Association between DNA damage response and repair genes and risk of invasive serous ovarian cancer.

Abstract

BACKGROUND: We analyzed the association between 53 genes related to DNA repair and p53-mediated damage response and serous ovarian cancer risk using case-control data from the North Carolina Ovarian Cancer Study (NCOCS), a population-based, case-control study. METHODS/PRINCIPAL FINDINGS: The analysis was restricted to 364 invasive serous ovarian cancer cases and 761 controls of white, non-Hispanic race. Statistical analysis was two staged: a screen using marginal Bayes factors (BFs) for 484 SNPs and a modeling stage in which we calculated multivariate adjusted posterior probabilities of association for 77 SNPs that passed the screen. These probabilities were conditional on subject age at diagnosis/interview, batch, a DNA quality metric and genotypes of other SNPs and allowed for uncertainty in the genetic parameterizations of the SNPs and number of associated SNPs. Six SNPs had Bayes factors greater than 10 in favor of an association with invasive serous ovarian cancer. These included rs5762746 (median OR(odds ratio)(per allele) = 0.66; 95% credible interval (CI) = 0.44-1.00) and rs6005835 (median OR(per allele) = 0.69; 95% CI = 0.53-0.91) in CHEK2, rs2078486 (median OR(per allele) = 1.65; 95% CI = 1.21-2.25) and rs12951053 (median OR(per allele) = 1.65; 95% CI = 1.20-2.26) in TP53, rs411697 (median OR (rare homozygote) = 0.53; 95% CI = 0.35 - 0.79) in BACH1 and rs10131 (median OR( rare homozygote) = not estimable) in LIG4. The six most highly associated SNPs are either predicted to be functionally significant or are in LD with such a variant. The variants in TP53 were confirmed to be associated in a large follow-up study. CONCLUSIONS/SIGNIFICANCE: Based on our findings, further follow-up of the DNA repair and response pathways in a larger dataset is warranted to confirm these results.

Department

Description

Provenance

Citation

Published Version (Please cite this version)

10.1371/journal.pone.0010061

Publication Info

Schildkraut, Joellen M, Edwin S Iversen, Melanie A Wilson, Merlise A Clyde, Patricia G Moorman, Rachel T Palmieri, Regina Whitaker, Rex C Bentley, et al. (2010). Association between DNA damage response and repair genes and risk of invasive serous ovarian cancer. PLoS One, 5(4). p. e10061. 10.1371/journal.pone.0010061 Retrieved from https://hdl.handle.net/10161/8883.

This is constructed from limited available data and may be imprecise. To cite this article, please review & use the official citation provided by the journal.

Scholars@Duke

Schildkraut

Joellen Martha Schildkraut

Professor Emeritus in Family Medicine and Community Health

Dr. Schildkraut is an epidemiologist whose research includes the molecular epidemiology of ovarian, breast and brain cancers. Dr. Schildkraut's research interests include the study of the interaction between genetic and environmental factors. She is currently involved in a large study of genome wide association and ovarian cancer risk and survival. Some of her work is also focused on particular genetic pathways including the DNA repair and apoptosis pathways. She currently leads a study of African American women diagnosed with ovarian cancer. She is also collaborating in a large a case-control study of meningioma risk factors and with which a genome wide association analysis is about to commence.

Iversen

Edwin Severin Iversen

Research Professor of Statistical Science

Bayesian statistical modeling with application to problems in genetic
epidemiology and cancer research; models for epidemiological risk
assessment, including hierarchical methods for combining related
epidemiological studies; ascertainment corrections for high risk
family data; analysis of high-throughput genomic data sets.

Clyde

Merlise Clyde

Professor of Statistical Science

Model uncertainty and choice in prediction and variable selection problems for linear, generalized linear models and multivariate models. Bayesian Model Averaging. Prior distributions for model selection and model averaging. Wavelets and adaptive kernel non-parametric function estimation. Spatial statistics. Experimental design for nonlinear models. Applications in proteomics, bioinformatics, astro-statistics, air pollution and health effects, and environmental sciences.

