Transcript Gene 210-cancer genomics_2015x

Gene 210
Cancer Genomics
May 5, 2015
Key events in investigating the cancer genome
M R Stratton Science 2011;331:1553-1558
Flow chart of the genome analysis for a cancer patient
O Kilpivaara, and L A Aaltonen Science 2013;339:1559-1562
Today’s 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
Colorectal Cancer
•3rd most common form of cancer in developed world (excluding skin cancers)
•Life time risk of developing colorectal cancer is ~5%
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
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
Familial adenomatous polyposis (FAP)
•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
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
Hereditary non-polyposis colon cancer
•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
Expression of hMSH2 causes a
dominant mutator phenotype
in E. coli
(Fisher et al., Cell 1993)
14 common variants associated with
increased risk of colorectal cancer
Houlston et al., Nat Genet 2010
Lubbe et al., Hum Mol Genet 2011
Prostate Cancer
•Most common cancer in men
•1 in 6 lifetime risk
•Large genetic component (42%)
Multiple prostate cancer risk
variants on 8q24
Witte Nat Genet 2007
12 common variants associated with
increased risk of prostate cancer
Estes et al., Nat Genet 2009
Takata et al., Nat Genet 2010
Lung Cancer
•#1 cause of cancer deaths in United States
•~90% of lung cancer caused by smoking
•Heritability of lung cancer 8-14%
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
Melanoma (Skin Cancer)
•Only accounts for <5% of skin cancers but responsible for most skin cancer
deaths
•Heritability of lung cancer 18-21%
Common variants that confer risk for
melanoma
Melanocortin-1 receptor: G-proteincoupled receptor expressed in
melanocytes. Variants in MC1R
associated with red hair and fair skin
Hayward Oncogene 2003
Breast Cancer
•2nd most common cancer in women (next to skin cancer)
•2nd leading cause of cancer deaths in women
•Heritability of lung cancer 27-40%
Science, 1990
Science, 1994
BRCA1 and BRCA2
•5-10% of breast cancer is inherited (mostly due to BRCA1/2 mutations)
•Also increases risk of ovarian cancer
23andMe reports 3 known BRCA mutations common in Ashkenzai
Jewish population
185delAG (BRCA1) – increases lifetime risk of breast cancer from 12% to
60% and ovarian cancer from 2% to 40%
5382insC (BRCA1) – increases lifetime risk of breast cancer from 12% to
60% and ovarian cancer from 2% to 40%
6174delT (BRCA2) – increases lifetime risk of breast cancer from 12% to
50% and ovarian cancer from 2% to 20%
By age 70, 50-60% of women who have a BRCA mutation will develop breast
cancer and 20-40% will develop ovarian cancer
BRCA1 and BRCA2 encode proteins that repair DNA double-strand breaks
Patenting Genes?
Discussion with Robin Starr
BREAK
Somatic mutations in cancer
Key events in investigating the cancer genome
M R Stratton Science 2011;331:1553-1558
Number of somatic mutations in various cancers
B Vogelstein et al. Science
2013;339:1546-1558
Flow chart of the genome analysis for a cancer patient
O Kilpivaara, and L A Aaltonen Science 2013;339:1559-1562
The Cancer Genome
Benefits and applications of cancer genome
sequencing?
1. Tumor heterogeneity
2. Design treatments based on tumor sequence
3. Response to therapy
Linking somatic genetic
alterations in cancer to targeted
therapeutics
Chronic myelogenous leukemia
Philadelphia chromosome formed by a
translocation t(9;22)
Generates the BCR-ABL oncogene
Constitutively active c-ABL kinase activity
Imatinib (Gleevec)
Dramatic therapeutic benefit
6-year survival rates ~90%
BRAF mutations in melanoma
Nature 2002
66% of malignant melanomas
80% have same mutation
(V600E), which increases kinase
activity
BRAF inhibitors
Key events in investigating the cancer genome
M R Stratton Science 2011;331:1553-1558
DNA copy number arrays
DNA methylation
Exome sequencing
Transcriptome
microRNA profiling
Proteomics
Class Exercise
•You work for a new genome interpretation startup company
•Your first customer sends you tumor biopsy DNA samples from 8 cancer
patients
•You perform genomic analyses on tumor biopsies and generate exome
sequence and expression analyses for several major cancer susceptibility
genes for each patient (cytogenetic analysis; DNA sequence for BRCA1,
BRCA2, EGFR, BRAF; expression analysis for estrogen receptor, HER2,
MET)
•Use personalized tumor genetic profile to suggest appropriate targeted
therapy
•Discuss rationale for each therapeutic choice (what is genetic lesion?
What defect (e.g. signaling pathway) does this cause? What does the
chosen therapy target?)