gene 210 cancer genomics

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

Somatic mutations in cancer

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

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?)

gene 210 cancer genomics

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