Moorman

Patricia Gripka Moorman

Professor Emeritus in Family Medicine and Community Health

Dr. Moorman's research focuses on the epidemiology of women's health issues. Her work includes research on ovarian cancer, breast cancer and hysterectomy. Areas of particular interest include disparities in cancer risk factors and outcomes and the effects of hysterectomy on ovarian function.  As part of the Duke Evidence Synthesis group, she has also been involved in systematic reviews and meta-analyses related to ovarian cancer, breast cancer and infertility.

Bentley

Rex Colle Bentley

Professor of Pathology

Outcome-based research on pathology of endometrial carcinoma, including prognostic significance of histologic features of endometrial carcinoma, variants of endometrial carcinoma, definitions of atypia and well-differentiated carcinoma, and collaborative studies of oncogenes and tumor suppressor genes in endometrial carcinoma.

Endometrial pathology, especially as it relates to molecular/genetic alterations in neoplasms.

Ovarian pathology, especially as it relates to molecular and genetic alterations in neoplasms.

Improving accuracy of radiographic screening for breast cancer, by careful patho-radiographic correlation and study of improved imaging techniques (especially ultrasound).

Use of electron microscopy as a diagnostic and research technique.

Objective measures of pathology resident performance.

Marks

Jeffrey R. Marks

Joseph W. and Dorothy W. Beard Distinguished Professor of Experimental Surgery

I have been engaged in basic and applied cancer research for over 28 years beginning with my post-doctoral fellowship under Arnold Levine at Princeton. Since being appointed to the faculty in the Department of Surgery at Duke, my primary interest has been towards understanding breast and ovarian cancer. I am a charter member of the NCI-Early Detection Research Network (EDRN) and have been an integral scientist in the breast and gynecologic collaborative group for 15 years including leading this group for a 5 year period. I am also a major contributor to the Cancer Genome Atlas and have worked in this context for the past 4 years. My research interests are in the molecular etiology of these diseases and understanding how key genetic events contribute to their onset and progression. My work has been very multi-disciplinary incorporating quantitative, population, genetic, and behavioral approaches.  I consider my specialty to be in the area of using human breast and ovarian cancer as the primary and only authentic model system to understand these diseases.  

Berchuck

Andrew Berchuck

James M. Ingram Distinguished Professor of Gynecologic Oncology

Dr. Andrew Berchuck is Director of the Duke Division of Gynecologic Oncology and holds the James M. Ingram Distinguished Professorship. He is a practicing oncologist who is actively involved in the surgical and chemotherapy management of women with ovarian, endometrial and lower genital tract cancers. This includes minimally invasive laparoscopic surgical approaches. He also has developed a research program that focuses on the molecular-genetic alterations involved in malignant transformation of the ovarian and endometrial epithelium. He has published over 300 peer-reviewed papers in these areas. The objectives of his research include 1) identification of ovarian cancer susceptibility polymorphisms through a population-based case-control molecular epidemiologic study, and 2) use of genomic approaches  to elucidate the molecular heterogenetity of ovarian cancer. Thirty fellows and residents have worked in his lab, several of whom are now funded investigators. His research efforts have been recognized nationally and he has received awards for best oral presentation at the annual meetings of both the Society of Gynecologic Oncology and the International Gynecologic Cancer Society. Dr. Berchuck was awarded the Barbara Thomason Ovarian Cancer Research Professorship by the American Cancer Society in 2006. He has served as editor of several books in the field including Principles and Practice of Gynecologic Oncology. Dr. Berchuck also has a major commitment to national activities, and was President of the Society of Gynecologic Oncology in 2008. He served as chair of the scientific advisory committee of the Ovarian Cancer Research Fund (http://www.ocrf.org) in New York City. Finally, he is also head of the steering committee of the international Ovarian Cancer Association Consortium (OCAC), a group of 50 case-control studies that are working together to identify ovarian cancer susceptibility polymorphisms (www.srl.cam.ac.uk/consortia/ocac/index.html).


Unless otherwise indicated, scholarly articles published by Duke faculty members are made available here with a CC-BY-NC (Creative Commons Attribution Non-Commercial) license, as enabled by the Duke Open Access Policy. If you wish to use the materials in ways not already permitted under CC-BY-NC, please consult the copyright owner. Other materials are made available here through the author’s grant of a non-exclusive license to make their work openly accessible.