gene 210 cancer genomics
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Gene 210 Cancer Genomics. April 29, 2014. 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. - PowerPoint PPT PresentationTRANSCRIPT
Gene 210Cancer Genomics
April 29, 2014
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 genesHNPCC, also known as Lynch syndrome, accounts for about 3-5% of all colorectal cancers
•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)
•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 (Fishel et al., Cell 1993)
14 common variants associated with increased risk of colorectal cancer
Houlston et al., Nat Genet 2010Lubbe 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 2009Takata 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 2008Amos et al., Nat Genet 2008Hung et al., Nature 2008
Melanoma (Skin Cancer)
•Only accounts for <5% of skin cancers but responsible for most skin cancer deaths•Heritability of melanoma 18-21%
Common variants that confer risk for melanoma
Hayward Oncogene 2003
Melanocortin-1 receptor: G-protein-coupled receptor expressed in melanocytes. Variants in MC1R associated with red hair and fair skin
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?
June, 2013
“A naturally occurring DNA segment is a product of nature and not patent eligible merely because it has been isolated.”
Discussion with Robin Starr
BREAK
Somatic mutations in cancer
Key events in investigating the cancer genome
M R Stratton Science 2011;331:1553-1558
B Vogelstein et al. Science 2013;339:1546-1558
Number of somatic mutations in various cancers
Flow chart of the genome analysis for a cancer patient
O Kilpivaara, and L A Aaltonen Science 2013;339:1559-1562
The Cancer GenomeBenefits and applications of cancer genome sequencing?
1. Tumor heterogeneity2. Design treatments based on tumor sequence3. Response to therapy
Linking somatic genetic alterations in cancer to targeted
therapeutics
Chronic myelogenous leukemiaPhiladelphia chromosome formed by a translocation t(9;22)Generates the BCR-ABL oncogeneConstitutively active c-ABL kinase activity
Imatinib (Gleevec)Dramatic therapeutic benefit6-year survival rates ~90%
BRAF mutations in melanoma
Nature 2002 66% of malignant melanomas80% have same mutation (V600E), which increases kinase activity
BRAF inhibitors
Relapse after 23 weeks of therapy because of therapeutic resistance to PLX4032
MEK1C121S mutation to increases kinase activity and confer robust resistance to both RAF and MEK inhibition
23 weeks of therapy
MEK1C121S mutation to increases kinase activity and confer robust resistance to both RAF and MEK inhibition
Key events in investigating the cancer genome
M R Stratton Science 2011;331:1553-1558
DNA copy number arraysDNA methylationExome sequencingTranscriptomemicroRNA profilingProteomics
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?)