FAN1 variants identified in multiple-case early-onset breast cancer families via exome sequencing: no evidence for association with risk for breast cancer
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We are interested in the characterisation of previously undescribed contributions to the heritable component of human cancers. To this end, we applied whole-exome capture, followed by massively parallel sequence analysis to the germline DNA of two greater than third-degree affected relatives from four multiple-case, early-onset breast cancer families. Prior testing for variants in known breast cancer susceptibility, genes in these families did not identify causal mutations. We detected and confirmed two different variants in the DNA damage repair gene FAN1 (R377W, chr15:31197995 C>T and R507H, chr15:31202961 G>A [hg19]) which were not present in dbSNP131. In one family, FAN1 R377W, predicted to be damaging by SIFT and PolyPhen2, was present in all six tested members with cancer (five with breast cancer, one with malignant melanoma). In another family, FAN1 R507H, predicted to be damaging by SIFT but benign by PolyPhen2, was observed in one of two tested members with breast cancer. We genotyped FAN1 R377W and R507H variants across 1417 population-based cases and 1490 unaffected population-based controls (frequency-matched for age). These variants were rare in the Australian population (minor allele frequencies of 0.0064 and 0.010, respectively) and were not associated with breast cancer risk (OR = 0.80, 95% CI[0.39–1.61], P = 0.50 and OR = 0.74, 95% CI[0.41–1.29], P = 0.26, respectively). Analysis of breast cancer risks for relatives of case and control carriers did not find evidence of an increased risk. Despite the biological role of FAN1, the plausibility of its role as a breast cancer predisposition gene, and the possible deleterious nature of the identified variants, these two variants do not appear to be causal for breast cancer. Future studies to extend the genetic analysis of FAN1 will further explore its possible role as a breast cancer susceptibility gene.
KeywordsWhole-exome sequencing Massively parallel sequencing Breast cancer FAN1
The Australian Breast Cancer Family Registry was supported by the National Health and Medical Research Council of Australia, the New South Wales Cancer Council, the Victorian Health Promotion Foundation (Australia), and the National Cancer Institute, National Institutes of Health under RFA-CA-06-503 and through cooperative agreements with members of the BCFR and Principal Investigators. The University of Melbourne (U01 CA69638) contributed data to this study. The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the BCFR, nor does mention of trade names, commercial products or organisations imply endorsement by the US government or the BCFR. We extend our thanks to the many women and their families that generously participated in the ABCFS and consented to us accessing their pathology material. We wish to thank Margaret McCredie for key role in the establishment and leadership of the ABCFS in Sydney, Australia. MCS is a National Health and Medical Research Council Senior Research Fellow and Victorian Breast Cancer Research Consortium (VBCRC) group leader. JLH is an Australia Fellow of the National Health and Medical Research Council and a VBCRC Group Leader. This research was supported by a Victorian Life Sciences Computation Initiative (VLSCI) grant number VR0053 on its peak computing facility at the University of Melbourne, an initiative of the Victorian Government.
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