, Division of Epidemiology, NYU Langone School of Medicine
  36. 36. GECCO: Comprehensive CRC Risk Prediction to Inform Personalized Screening • Fred Hutchinson Cancer Research Center • Kaiser Permanente Northern California • NYU Langone Health R01CA206279, R03CA215775
  37. 37. Polygenic risk score and recommended age to start CRC screening The risk threshold to determine the age for the first screening was set as the average of 10-year CRC risks for a 50-year-old man (1.25%) and woman (0.68%) who have not previously received an endoscopy Huyghe JR et al., Nature Genetics, 2018
  38. 38. A Second Motivation to Reconsider Age to Start Screening • Early-onset CRC projected to account for 10% to 25% of newly- diagnosed CRC in the U.S. by 2030 • Presents with: – Higher pathologic grade – Distant disease – Greater incidence of recurrence and metastatic disease – Tend toward more disease of the distal colon and rectum 93 Siegel, Rebecca L. et al. “Colorectal cancer statistics, 2014.” CA: a cancer journal for clinicians 64 2 (2014): 104-17.
  39. 39. Early-onset CRC, by Birth Cohort, United States, 1930-1990 Division Name or Footer94 Murphy CC et al., Gatroenterology, 2018
  40. 40. Division Name or Footer95 Objective • Investigate CRC risks associated with a 95 SNP polygenic risk score (PRS) for participants of European ancestry by age (<50, >50) at CRC diagnosis • Determine whether younger individuals are more susceptible to these risks
  41. 41. Discovery Dataset • 50,023 CCR Cases and 58,039 Controls – Colon Cancer Family Registry (CCFR) – Colorectal Transdisciplinary (CORECT) Study – Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO) • 5,479 CRC and 6,718 Controls, <50 years of age • Limited to European ancestry • First-degree family history by self-report or interview-administered questionnaire • Case-control, cohort and family-based studies Division Name or Footer96
  42. 42. 97 Relative Risk of CRC, by age and First- degree family history of CRC (A) All participants (B) Negative for a family history of CRC (C) Positive for a family history of CRC
  43. 43. Division Name or Footer98 Family History Negative Relative Risk of CRC, by Disease Site
  44. 44. Replication Dataset • 72,573 Kaiser Permanente Members participating in the Research Program on Genes, Environment and Health (RPGEH) • Limited to European ancestry (genetically defined) • Cohort linked to the KPNC cancer registry • First-degree family history by self-report through questionnaire and medical records • Cohort Analysis by Kaplan-Meier and Cox regression Division Name or Footer99
  45. 45. Further Considerations • Combining the PRS with environmental/lifestyle risk factors • 95 SNP PRS was not specific for young-onset CRC • Assessment was for Europeans only • We did not take into account Lynch and other rarer syndromes Division Name or Footer101
  46. 46. Classic germline mutations and Early-Onset CRC Ohio, 2013-16 Germline Mutations Early-onset Cases MMR only Other CRC None Family History Positive (n=86) N 27 6 53 % 31.4 7.0 61.6 Family History Negative (n=364) N 10 29 325 % 2.7 7.8 89.3 Division Name or Footer102 Pearlman R. JAMA Oncol. 2017 Apr 1; 3(4): 464–471.
  47. 47. • This is the first study to evaluate an individual’s cumulative genetic risk profile for common at-risk alleles and early- onset CRC • PRS is more strongly associated with early-onset cancer than with late-onset cancer 103 Conclusions
  48. 48. Thank You! NYU Langone Health: Alexi Archambault Fred Hutchinson Cancer Research Center: Ulrike Peters Yu-Ru Su Minta Thomas Yi Lin Li Su Jeroen R Huyghe Kaiser Permanente Northern California: Douglas A Corley Lori C. Sakoda University of Michigan: Jihyoun Jeon 104 Research Program on Genes, Environment and Health (RPGEH), Kaiser Permanente Northern California (KPNC) The french Association STudy Evaluating RISK for sporadic colorectal cancer (ASTERISK) Alpha-Tocopherol, Beta Carotene Cancer Prevention Study (ATBC) Colon Cancer Family Registry (CCFR) Hawai’i Colorectal Cancer Studies 2 & 3 (Colo2&3) ColoCare Consortium (ColoCare) Colorectal Cancer: Longitudinal Observational study on Nutritional and lifestyle factors that influence colorectal tumor recurrence, survival and quality of life (COLON) Colorectal Cancer Study of Austria (CORSA) American Cancer Society Cancer Prevention Study II nested case-control study (CPS-II) Czech Republic Colorectal Cancer Study (Czech Republic CCS) Darmkrebs: Chancen der Verhütung durch Screening (DACHS) Diet, Activity, and Lifestyle Study (DALS3) Early Detection Research