Key events in investigating the cancer genome M R Stratton
Science 2011;331:1553-1558
Slide 3
Flow chart of the genome analysis for a cancer patient O
Kilpivaara, and L A Aaltonen Science 2013;339:1559-1562
Slide 4
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
Slide 5
Colorectal Cancer 3 rd most common form of cancer in developed
world (excluding skin cancers) Life time risk of developing
colorectal cancer is ~5%
Slide 6
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
Slide 7
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
Slide 8
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)
Slide 9
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
Slide 10
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)
Slide 11
14 common variants associated with increased risk of colorectal
cancer Houlston et al., Nat Genet 2010 Lubbe et al., Hum Mol Genet
2011
Slide 12
Prostate Cancer Most common cancer in men 1 in 6 lifetime risk
Large genetic component (42%)
Slide 13
Multiple prostate cancer risk variants on 8q24 Witte Nat Genet
2007
Slide 14
12 common variants associated with increased risk of prostate
cancer Estes et al., Nat Genet 2009 Takata et al., Nat Genet
2010
Slide 15
Lung Cancer #1 cause of cancer deaths in United States ~90% of
lung cancer caused by smoking Heritability of lung cancer
8-14%
Slide 16
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
