Adenoma to colonic carcinoma transformation

Oct. 26, 2018

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Adenoma to colonic carcinoma transformation

  1. Adenoma to Colonic Carcinoma transformation Dr.Vikram Prabhakar (DCP,DNB)
  2. p53 • Guardian gene, located on short arm of chromosome 17 (17p13.1)
  3. WNT pathway
  4. EGFR-KRAS • Encode proteins that regulate cellular signal transduction of extracellular growth signals(e.g., epidermal growth factors) to the nucleus • Point mutations resulting in a constitutively active GTP- bound protein and a continuous growth stimulus. • The activation of RAS genes can promote cell survival and suppress apoptosis
  5. CpG Island
  6. CpG island • Region of the genome with high frequency of CpG sites than the rest of the genome. • Formal Definition - CpG island is a region with at least 200 bp, and a GC percentage that is greater than 50 % . • CpG is shorthand for “—C—phosphate—G— that is, cytosine and guanine separated by only one phosphate
  7. Genome ~ 3 billion characters. Find gene ?
  8. Importance of CpG Islands • CpG island acts as a proxy to identify a gene. • They often occur at the start of the gene.
  9. • microsatellites are short, sequences of 1 to 6 nucleotide base pairs which are repeated dozens to hundred times throughout the genome. – aka simple sequences or short tandem repeats • are a ubiquitous component of the genome of higher organisms. • The most common microsatellite in humans is a dinucleotide repeat of the nucleotides C and A, which occurs tens of thousands of times across the genome. • microsatellite loci with many repeats are rarely detected in the genome Microsatellites
  10. Microsatellites… • due to their repetitive nature they are liable for backward slippage during DNA replication, if miss-match repair genes are defective, so that the same short sequence is copied twice – a higher number of repeats causes a higher mutation rates single-stranded loop or insertion/deletion loops
  11. • CRC accounts for about 9 percent of all cancer deaths; ranks third in both incidence and cause of cancer death in both men and women. • Approximately 782,000 new cases are diagnosed worldwide each year, of which 70% originate in the colon and the rest in the rectum
  12. Etiology Genetic mutations • inherited – can be transmitted from parent to offspring – occurs at or before fertilization • Acquired – occurs spontaneously in the sperm, ovum, or zygote - future progeny may inherit such mutation – somatic mutation - during the growth and/or development • Common in CRC (65%)
  13. Types of CRC • Sporadic = 70% of cases – there is no family history, common above age of 50 • Inherited = 1 – 6% of cases – Hereditary NonPolyposis CRC (HNPCC, Lynch syndrome) – Multiple polyps CRC • familial adenomatous polyposis (FAP) • hamartomatous polyposis syndromes (e.g. Peutz-Jeghers, juvenile polyposis) • MUTYH-associated polyposis (MAP) • Familial CRC = 25% of cases – have a family history of CRC, but the pattern is not consistent and the risk is not as high as with the inherited syndromes. • single affected first-degree relative = 1.7 ↑ed risk • two affected first-degree relatives or if Dx before age 55 = Further ↑ risk
  14. The adenoma-carcinoma sequence • Most CRCs arise from adenomas (adenomatous polyps) which are formed when normal mechanisms regulating epithelial renewal are disrupted. • the accumulation of multiple germ-line or somatic mutations determines the behavior of a tumor • cancers result from the stepwise accumulation of multiple somatic mutations. Therefore, many CRCs remain asymptomatic for years before diagnosis.
  15. • Comprehensive sequencing has revealed that individual CRCs harbor an average of 76 gene mutations and the mutated genes in the 2 tumors overlap to only a small extent; a few genes such as APC are mutated at high frequency, whereas a much larger number of genes are mutated at relatively low frequency.
  16. MOLECULAR PATHOGENESIS /Molecular tumorigenesis/ CRC can arise in more than one molecular pathways 1. Chromosomal instability (CIN), 2. Mismatch repair pathway 3. Epigenetic gene silencing
  17. 1. The chromosomal instability (CIN/APC) pathway • encompasses 80% to 85% of all CRC and adenoma • Result in abnormal karyotypes, gross chromosomal abnormalities, such as aneuploidy, chromosome rearrangement, oncogene activation and loss of heterozygosity of tumor suppressor genes. • Results "gain of function" mutations which may result in – loss or mutation of tumor suppressor genes such as APC, TP53 – activation of oncogenes such as KRAS – apoptotic pathways • CRC caused by CIN usually have poor prognosis