Network (EDRN) European Prospective Investigation into Cancer and Nutrition (EPIC) The EPICOLON Consortium (EPICOLON) Epidemiologische Studie zu Chancen der Verhütung, Früherkennung und optimierten Therapie chronischer Erkrankungen in der älteren Bevölkerung, Verlauf der diagnotischen Abklärung bei Krebspatienten (ESTHER-VERDI) Columbus-area HNPCC study, Ohio Colorectal Cancer Prevention Initiative, and Ohio State University Medical Center (HNPCC, OCCPI, and OSUMC) Health Professionals Follow-up Study (HPFS) Kentucky Case-Control Study (Kentucky) PopGen Biobank (Kiel) Leeds Colorectal Cancer Study (LCCS) Melbourne Collaborative Cohort Study (MCCS) Multiethnic Cohort study (MEC) Molecular Epidemiology of Colorectal Cancer Study (MECC) Memorial Sloan Kettering Cancer Center Cohort (MSKCC) North Carolina Colon Cancer Study-I (NCCCS I) North Carolina Colon Cancer Study-II (NCCCS II) Newfoundland Case-Control Study (NFCCR) Nurses’ Health Study (NHS) Nurses’ Health Study (NHS II) The Northern Sweden Health and Disease Study (NSHDS) Ontario Familial Colorectal Cancer Registry (OFCCR) Physicians’ Health Study (PHS) Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) Postmenopausal Hormones Supplementary Study to the CCFR (PMH-CCFR) Studies of Epidemiology and Risk Factors in Cancer Heredity (SEARCH) Swedish Low-Risk Colorectal Cancer Study (SLRCCS) Swedish Mammography Cohort and Cohort of Swedish Men (SMC and COSM) The Spanish study (University Hospital of Bellvitge, Hospital of Leon) (Spain) United Kingdom Biobank (UK Biobank) Los Angeles County Cancer Surveillance Program (USC-HRT-CRC) VITamins And Lifestyle (VITAL) Women’s Health Initiative (WHI) And all the participating studies…
  49. 49. Early life exposures and colorectal neoplasia Kana Wu, MD, MPH, PhD Department of Nutrition Harvard T. H. Chan School of Public Health
  50. 50. 106
  51. 51. Why study early life exposures and CRC?
  52. 52. • CRC development can take several decades • By focusing on exposures during adulthood only, etiologically relevant time periods may have been missed • The recent increase in EOCRC incidence (sporadic) support that early life factors may be involved in development of colorectal cancers • Except for body fatness data on early life risk factors and colorectal neoplasia are limited
  53. 53. Previous Studies- Early Life Exposures and Colorectal Neoplasia (NHS 2)
  54. 54. Nurses’ Health Study 2 (NHS 2) In 1998, 45,774 nurses completed a validated food frequency questionnaire to assess diet during high school (HS-FFQ)
  55. 55. Previous findings in NHS 2 (HS-FFQ) • Western dietary pattern during adolescence • Derived using principal component analysis • High intake of desserts and sweets, snack foods, red and processed meat, fries and refined grains • Higher risk of rectal adenoma (adenomatous polyps) • Q5 vs. Q1: OR 1.78, 95% CI 1.12-2.85, p-trend 0.005 • Higher risk of advanced/high risk adenoma • Q5 vs. Q1: OR 1.58, 95% CI 1.07-2.33, p-trend 0.08 Nimptsch et al., Int J Cancer 2014
  56. 56. Physical activity during adolescence and adulthood and advanced colorectal adenoma (total all age-groups) in NHS 2 (Rezende et al. in press, under embargo, do not cite)
  57. 57. Recently funded NCI grant: EOCRN • FOA (NCI): Exploratory Grants in Cancer Epidemiology and Genomics Research (R21) • Principal investigators (MPI): Kana Wu and Shuji Ogino (Brigham and Women’s Hospital) • Title: “Integrating diet, lifestyle and tumor tissue molecular subtyping to study the role of adolescent calcium intake on the risk of early onset colorectal neoplasia” (R21 CA230873)
  58. 58. Conclusions Based on a limited number of studies, there is evidence that diet during adolescence may play a role in development of colorectal neoplasia (relevant for sporadic EOCRC ?)
  59. 59. Acknowledgements • All participants and staff in the Nurses’ Health Study 1 and 2 and the Health Professionals Follow-up Study • Brigham and Women’s Hospital/Harvard Medical School, Boston, MA • Shuji Ogino (MPI on R21) • Xuehong Zhang • Dana Farber Cancer Institute, Boston, MA • Marios Giannakis • Jeffrey Meyerhardt • Kimmie Ng • Yale Cancer Center, New Haven, CT • Charles Fuchs • Harvard T. H. Chan School of Public Health • Edward Giovannucci • Walter Willett • Mingyang Song • Donghoon Lee • NaNa Keum • Leandro Rezende • Massachusetts General Hospital, Boston, MA • Andrew Chan • Yin Cao • Molecular Epidemiology Research Group, Max Delbrück Center for Molecular Medicine (MDC), Berlin, Germany • Katharina Nimptsch
  60. 60. Thank you for your attention!
