colorectal cancer molecular biology 15 feb final

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ADENOMA – CARCINOMA SEQUENCE IN COLORECTAL CARCINOMA (CRC) : 

ADENOMA – CARCINOMA SEQUENCE IN COLORECTAL CARCINOMA (CRC) Dr. Anurag Mehta RGCI & RC

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Genetic Instability MSI CIN Accumulation of numerical or structural chromosomal abnormalities (aneuploidy) Impaired recognition & repair of mismatched bases in the daughter strand of DNA during DNA replication

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Arise from at least two different carcinogenic Pathways THE TRADITIONAL PATHWAY(~80%) also called the suppressor or chromosomal instability pathway (CIN) THE CpG ISLAND METHYLATOR PATHWAY(CIMP) (15%) of all cases of sporadic CRC

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Hereditary CRC Microsatellite instability (MSI) Caused by germline mutation in MMR gene Chromosomal instability (CIN) Germline mutation in APC gene

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Pino MS, Chung DC. Gastroenterology 2010;138:2059 CIN Pathway

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BUB1 BUB1 BUB1 BUB1 BUB1 Mitotic Origins of Chromosomal Instability in Colorectal Cancer W. Brian Dalton, BA and Vincent W. Yang, MD, PhD Curr Colorectal Cancer Rep. 2007 April ; 3(2): 59–64. On the Road to Cancer: Aneuploidy and the Mitotic Checkpoint Geert J.P.L. Kops; Beth A.A. Weaver; Don W. Cleveland Posted: 10/10/2005; © 2005 Nature Publishing Group

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Adenomatous Polyposis Coli Associates with the Microtubule-Destabilizing Protein XMCAK Jennifer D. Banks and Rebecca Heald*,   Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720 USA Curr Biol. 2004 Nov 23;14(22):2033-8 Abstract During cell division, the proper formation of a bipolar spindle and its function to segregate chromosomes requires precise coordination of microtubule-stabilizing and destabilizing activities. Globally destabilized, dynamic microtubules radiating from duplicated centrosomes are locally regulated by chromosomes. Proteins at the kinetochore of each sister chromatid mediate a dynamic attachment, allowing chromosome movement coupled to microtubule polymerization/depolymerization and error-correction mechanisms for improperly attached chromosomes [[2]]. The tumor suppressor protein adenomatous polyposis coli (APC) stabilizes microtubules both in vitro and in vivo [[3–5]] and is implicated in mitosis [[6–9]], although its mechanisms of action are not well characterized.

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Inactivation of APC has also been related to the promotion of tumorigenesis, through loss of cell adhesion. It has been shown that a mutation in APC in mice can decrease the level of E-cadherin at the cell membrane

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Loss of p53, usually through allelic loss of 17p A late event in the traditional pathway Heralds the transition from pre-invasive to invasive disease. Adenomas - 4%-26%, Adenomas with invasive foci - 50% CRCs - 50%

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SMAD2, SMAD4 and DCC DCC, SMAD2 and SMAD4 are all located at 18q21.1 Allelic loss at this site is found in up to 60% of CRCs. SMAD2 and SMAD4 are involved in the TGF-β signalling pathway. regulate growth Apoptosis. SMAD4 germline mutation – Juvenile polyposis syndrome & increased risk of CRC

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DNA repair pathways Direct enzymatic repair Base excision repair Nucleotide excision repair Mismatch repair Double-strand break repair Non-homologous end joining Homologous recombination

Mismatch repair pathway : 

Mismatch repair pathway Defects in mismatch excision repair lead to colon and other cancers. MSH2:MSH6 complex binds the mismatch and identifies newly synthesized strand. MLH1 endonuclease and other factors such as PMS2 bind, recruiting a helicase and exonuclease, which together remove several nucleotides including the lesion. The gap is filled by Pol δ and sealed by DNA ligase. There are at least seven genes in the MMR system: hMLH1, hMLH3, hMSH2, hMSH3, hMSH6, hPMS1 and hPMS2

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4 important hMLH1, hMSH2, hMSH6, hPMS2 Loss of function mutation in any one of the four 90% in hMLH1, hMSH2 (MSI PATHWAY) Or Epigenetic silencing - almost always of hMLH1 (CIMP PATHWAY) Genetic Instability Mutations CRC

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Jass JR, Histopathology2007,50, 113-130

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Thank you

INHERITANCE OF COLORECTAL CANCER : 

INHERITANCE OF COLORECTAL CANCER Feuer EJ: DEVCAN: National CA Inst. 1999

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