Germline copy number variation and ovarian cancer survival - PubMed (original) (raw)

doi: 10.3389/fgene.2012.00142. eCollection 2012.

Prabhakar Chalise, Ya-Yu Tsai, Zhifu Sun, Robert A Vierkant, Melissa C Larson, Julie M Cunningham, Edwin S Iversen, David Fenstermacher, Jill Barnholtz-Sloan, Yan Asmann, Harvey A Risch, Joellen M Schildkraut, Catherine M Phelan, Rebecca Sutphen, Thomas A Sellers, Ellen L Goode

Affiliations

Germline copy number variation and ovarian cancer survival

Brooke L Fridley et al. Front Genet. 2012.

Abstract

Copy number variants (CNVs) have been implicated in many complex diseases. We examined whether inherited CNVs were associated with overall survival among women with invasive epithelial ovarian cancer. Germline DNA from 1,056 cases (494 deceased, average of 3.7 years follow-up) was interrogated with the Illumina 610 quad genome-wide array containing, after quality control exclusions, 581,903 single nucleotide polymorphisms (SNPs) and 17,917 CNV probes. Comprehensive analysis capitalized upon the strengths of three complementary approaches to CNV classification. First, to identify small CNVs, single markers were evaluated and, where associated with survival, consecutive markers were combined. Two chromosomal regions were associated with survival using this approach (14q31.3 rs2274736 p = 1.59 × 10(-6), p = 0.001; 22q13.31 rs2285164 p = 4.01 × 10(-5), p = 0.009), but were not significant after multiple testing correction. Second, to identify large CNVs, genome-wide segmentation was conducted to characterize chromosomal gains and losses, and association with survival was evaluated by segment. Four regions were associated with survival (1q21.3 loss p = 0.005, 5p14.1 loss p = 0.004, 9p23 loss p = 0.002, and 15q22.31 gain p = 0.002); however, again, after correcting for multiple testing, no regions were statistically significant, and none were in common with the single marker approach. Finally, to evaluate associations with general amounts of copy number changes across the genome, we estimated CNV burden based on genome-wide numbers of gains and losses; no associations with survival were observed (p > 0.40). Although CNVs that were not well-covered by the Illumina 610 quad array merit investigation, these data suggest no association between inherited CNVs and survival after ovarian cancer.

Keywords: association testing; copy number variation; genotyping array; ovarian cancer; overall survival.

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Figures

Figure 1

Figure 1

Association between ovarian cancer survival and normalized intensities at individual markers (black dots) and smoothed regional association (red line) in (A) 14q31 and (B) 22q13; Genomic Build 36. Analysis adjusted for study site, age at diagnosis, and first two population structure principal components.

Figure 2

Figure 2

Kaplan–Meier plot of the 22q13 CNV association with ovarian cancer survival. The different lines represent the survival curve for subjects with a “loss,” “gain,” or “normal” for the genomic segment.

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