  61. 61. Young Onset CRC: Causation, Treatment and Outcomes Irit Ben-Aharon MD, PhD Head, Division of Oncology Rambam Health Care Campus, Haifa, Israel Head, Young-onset Task Force, GI Group, EORTC
  62. 62. Disclosure: None
  63. 63. Statistics: Digestive tract Cancer Long-Term Trends in SEER Incidence Rates, 1975-2015 <50y http://seer.cancer.gov/statfacts/html/ Colorectal Cancer Long-Term Trends in SEER Incidence Rates, 2000-2015 <50y
  64. 64. Early-Onset CRC across Europe: The trend observed in Europe is not homogenous:  Increased incidence in Western Europe  Mixed trends in Middle Europe  Stable trend in Mediterranean countries
  65. 65.  Current main areas of AYA -  Leukemia/Lymphoma, Sarcoma, Breast  Lack of evidence for counselling for all young patients groups (relevance of ASCO or ESMO guidelines for FP)  Registry of reproductive outcomes and cardiovascular morbidity  Documenting the unmet needs  Unique environmental factors (microbiome, etc.)  Efficacy and toxicity of anti-cancer treatment The need for action - EOCRC:
  66. 66. Relevant issues for young-onset cancer patients Treatment-induced Sequel: Psychosocial unique unmet needs Potential causation
  67. 67. • Reproductive/Sexual outcomes • Cardiovascular morbidity • Secondary cancers Treatment-related toxicities
  68. 68. • The authors evaluated from the SEER-Medicare database patients with stage I-III CRC diagnosed at age > 65 years between 2000-2011 (n = 72,408) and compared these patients with a matched cohort of Medicare patients without cancer (n = 72,408). • Median age at diagnosis of CRC was 78 years (66-106y), and median follow-up was 8 years. • The 10-year cumulative incidence of new-onset CVD and CHF were 57.4% and 54.5% compared with 22% and 18% for control, respectively (P < .001). • The authors concluded that older patients with CRC are at increased risk of developing CVD and CHF. Kenzik et al., JCO 2018 Chemotherapy-induced vascular toxicity No evidence regarding young patients… Can we detect the seed of evil?
  69. 69. Chemotherapy-induced secondary cancers
  70. 70.  Registry with Biobanking / Translational Research  Quality of life issues  Causation: Diet, Ethnicity  Long-term toxicities  Future design of clinical trials Young-Onset Colorectal Cancer Task Force (GITCG)
  71. 71. • Registry (prevalence + clinical data) • Tissue sample storage CRC patients <50 Female patients <43 Male patients <45 Curable disease – • Non-metastatic • Oligometastatic Female patients >43 Male patients >45 • Fertility • Cardiovascular • QOL • Microbiome • Disease outcome • Dietary Quest. Survivorship– 10y: Registry of morbidity • Cardiovascular • QOL • Microbiome • Disease outcome • Dietary Quest. Late – 5y: Registry of morbidity Pregnancies/ART Disease outcome Study Protocol
  72. 72. Study design Inclusion criteria: CRC, age<43y (F) <45 (M) T0 Baseline T1 T2 T3 T4 CHEMO 3m 6m 12m 18m T5 24m Early evaluation (0-2y) • Clinical data • Menstrual documentation • Fertility biomarkers • Vascular biomarkers • QOL questionnaires (EORTC) • Toxicity assessment • Microbiome
  73. 73. Study design Inclusion criteria: CRC, age<43y (F) <45 (M) T0 Baseline CHEMO 24m Late evaluation (2-5y) • Clinical data • Menstrual documentation • ART documentation • Pregnancies • CV performance/morbidity 36m 48m 60m
  74. 74. Study design Inclusion criteria: CRC, age<43y (F) <45 (M) Survivorship (5-10y) • Clinical data • ART documentation • Pregnancies • CV performance/morbidity T0 Baseline CHEMO 5y 6y 7y 8y 9y 10y
  75. 75. Statistics: Digestive tract Cancer Long-Term Trends in SEER Incidence Rates, 1975-2015 <50y http://seer.cancer.gov/statfacts/html/ Hereditary background underlies ~20% of young-onset CRC Environmental Factors??
  76. 76. Potential interaction between microbiome and the immune system Geva-Zatorsky et al., Cell 2017
  77. 77. Metabolic Profiling (blood) SFB- SFB+ IL-17 IFN- 0.22 2.49 3.8 4.11 3.98 0.56 2.47 0.063 0.86 0.36 0.49 0.2 0.61 3.06e-3 0.64 0.017 SpleenSI-LP Colon-LP PLN Immunologic profiling - Cell/lineage frequencies, differentiation SFB+ B6 SFB+ NOD SFB- NOD SFB+ B6 SFB+ NOD SFB- NOD Lamina Propria Spleen SFB+ B6 SFB+ NOD SFB- NOD SFB+ B6 SFB+ NOD SFB- NOD Lamina Propria Spleen Genomic Profiling Studying the functional potential of the microbiota Plasma Biopsy Rectal Swab Analysis Geva-Zatorsky et al., Cell 2017
  78. 78. Status (4/2019)  Protocol was approved for seed funding by GITCG - EORTC  Initial funding from the GITCG will be used for establishment of collaborative infrastructure – sited were determined  The protocol is being finalized nowadays - local sites
  79. 79. Pilot prospective study sites – Participating sites
  80. 80. Progress Depends on Collaboration “To go fast, go alone. To go far, go together.” --African Proverb
  81. 81. European Study of Early-Onset Colorectal Cancer (EUREOC): A Collaborative Study of the Biology of Young Onset CRC JOSÉ PEREA GARCÍA Surgery Department. Fundación Jiménez Díaz University Hospital, Madrid. Spain. Cancer Group. Research Institute FJD.
  82. 82. COLORECTAL CANCER RESEARCH TRASLATIONAL MULTICENTER GROUP
  83. 83. MSS CHARACTERIZATION: EOCRC Comparative analysis of carcinogenetic pathways (LOCRC). Other approaches: Colon locations, etc aCGH. Identification of possible EOCRC-related genes. .