  18. • In 90% of CRCs inactivation of the Wnt signaling pathway /APC or β-catenin gene/; usually by mutation of one copy of the APC gene (70%). • a tumor suppressor adenomatous polyposis coli gene mutation + (allelic deletion or an additional mutation → inactivation of the other allele) → development of dysplasia in aberrant crypt foci and early adenomas → accumulation of additional genetic mutations (KRAS, DCC, p53 and others) → tumor progression
  19. kRAS oncogene • RAS mutations are found in up to 50% of sporadic CRCs and 50% of colonic adenomas larger than 1 cm; they are rarely seen in smaller adenomas → acquired during later adenoma progression • The presence of a RAS mutation in CRC is significantly associated with the absence of response to agents targeting the epidermal growth factor receptor (EGFR) such as cetuximab and panitumumab.
  20. – Causes mutation of serine/threonine protein kinase which is involved with that acts as a downstream effector of the KRAS gene. – substitution of valinefor glutamate – Not detected inany LS/HNPCCtumors – occurs in approximately 12% of all CRC, mutually exclusive of KRAS mutation – a prognostic and predictive marker to predict resistance to anti-EGFR therapy BRAF gene mutation
  21. Roleand ExpressionPatternofEpidermal GrowthFactor Receptor inColonCancer • EGFRisexpressed innormal colon epitheliumand in80-100% of colorectal cancers (by IHC) • Up to 40%response rate to anti- EGFRinwild type tumors • BRAF,NRAS,and PIK3CA exon 20mutationsare significantly associated with a low response rate
  22. 2. mismatch repair pathway /The mutator phenotype / • accounts for 15% of CRC • Mismatch repair corrects errors made when DNA is copied. For example, a C could be inserted opposite an A, or the polymerase could slip or stutter and insert two to five extra unpaired bases. • If a mismatch or small loop is found, endonuclease (MSH2 protein recognizes, MSH6 or MSH3) cuts the strand bearing the mutation and exonuclease (MLH1 and PMS2) then digests this strand. • Finally it will be filled in by normal cellular enzymes.
  23. Microsatellite instability (MSI) • due to the presence of the mismatch repair system, in vivo microsatellite mutation rates range from 10-6 to 10-2 per generation. • Mutation of both alleles of mismatch repair (MMR) system → DNA strand (microsatellites) might be displaced, and realigns out of register creating small loop of unpaired DNA → unable to remove the loops → microsatellite increases or decrease in size due to either insertion or deletion of repeating units when compared to the normal cell’s = Microsatellite instability (MSI) • MSI is implicated in 50–60% of inherited condition HNPCC(Lynch syndrome) → germline mutations
  24. 3. Epigenetic gene silencing (Hypermethylation phenotype (CIMP+)) pathway • DNA methylation is involved in normal cellular control of gene expression – (CpG island) are usually found in the regions close to promoters • characterized by methylation of a number of genes rich in CpG islands → silencing of multiple genes or promoter region → loss of gene function or transcriptional inactivation (e.g. tumor-suppressor genes, APC) • methylation phenotype (CIMP) positive tumors
  25. 3. Epigenetic gene silencing… • encompasses 35%-40% of sporadic CRC • begin with serrated polyps, especially sessile serrated adenomas (SSAs) bearing an activating mutation in the BRAF gene. • Epigenetic changes are potentially reversible by drugs. • CIMP+ CRCs – microsatellite stable (MSS) cancer (60% of CIMP+ ) or – MSI-H (40% of CIMP+) • Methylation occur in hMLH1 – methylation may occur in tumor suppressor genes
  26. • If MMR system is silenced→ MSI • CRCs with high frequency of methylation of some CpG islands are referred to as CpG island
  27. Molecular Pathologic classification of colorectal cancer
  28. FAP • FAP is the most common polyposis syndrome. • the risk of CRC by the age of 40 years is almost 100%. • It is autosomal dominant and is caused by de novo germline mutations.
  29. • The presence of FAP can be diagnosed by direct sequencing of the germ-line mutations in APC gene on chromosome 5q21. • Somatic APC mutations are also present in most sporadic colorectal adenomas and cancers.
  30. HNPCC (Lynch syndrome) • The presence of HNPCC is defined as the presence of germ-line mutation found in one of the four MMR genes, namely MLH1, MSH2, MSH6 and PMS2. • HNPCC is the most common hereditary colon cancer syndrome.
  31. • It is autosomal dominant. • 2-hit hypothesis = germline mutation in 1 copy of 1 MMR gene represents the “first hit,” and somatic inactivation of the wild type allele the “second hit.” • The BRAF gene is almost never mutated in Lynch syndrome–associated CRCs; however, KRAS and p53 mutations can be present.
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