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Open Access 01-12-2019 | Ovarian Cancer | Research

Age-adjusted association of homologous recombination genes with ovarian cancer using clinical exomes as controls

Authors: Kevin J. Arvai, Maegan E. Roberts, Rebecca I. Torene, Lisa R. Susswein, Megan L. Marshall, Zhancheng Zhang, Natalie J. Carter, Lauren Yackowski, Erica S. Rinella, Rachel T. Klein, Kathleen S. Hruska, Kyle Retterer

Published in: Hereditary Cancer in Clinical Practice | Issue 1/2019

Abstract

Background

Genes in the homologous recombination pathway have shown varying results in the literature regarding ovarian cancer (OC) association. Recent case-control studies have used allele counts alone to quantify genetic associations with cancer.

Methods

A retrospective case-control study was performed on 6,182 women with OC referred for hereditary cancer multi-gene panel testing (cases) and 4,690 mothers from trios who were referred for whole-exome sequencing (controls). We present age-adjusted odds ratios (OR_Adj) to determine association of OC with pathogenic variants (PVs) in homologous recombination genes.

Results

Significant associations with OC were observed in BRCA1, BRCA2, RAD51C and RAD51D. Other homologous recombination genes, BARD1, NBN, and PALB2, were not significantly associated with OC. ATM and CHEK2 were only significantly associated with OC by crude odds ratio (OR_Crude) or by OR_Adj, respectively. However, there was no significant difference between OR_Crude and OR_Adj for these two genes. The significant association of PVs in BRIP1 by OR_Crude (2.05, CI = 1.11 to 3.94, P = 0.03) was not observed by OR_Adj (0.87, CI = 0.41 to 1.93, P = 0.73). Interestingly, the confidence intervals of the two effect sizes were significantly different (P = 0.04).

Conclusion

The lack of association of PVs in BRIP1 with OC by OR_Adj is inconsistent with some previous literature and current management recommendations, highlighted by the significantly older age of OC onset for BRIP1 PV carriers compared to non-carriers. By reporting OR_Adj, this study presents associations that reflect more informed genetic contributions to OC when compared to traditional count-based methods.

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Title: Age-adjusted association of homologous recombination genes with ovarian cancer using clinical exomes as controls
Authors: Kevin J. Arvai
Maegan E. Roberts
Rebecca I. Torene
Lisa R. Susswein
Megan L. Marshall
Zhancheng Zhang
Natalie J. Carter
Lauren Yackowski
Erica S. Rinella
Rachel T. Klein
Kathleen S. Hruska
Kyle Retterer
Publication date: 01-12-2019
Publisher: BioMed Central
Keywords: Ovarian Cancer
Ovarian Cancer
Published in: Hereditary Cancer in Clinical Practice / Issue 1/2019
Electronic ISSN: 1897-4287
DOI: https://doi.org/10.1186/s13053-019-0119-3

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