  84. 84. MSS CHARACTERIZATION: EOCRC Comparative analysis of carcinogenetic pathways (LOCRC). Other approaches: Colon locations, etc aCGH. Identification of possible EOCRC-related genes. .
  85. 85. BRAF MUTATION DUKES A y B MALE FAMILIAL AGGREGATION LS. LS HISTOLOGY MSI EOCRC DUKES B FEMALE MSI LOCRC DUKES A, B,C,D BOTH GENDERS FAMILIAL AGGREGATION AND SPORADIC CRC MSS EOCRC DUKES B,C,D SPORADIC CRC MSS LOCRC BOTH GENDERS Perea J et al. J Mol Diagn, 2014 EOCRC vs LOCRC. MSI/MSS
  86. 86. MSS CHARACTERIZATION: EOCRC Comparative analysis of carcinogenetic pathways (LOCRC). Other approaches: Colon locations, etc aCGH. Identification of possible EOCRC-related genes. .
  87. 87. Comparative study between EOCRC and LOCRC (R-R; L-L; Rc-Rc) Álvaro E. et al. Int J Mol Sci 2019
  88. 88. MSS CHARACTERIZATION: EOCRC Comparative analysis of carcinogenetic pathways (LOCRC). Other approaches: Colon locations, etc aCGH. Identification of possible EOCRC-related genes. .
  89. 89.  Common CNVs and/or potentially group-specific: p≤0,05 FDR≤0,09 Very frequent within EOCRC and very rare in LOCRC. More frequent within EOCRC than in LOCRC. More frequent within LOCRC than in LOCRC. Arriba M et al. Mol Carcinogen, 2016 Gains Losses
  90. 90. - 20 EOCRC of the initial cohort with 16p13.12-p13.11 deletion All of them with NOMO1 homozygous loss EOCRC. NOMO1 status - 14 EOCRC of the initial cohort without 16p13.12-p13.11 deletion All of them with NOMO1 homozygous loss - 60 additional EOCRC 25 NOMO1 homozygous loss 9 NOMO1 heterozygous loss 26 NOMO1 normal ______________________________________________________________ Total 59 (62.7%) NOMO1 homozygous loss 9 (9.5%) NOMO1 heterozygous loss 26 (27.6%) NOMO1 normal Perea J et al. Oncotarget 2017 > 90% MSS
  91. 91. 16p13.11 REGION EOCRC: n=94 •Homozygosis: 59 (62.7%) •Heterozygosis: 9 (9.5%) •Normals: 26 (27.6%) LOCRC: n=67 •Homozygosis: 3 (4.5%) •Heterozygosis: 9 (13.4%) •Normals: 55 (82.1%) PERYPHERAL BLOOD SAMPLES Peripheral blood DNA: n=13 (9 somatic homozygotic deletion) •Homozygosis: 0 •Heterozygosis: 0 •Normals: 13 (100%) Perea J et al. Oncotarget 2017 TUMOR SAMPLES Intermediate: Between 45 and 70 y/o. n=50 •Homozygosis: 5 (10%) •Heterozygosis: 10 (20%) •Normals: 35 (70%)
  92. 92. IN-VITRO STUDIES GENERATION OF A KNOCKOUT CELLULAR LINE FOR NOMO THROUGH GENE EDITION TECHNIQUE CRISPR / CAS9
  93. 93. IN-VIVO STUDIES GENERATION OF CONDITIONAL KNOCKOUT MICE
  94. 94.  Retrospective study of other populations: - Validation sample (EOCRC). - Colorectal polyps (<50 y/o). - CRC sample without age-of-onset criterion. - NOMO1 status in hepatic metastasis and local recurrence.  Prospective study (EOCRC): Liquid biopsy: EARLY DIAGNOSIS / RECURRENCE. Epidemiological study: enviromental / Microbiome.
  95. 95. SPANISH PROSPECTIVE STUDY
  96. 96. EUROPEAN EOCRC STUDY (EUREOC)
  97. 97. WORLDWIDE COLLABORATIONS
  98. 98.  EOCRC: CRC diagnosed younger than 50 y/o (exclud. IBD)  Clinical and familial data.  Epidemilogical questionnaire. TUMOR AND HEALTHY COLON TISSUE. STOOL. PERIPHERAL BLOOD SAMPLES (COMPLETE BLOOD AND PLASMA-SERUM).
  99. 99.  Demographic data.  BMI  Eating habits  Other habits: alcohol, smoking and medicines  Dental history and examination  Physical activity  Personal medical history  Familial medical history
  100. 100. Rectal ADCA: Also, tissue (endoscopy?) and blood sample before neoadjuvant treatment
  101. 101.  Samples collected and data so far: 59 EOCRC samples (Spain): All clinical and familial data. Tumor and normal tissue. Blood samples (germline and serum/plasma). 5 stool. 47% Rectal; 31% Right; 22% Left. 54 EOCRC samples (Italy)
  102. 102.  Whole exome sequencing. APC - / No mutated cases within NGS  Microbiome-MD2-Obesity and EOCRC. Insuline resistance.  Immunoresponse
  103. 103. SCREENING BASED STRATEGIES.  Blood-based, circulating miRNA signature for the diagnosis-prognosis of patients with EOCRC.  Defining risk populations for EOCRC: Obesity/MD2/Insuline resistance.  Liquid biopsy: Early diagnosis and recurrence.
