FAN1 variants identified in multiple-case early-onset breast cancer families via exome sequencing: no evidence for association with risk for breast cancer

Abstract

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.

Next-Generation Sequencing in Oncology: Genetic Diagnosis, Risk Prediction and Cancer Classification

“…Several studies identified novel HBOC susceptibility genes like XRCC2 , FANCC and BLM [88,89,90,91,92,93]. Although it is feasible to apply WES and WGS in the near future as a generic test for every genetic diagnostic question, due to the costs (still high), the need of complex bioinformatics pipelines, of large storage capacity and the expected high number of VUS detected, today the clinical utility of mutation discovery throughout the complete exome or genome analysis is not convenient yet [91,94] and should be directed to specific patient groups [95].…”

Effect of Next-Generation Exome Sequencing Depth for Discovery of Diagnostic Variants

“…Furthermore, Huh et al [ 5 ] used exome sequencing to show that the c.234 G > A and c.1150C > T mutations in exon 18 of the HGSNAT gene were common in mucopolysaccharide patients. Exome sequencing techniques have also been used to understand the risks of various cancers, including those of the breast [ 6 7 ], prostate [ 8 ], pancreas [ 9 ], and others [ 10 11 12 ]. Therefore, exome sequencing techniques have become a new primary paradigm for research on genetic diseases and cancers.…”

Identification of novel hereditary cancer genes by whole exome sequencing

“…However, most of the breast cancer exome studies reported so far failed to discover genes, whose significance is similar to BRCA1, BRCA2, CHEK2, PALB2, etc. [19][20][21][22]25,28,[132][133][134][135][136]. For example, Snape et al [133] subjected to WES 50 patients with familial breast cancer; they composed the list of promising candidates, but did not communicate yet the results of subsequent case-control study or segregation analysis.…”