Abstract
The increasing application of gene panels for familial cancer susceptibility disorders will probably lead to an increased proposal of susceptibility gene candidates. Using ERCC2 DNA repair gene as an example, we show that proof of a possible role in cancer susceptibility requires a detailed dissection and characterization of the underlying mutations for genes with diverse cellular functions (in this case mainly DNA repair and basic cellular transcription). In case of ERCC2, panel sequencing of 1345 index cases from 587 German, 405 Lithuanian and 353 Czech families with breast and ovarian cancer (BC/OC) predisposition revealed 25 mutations (3 frameshift, 2 splice-affecting, 20 missense), all absent or very rare in the ExAC database. While 16 mutations were unique, 9 mutations showed up repeatedly with population-specific appearance. Ten out of eleven mutations that were tested exemplarily in cell-based functional assays exert diminished excision repair efficiency and/or decreased transcriptional activation capability. In order to provide evidence for BC/OC predisposition, we performed familial segregation analyses and screened ethnically matching controls. However, unlike the recently published RECQL example, none of our recurrent ERCC2 mutations showed convincing co-segregation with BC/OC or significant overrepresentation in the BC/OC cohort. Interestingly, we detected that some deleterious founder mutations had an unexpectedly high frequency of > 1% in the corresponding populations, suggesting that either homozygous carriers are not clinically recognized or homozygosity for these mutations is embryonically lethal. In conclusion, we provide a useful resource on the mutational landscape of ERCC2 mutations in hereditary BC/OC patients and, as our key finding, we demonstrate the complexity of correct interpretation for the discovery of “bonafide” breast cancer susceptibility genes.
Highlights
Since it became evident that only 15%-20% of the familial risk for breast/ovarian cancer (BC/OC) can be explained by mutations in the major breast cancer-susceptibility genes BRCA1 and BRCA2 [1], the search for additional BC/OC susceptibility loci has been pursued
We provide a useful resource on the mutational landscape of ERCC2 mutations in hereditary BC/OC patients and, as our key finding, we demonstrate the complexity of correct interpretation for the discovery of “bonafide” breast cancer susceptibility genes
We identified 25 potential candidate mutations for cancer breast cancer susceptibility, some of them affecting ERCC2 functional activity in appropriate cell-culture based assays
Summary
Since it became evident that only 15%-20% of the familial risk for BC/OC can be explained by mutations in the major breast cancer-susceptibility genes BRCA1 and BRCA2 [1], the search for additional BC/OC susceptibility loci has been pursued. Since sequencing power is no longer an issue, the candidate approach is on its decline and about to be replaced by generation sequencing (NGS) of large gene panels which, taken together, cover a total of more than 100 genes, only 21 of which have been associated with breast cancer so far [4] This offers amazing opportunities for detection of novel susceptibility loci and bears the danger of substantial misuse [4], because variants picked up by these panels are not clinically validated. Rare variants need huge case-control datasets in order to reach the requested statistical significance of P
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