  104. 104. ColoRectal Cancer in Adults of Young ONset “CRAYON” Study Steven Itzkowitz, MD, FACP, FACG, AGAF Professor of Medicine and Oncological Sciences Director, GI Fellowship Program Icahn School of Medicine at Mount Sinai
  105. 105. CRAYON Study: Rationale 1. Rates of CRC are increasing among 20-49 yr olds worldwide. Why?? 2. Many retrospective studies being performed in USA and abroad. 3. Most experts call for PROSPECTIVE studies to be done. 4. Some prospective studies already being performed (MSKCC, Spain/Europe) 5. Can CRAYON provide more detailed information related to risk factors/causation?
  106. 106. CRAYON Study: Purpose 1. To identify risk factors of Early Onset CRC 2. To use these factors to predict individuals <50 yrs old who are at higher risk of having (current) or developing (future) CRC
  107. 107. CRAYON Study: Why in NYC? 165 1. NYC GI community: a track record of collaboration • C5 Coalition, NYCCO, NYSGE 2. Density of population conducive to collecting CRC cases and controls in a timely fashion • ~350 EO-CRC/year (source: NY State Cancer Registry) 3. Geographic proximity: • Relatively shared environmental exposures • Facilitates collaboration, specimen acquisition • Enables patients to be captured even if they change institutions for careF facilitate collaboration, specimen acquisition, and
  108. 108. CRAYON Study: History October, 2017 NCCRT Summit – initial idea developed May, 2018 DDW - Imperiale/Itzkowitz June, 2018 Identify group of interested site PIs July 24, 2018 First Investigators Meeting Aug 2018 – Feb 2019 Monthly Conference Calls Mar 26, 2019 CRAYON Retreat (Epidemiology) Sept 17, 2019 Retreat #2
  109. 109. CRAYON Retreat (Mar 26, 2019)  What questions could be answered by CRAYON?  What is the best study design?  Discussion of cases; controls 167
  110. 110. CRAYON Investigators Institution Investigator Division/Dept Mount Sinai Steven Itzkowitz Lina Jandorf Pascale White Cristina Villagra Sarah Miller Jamilia Sly Alec Levine GI TCI GI TCI TCI TCI TCI Columbia Benjamin Lebwohl GI Weill Cornell Felice Schnoll-Sussman GI MSKCC Robin Mendelsohn GI NYU Peter Liang GI Montefiore Parvathi Myer GI Northwell Health Thomas Weber Surgery Indiana University Thomas Imperiale GI
  111. 111. CRAYON Retreat: Outside Consultants Consultant Institution Title Christine Ambrosone Roswell Park Cancer Institute Chair, Cancer Prevention & Control Margaret Du, ScD MSKCC Assistant Attending Epidemiologist Richard Hayes, PhD (unable to attend) NYU Professor of Population Health & Environmental Medicine Elizabeth Kantor, PhD MSKCC Assistant Attending Epidemiologist David Ransohoff, MD Univ North Carolina Professor of Medicine; Clinical Prof of Epidemiology Rebecca Siegel, MPH American Cancer Society Strategic Director, Surveillance Information Services Ann Zauber, PhD MSKCC Member, Attending Biostatistician
  112. 112. What questions would you like to see answered by the CRAYON study? ▶ Is the increasing CRC incidence caused by established risk factors or something novel? What preventable factors exists for EOCRC? ▶ Is there a target Risk Ratio or Odds Ratio that would be clinically relevant in decision making, and could we reach it with better risk markers? ▶ Can we capture information regarding early life events, include in utero, early life, and young adult exposure? ▶ Can we create a registry of all colonoscopies for patients under 50, including both the reason for colonoscopy and the outcome of the colonoscopy? ▶ To what extent does our population of EOCRC patients have an unknown family history of genetic conditions, such as Lynch Syndrome, that contributes to the development of EOCRC? Can we better educate that sub-population of their risk for EOCRC?
  113. 113. CRAYON: Study Design ▶ Prospective Case-Control Study ▶ Cases: individuals age 25-49 with newly diagnosed CRC. ▶ Controls: individuals age 25-49 from two groups: – Colonoscopy-Negative controls (CNC): Underwent colonoscopy for symptoms (change in BM, abd pain, minor bleeding) found to have no neoplasia. – Waiting Room Controls: healthy individuals who are escorting patients for colonoscopy and/or colon cancer surgery. – ?Friend controls – Cases:Controls 1:4 (2 CNC; 2 WRC) ▶ Eventual Sample size: 400 Cases: 1600 Controls.
  114. 114. CRAYON: Phases of Investigation Phase Purpose Institution Goal Phase 1 Feasibility Study (3/19-12/19) Mount Sinai • Enroll cases/controls • Willingness to participate Phase 2 Pilot Study (10/19-12/20) 4-5 Sites • Expand to other sites • Demonstrate collaboration • Refine instruments/bio- specimens Phase 3 Main Study (Spring 2020 submission) All Sites • Definitive study
  115. 115. CRAYON: Feasibility Study ▶ To be conducted at Mount Sinai (Funded: The Chemotherapy Foundation) ▶ Goal: Enroll 10 Cases and 40 Controls ▶ Conduct interviews to determine willingness to participate in a study that involves an extensive questionnaire, as well as biospecimen collection. ▶ Interview Questions: – Would you be willing to spend 1-2 hours for the initial interview? – Would you be willing to complete annual follow-up surveys? – We want to learn more about your early childhood experiences. Do you think your parents would be willing to participate? Would you be able to ask them? – Would you be willing to provide a blood sample? Stool sample? Saliva sample? Baby teeth (if you/your parents have them)? – [For Cases]: Would you be willing to share our flyer and potentially recruit 1-2 friends or family members?
