ASHG 2012 SESSION 13 – Cancer Genetics I: Rare Variants

25/10:30 Exome sequencing of more than 6,700 samples and the study of genetic susceptibility to common cancer

Not much has been uncovered for common cancer

GWAS focused on common variants, but candidate gene-studies imply low-freq and rare variants have substantial impact on cancer risk.

Need really large sample sizes to get over statistical biases

This study = ~7000 exomes (>2700 cancer) for association of low-freq/rare variants with cancer phenotype

Pipeline = QC, BWA/Picard and multi-sample variant calling using GATK (1000s of CPU days) – VCF files

–        single-site associations of low-frequency variants

–        gene-based rare-variant burden using Morris-Zeggini, Madsen-Browning, Variable-Threshold, Sequence Kernel Association Test

–        differential missingness (?? Don’t know what this means)

Analysis divided into germline, somatic and germline+somatic

Family Cancer DB (


–        vast abundance of rare coding variation – highly enriched for functional sites

–        significant inter-population differences in rare variants

–        importance of carefully selecting variants for analysis

–       >150,000 LOH events

–       20+ tools developed over the course of this work!


26/10:45 Exome sequencing of families severely affected with breast cancer suggests eight new candidate genes: ATR, BAP1, CHEK1, GEN1, KANK4, OBSL1, RAD51B and TP53BP1.

exome sequencing of genomic DNA from 2 or 3 affected sisters or cousins per family

all rare truncating mutations tested for co-segregation with breast cancer in the family as a whole

45 families revealed 8 genes – function in biological pathways related to homologous recombination repair

Lots of pathway and gene candidate slides!

high-throughput Molecular Inversion Probe (MIP) approach

– capture all exons and splice junctions of each gene

– multiplex 384 DNA samples per lane for sequencing on HiSeq

– allows efficient investigation of all candidate genes

– identify those in which multiple rare mutations of functional significance co-segregate


27/11:00 Rare variants in XRCC2 as breast cancer susceptibility alleles.

XRCC2 is involved in DNA repair through homologous recombination and was recently identified as a Fanconi anemia gene

coding regions of (international cohort of 3548 non-BRCA1/2 familial BC cases / 1435 controls)

similar # of rare variants, missense variants, etc b/w cases and controls

genetic association results suggest that XRCC2 variants do not confer risk of breast cancer

functional analyses may still reveal extremely rare variants to impact XRCC2 function


28/11:15 HOXB13 is a susceptibility gene for prostate cancer: Results from the International Consortium for Prostate Cancer Genetics.

G84E in HOXB13 was recently reported to be associated with prostate cancer risk (5x increased risk)

genotyped this mutation + 14 other SNPs in or flanking HOXB13 in 2,443 prostate cancer families

the mutation found in 283 subjects in 112 (Euro descent) families (4.6%)

more common in men with a diagnosis of prostate cancer (194/382, 51%) than those without (42/137, 30%)

family-based association test – G84E mutation significantly over-transmitted from parents to affected offspring

flanking markers => G84E mutation resides in a rare haplotype in 95% of carriers (founder effect)


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