Transcript of Gene 210 Cancer Genomics May 5, 2015. Key events in investigating the cancer genome M R Stratton...
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- Gene 210 Cancer Genomics May 5, 2015
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- Key events in investigating the cancer genome M R Stratton
Science 2011;331:1553-1558
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- Flow chart of the genome analysis for a cancer patient O
Kilpivaara, and L A Aaltonen Science 2013;339:1559-1562
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- Todays Plan Genetics of common cancers (rare variants and
common variants) Colorectal cancer Prostate cancer Lung cancer
Melanoma Breast cancer BRCA1 and BRCA2 genes Robin Starr **Break**
Linking somatic genetic alterations in cancer to targeted
therapeutics Class exercise
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- Colorectal Cancer 3 rd most common form of cancer in developed
world (excluding skin cancers) Life time risk of developing
colorectal cancer is ~5%
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- Colorectal Cancer Most colorectal cancers usually begin as a
non-cancerous polyp on the inner lining of the colon or rectum ~95%
of colorectal cancers are adenocarcinomas
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- Inherited colorectal cancer syndromes 5-10% of colorectal
cancers are caused by inherited gene mutations Familial adenomatous
polyposis (FAP) Caused by mutations in the APC gene ~1% of all
colorectal cancer cases due to FAP Hereditary non-polyposis colon
cancer (HNPCC; Lynch syndrome) Caused by mutations in DNA damage
repair genes HNPCC, also known as Lynch syndrome, accounts for
about 3-5% of all colorectal cancers
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- Individuals with FAP usually develop hundreds or thousands of
polyps in their colon and rectum Cancer usually develops in 1 or
more polyps as early as age 20 By age 40, most people with this
disorder will develop cancer Surgery to remove colon is a
preventive treatment for FAP individuals Familial adenomatous
polyposis (FAP)
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- Inherited colorectal cancer syndromes 5-10% of colorectal
cancers are caused by inherited gene mutations Familial adenomatous
polyposis (FAP) Caused by mutations in the APC gene ~1% of all
colorectal cancer cases due to FAP Hereditary non-polyposis colon
cancer (HNPCC; Lynch syndrome) Caused by mutations in DNA damage
repair genes HNPCC, also known as Lynch syndrome, accounts for
about 3-5% of all colorectal cancers due to Lynch syndrome
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- Not as many polyps as FAP individuals ~80% lifetime risk of
developing colorectal cancer Mutations in MLH1, MSH2, MSH6, and
PMS2, which encode proteins involved in DNA repair Hereditary
non-polyposis colon cancer Expression of hMSH2 causes a dominant
mutator phenotype in E. coli (Fisher et al., Cell 1993)
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- 14 common variants associated with increased risk of colorectal
cancer Houlston et al., Nat Genet 2010 Lubbe et al., Hum Mol Genet
2011
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- Prostate Cancer Most common cancer in men 1 in 6 lifetime risk
Large genetic component (42%)
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- Multiple prostate cancer risk variants on 8q24 Witte Nat Genet
2007
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- 12 common variants associated with increased risk of prostate
cancer Estes et al., Nat Genet 2009 Takata et al., Nat Genet
2010
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- Lung Cancer #1 cause of cancer deaths in United States ~90% of
lung cancer caused by smoking Heritability of lung cancer
8-14%
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- A susceptibility locus for lung cancer maps to nicotinic
acetylcholine receptor subunit genes on 15q25 Thorgeirsson et al.,
Nature 2008 Amos et al., Nat Genet 2008 Hung et al., Nature
2008
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- Melanoma (Skin Cancer) Only accounts for