  116. 116. Next Steps  Work on Feasibility Study  Prepare for Retreat #2 (Sept 2019)  Develop sites for Pilot phase  Explore funding sources for pilot projects 174
  117. 117. ColoRectal Cancer in Adults of Young ONset “CRAYON” Study Steven Itzkowitz, MD, FACP, FACG, AGAF Professor of Medicine and Oncological Sciences Director, GI Fellowship Program Icahn School of Medicine at Mount Sinai
  118. 118. CRAYON Study: Rationale 1. Rates of CRC are increasing among 20-49 yr olds worldwide. Why?? 2. Many retrospective studies being performed in USA and abroad. 3. Most experts call for PROSPECTIVE studies to be done. 4. Some prospective studies already being performed (MSKCC, Spain/Europe) 5. Can CRAYON provide more detailed information related to risk factors/causation?
  119. 119. CRAYON Study: Purpose 1. To identify risk factors of Early Onset CRC 2. To use these factors to predict individuals <50 yrs old who are at higher risk of having (current) or developing (future) CRC
  120. 120. CRAYON Study: Why in NYC? 179 1. NYC GI community: a track record of collaboration • C5 Coalition, NYCCO, NYSGE 2. Density of population conducive to collecting CRC cases and controls in a timely fashion • ~350 EO-CRC/year (source: NY State Cancer Registry) 3. Geographic proximity: • Relatively shared environmental exposures • Facilitates collaboration, specimen acquisition • Enables patients to be captured even if they change institutions for careF facilitate collaboration, specimen acquisition, and
  121. 121. CRAYON Study: History October, 2017 NCCRT Summit – initial idea developed May, 2018 DDW - Imperiale/Itzkowitz June, 2018 Identify group of interested site PIs July 24, 2018 First Investigators Meeting Aug 2018 – Feb 2019 Monthly Conference Calls Mar 26, 2019 CRAYON Retreat (Epidemiology) Sept 17, 2019 Retreat #2
  122. 122. CRAYON Retreat (Mar 26, 2019)  What questions could be answered by CRAYON?  What is the best study design?  Discussion of cases; controls 181
  123. 123. CRAYON Investigators Institution Investigator Division/Dept Mount Sinai Steven Itzkowitz Lina Jandorf Pascale White Cristina Villagra Sarah Miller Jamilia Sly Alec Levine GI TCI GI TCI TCI TCI TCI Columbia Benjamin Lebwohl GI Weill Cornell Felice Schnoll-Sussman GI MSKCC Robin Mendelsohn GI NYU Peter Liang GI Montefiore Parvathi Myer GI Northwell Health Thomas Weber Surgery Indiana University Thomas Imperiale GI
  124. 124. CRAYON Retreat: Outside Consultants Consultant Institution Title Christine Ambrosone Roswell Park Cancer Institute Chair, Cancer Prevention & Control Margaret Du, ScD MSKCC Assistant Attending Epidemiologist Richard Hayes, PhD (unable to attend) NYU Professor of Population Health & Environmental Medicine Elizabeth Kantor, PhD MSKCC Assistant Attending Epidemiologist David Ransohoff, MD Univ North Carolina Professor of Medicine; Clinical Prof of Epidemiology Rebecca Siegel, MPH American Cancer Society Strategic Director, Surveillance Information Services Ann Zauber, PhD MSKCC Member, Attending Biostatistician
  125. 125. What questions would you like to see answered by the CRAYON study? ▶ Is the increasing CRC incidence caused by established risk factors or something novel? What preventable factors exists for EOCRC? ▶ Is there a target Risk Ratio or Odds Ratio that would be clinically relevant in decision making, and could we reach it with better risk markers? ▶ Can we capture information regarding early life events, include in utero, early life, and young adult exposure? ▶ Can we create a registry of all colonoscopies for patients under 50, including both the reason for colonoscopy and the outcome of the colonoscopy? ▶ To what extent does our population of EOCRC patients have an unknown family history of genetic conditions, such as Lynch Syndrome, that contributes to the development of EOCRC? Can we better educate that sub-population of their risk for EOCRC?
  126. 126. CRAYON: Study Design ▶ Prospective Case-Control Study ▶ Cases: individuals age 25-49 with newly diagnosed CRC. ▶ Controls: individuals age 25-49 from two groups: – Colonoscopy-Negative controls (CNC): Underwent colonoscopy for symptoms (change in BM, abd pain, minor bleeding) found to have no neoplasia. – Waiting Room Controls: healthy individuals who are escorting patients for colonoscopy and/or colon cancer surgery. – ?Friend controls – Cases:Controls 1:4 (2 CNC; 2 WRC) ▶ Eventual Sample size: 400 Cases: 1600 Controls.
