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5th Annual Early Age Onset Colorectal Cancer - Session VI


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5th Annual Early Age Onset Colorectal Cancer - Session VI: Palliative Care: Why Early is Best Including Guidance, Support and Resources to Patients and Caregivers During Their Treatment Journey/Continuum of Care. Epigenetics and its Future Role in the Diagnosis and Treatment of Individuals More Specifically and Accurately.

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5th Annual Early Age Onset Colorectal Cancer - Session VI

  1. 1. 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, September 6, 2018
  3. 3. April 2010
  5. 5. What’s missing from palliative care??
  6. 6. Mental Health – Family Therapy Changes in the family system • Boundaries • Roles • Communication • Depression • Anxiety Changes in the cancer patient • Depression • Anxiety • Trauma
  7. 7. 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
  8. 8. OUR FAMILY NOW 10/18
  9. 9. 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
  10. 10. 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
  11. 11. 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
  12. 12. 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
  13. 13. 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
  14. 14. 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
  15. 15. 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
  16. 16. LINE-1 METHYLATION IN CRC SUBSETS Antelo et al., PLoS One, 2012
  17. 17. SURVIVAL IN EOCRC AND LINE-1 HYPOMETHYLATION Antelo et al., PLoS One, 2012 LINE-1 hypomethylated
  18. 18. Baba et al, LINE-1 methylation at a prognostic Marker in GI cancers. (Review) Digestion, 2018
  19. 19. 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
  20. 20. 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
  21. 21. 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
  22. 22. 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
  23. 23. 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
  24. 24. 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
  25. 25. Questions?