  127. 127. CRAYON: Phases of Investigation Phase Purpose Institution Goal Phase 1 Feasibility Study (3/19-12/19) Mount Sinai • Enroll cases/controls • Willingness to participate Phase 2 Pilot Study (10/19-12/20) 4-5 Sites • Expand to other sites • Demonstrate collaboration • Refine instruments/bio- specimens Phase 3 Main Study (Spring 2020 submission) All Sites • Definitive study
  128. 128. CRAYON: Feasibility Study ▶ To be conducted at Mount Sinai (Funded: The Chemotherapy Foundation) ▶ Goal: Enroll 10 Cases and 40 Controls ▶ Conduct interviews to determine willingness to participate in a study that involves an extensive questionnaire, as well as biospecimen collection. ▶ Interview Questions: – Would you be willing to spend 1-2 hours for the initial interview? – Would you be willing to complete annual follow-up surveys? – We want to learn more about your early childhood experiences. Do you think your parents would be willing to participate? Would you be able to ask them? – Would you be willing to provide a blood sample? Stool sample? Saliva sample? Baby teeth (if you/your parents have them)? – [For Cases]: Would you be willing to share our flyer and potentially recruit 1-2 friends or family members?
  129. 129. Next Steps  Work on Feasibility Study  Prepare for Retreat #2 (Sept 2019)  Develop sites for Pilot phase  Explore funding sources for pilot projects 188
  130. 130. THE LAYERS OF PALLIATIVE CARE | Treating the whole patient Oncologist treats disease Pharmacist helps manage side effects Radiologist helps treat disease, pain management Surgeon helps treat disease PT/OT surgical/treatment side effects Podiatrist Treatment side effects Dermatologist Treatment side effects Pulmonologist treatment side effects GYN Fertility, radiation damage Pain Management Mental Health depression, anxiety, PTSD Social Worker financial toxicity, psychosocial support Community Support family, parenting Support Groups apps, online, peer-to-peer Counselor relationships Chaplain spiritual support WOCN ostomy Gastroenterologist Colorectal Surgeon Based on The Layers of Palliative Care by Sarah DeBord, published at curetoday.com, September 6, 2018
  131. 131. CHACE JOHNSON • DIAGNOSED AGE 24 • NOT A FACTOR – AGE-HEALTH- FAMILY HISTORY • SEVERAL SURGERIES AND TREATMENTS • DIED AFTER 3 ½ YEARS – 1/5/15 • PASSED AGE 28
  132. 132. April 2010
  133. 133. ONE WEEK BEFORE
  134. 134. What’s missing from palliative care??
  135. 135. Mental Health – Family Therapy Changes in the family system • Boundaries • Roles • Communication • Depression • Anxiety Changes in the cancer patient • Depression • Anxiety • Trauma
  136. 136. GRIEF & LOSS CHACE • Dating • Being a husband, dad, uncle • Career Goals • Body – digestive system, weight • energy HIS FAMILY • Family Times • Family discussion on topics besides cancer, etc. • Family vacations • Son, brother, grandson, uncle
  137. 137. OUR FAMILY NOW 10/18
  138. 138. Epigenetics and its Future Role in the Diagnosis and Treatment of Individuals More Specifically and Accurately C. Richard Boland, MD Professor of Medicine UCSD School of Medicine May 3, 2019
  139. 139. What is suspected about the cause of EOCRC? • Just the left (young) end of the Gaussian curve of all CRCs? • Are there some unique causes for EOCRCs vs LOCRCs? • Less than 20% can be traced to strong genetic (heritable) factors • this is twice what it is for all cases of CRC • what about the other 80%? • Epidemiological clues: rising incidence vs LOCRC, more distal location, possibly more virulent forms of CRC involved in some instances
  140. 140. What are the presumed “causes” of EOCRC? • Known hereditary CRC syndromes: polyposis and non-polyposis • dMMR activity in 16-21%, about half are Lynch Syndrome (LS) • dMMR in EOCRC is dominated by LS (heritable) and Lynch-like syndrome (2 somatic mutations) • dMMR in LOCRC is mostly acquired hypermethylation of MLH1 (not familial) • These are both predominantly proximal CRCs with better outcomes • Some proportion of EOCRCs are microsatellite and chromosomally stable (MACS) • what is driving these tumors? • Proposed changes in environmental exposures (lots) • How does that work? • IBD (uncommon and falling in incidence) • the increase in EAOCRC is not IBD
  141. 141. What Does Epigenetics Refer To? • Heritable changes in gene expression without a change in the DNA sequence • Often, but not only, DNA methylation; chromatin changes • post-replicative addition of a methyl group to cytosine (5’-me-C) • this is stably copied in the cellular progeny by DNA methyltransferase 1 • C-G sequences (“CpG”) have been relatively edited out of the genome • ~45,000 sites CpG sites (1-2% of genome) • non-uniform over-distributed in “CpG islands” in gene promoters • When highly methylated (meC-G), the DNA changes compaction to heterochromatin • genes silenced by promoter methylation by altering access to transcription factors and enhancers • a normal regulatory mechanism for permanent silencing of gene expression • but, it can be altered as hypermethylation or hypomethylation
  142. 142. Repetitive Sequences in Human DNA • Lots of tandem repeats throughout our genome; ~45% of the genome • includes long interspersed nuclear elements (LINEs), long terminal repeats (LTRs), and short interspersed nuclear elements (SINEs) • LINE-1 is a retrotransposon, makes up 17% of the genome, but not expressed • over 106 SINEs called “Alu repeats” • mediate genomic rearrangements (evolutionary and pathological) • 25% of our genome are shorter tandem repeats: satellites, mini-satellites and microsatellites • 10,000s of long non-coding RNAs (lncRNAs) that are functional • RNA is expressed in low levels from many of these repetitive sequences • It’s a mess in there • Promoter methylation silences many of these DNA sequences Boland, Dig Dis Sci 62:1107, 2017
  143. 143. Epigenetic Changes in CRC: two varieties • CpG Island Methylator Phenotype (CIMP): hypermethylated promoters • Common in CRC; ~20% are CIMP-H, 39% CIMP-L, 42% no CIMP • CIMP is highly associated with somatic mutations in BRAF and KRAS • Methylation silences gene expression • Occurs in older patients, 90% proximal colon, more in women • CIMP CRCs may progress through hypermethylation and silencing TSGs • Or, if MLH1 undergoes biallelic methylation-silencing -> MSI • Hypomethylation (global methylation) at LINE-1 sequences) • One of the first DNA abnormalities found in CRC (Nature 1985) • Associated with more aggressive tumors, poor clinical outcomes
  144. 144. Epigenetic Changes in EAO-CRC • Cohorts of EAO-CRC (N=188) and LO-CRC (N=135), and LS (N=20) studied for methylation, compared with normal mucosa • No evidence of familial hypermethylation (CIMP) • A subset of EAO-CRC have hypomethylation of LINE-1 sequences • LINE-1 RNA expressed • Encodes an RNA polymerase • Most LINE-1’s (90%) are truncated and non-functional • If activated, can move (transpose) itself throughout the genome • Normally silenced by methylation of promoters M. Antelo et al, PLOS One 7:e45357, 2012
  145. 145. LINE-1 METHYLATION IN CRC SUBSETS Antelo et al., PLoS One, 2012
  146. 146. SURVIVAL IN EOCRC AND LINE-1 HYPOMETHYLATION Antelo et al., PLoS One, 2012 LINE-1 hypomethylated
  147. 147. Baba et al, LINE-1 methylation at a prognostic Marker in GI cancers. (Review) Digestion, 2018
  148. 148. Consequences of Demethylating LINE-1 • LINE-1 expression can lead to genomic instability • insertional mutagenesis • LINE-1 methylation is lower in liver mets than in primary CRC • Bi-cistronic promoter regulates LINE-1 expression as well as intronic proto- oncogenes: MET, RAB31P, CHRM3 • All 3 oncogenes are expressed (mRNA and protein) in the presence of LINE-1 hypomethylation • This adds additional driver mutations and possibly virulence Hur, Gut 63:635,2014
  149. 149. How is DNA Methylation Maintained? • DNA methyltransferase recognizes hemi-methylated CpG sites • methylates the daughter strand • stably silences specific genes in the cellular progeny • De novo methylation occurs (de novo transferases) • DNA methylation can be erased (TET) • It has been proposed that epigenetic effects occur very early, perhaps as a field effect in carcinogenesis • some pediatric tumors have hypomethylation but few mutations
  150. 150. Global DNA Hypomethylation in vitro • Cultured diploid CRC cell lines (i.e., RKO or HCT116 cells) • Add inhibitor of DNA methylation (5-azacytidine) in vitro • Inhibits DNA methyltransferases • Cells become hypomethylated, and aneuploid • i.e., the epigenetic effect led to widespread genetic effects • 50% increase in cloning efficiency in some models • 5-AZA is lethal in some in vitro models
  151. 151. What Can Activate “Epigenetic Modulators”? • Both environmental and genetic factors • Infections, such as H. pylori; • Aging • Smoking, other environmental toxins • Diet (surfeit and fetal famine) • Methionine and folate deficiency (humans and animal models) • Mutations in epigenetic modifier genes (H3, TET, DNMT, HCAC) • Altered expression of epigenetic mediator genes (IGF-2, OCT4, WNT) • Hypomethylation in 100’s of KB of heterochromatin is common in the transition to cancer Feinberg, NEJM 378:1323-34, 2018
  152. 152. How Can Understanding Epigenetics Be Applied to CRC and EAOCRC? • What causes abnormalities of DNA methylation in cancer? • mixed data on the role of dietary folate on hypomethylation in cancer • folate supplemented patients less likely to have LINE-1 hypomethylated tumors and inverse relationship between LINE-1 hypomethylation and ethanol consumption (Gut 59:794, 2009) • LINE-1 hypomethylation (normal colon) is not influenced by folate supplementation (CEBP 18:1041, 2009) • Can we impact EAOCRC by dietary intervention? • Does global hypomethylation explain the MACS tumors? • (Silver et al, Int J Cancer 130:1082, 2012) • There are multiple drugs that inhibit hypermethylation, but none to reverse or inhibit hypomethylation
  153. 153. Suggested Topics for Future Investigation • EAOCRC is a heterogeneous group of tumors • We need to determine how many discrete groups are in EAOCRC • separate out the hereditary group, which are better understood, and different • Lynch Syndrome and LLS tumors have different outcomes and will confound our interpretation of the data • understand what the drivers mutations are for MACS tumors • What are the unifying characteristics of the EAOCRCs with LINE-1 hypomethylation? • are they similar to the hypomethylated LOCRCs or is there more to the story? • It may be helpful to look at normal colorectum in the EAOCRC group to look for epigenetic field effects, and trace them to possible causes • diet, microbiome lead the list of culprits
  154. 154. Questions?

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