Proffered papers and posters presented at the Sixth International Symposium on Hereditary Breast and Ovarian Cancer— BRCA: Challenges and Opportunities

Poster P100 Whole-Exome Sequencing Revealed a Novel PALB2 Mutation in a Male Breast Cancer Family Objectives Male breast cancer (mbc) is a rare disease, whose causation appears to be largely associated with genetic factors. Whole-exome sequencing (wes) is a powerful tool to explore the heritability of complex diseases, including breast cancer (bca). Our aim was to evaluate whether rare mutations may explain a fraction of mbc not accounted for by BRCA1/2 genes. Here, we applied wes analysis to a high-risk mbc family. Methods A BRCA1/2–negative family with 2 first-degree male and 4 female bca cases was selected for the study. Peripheral-blood dna samples from 1 male and 2 female bca cases were examined. Libraries were prepared and sequenced on the Illumina HiSeq instrument. A bioinformatic pipeline available at https://bioinformatics.cineca.it/wep/ was used. A validation series of 48 high-risk BRCA1/2–negative mbc patients from the Italian Multicenter Study on mbc was analyzed by Sanger sequencing. Results A novel PALB2 truncating mutation, c.419delA (p.K140fsX35), was identified by wes in a female bca case and her paternal uncle, diagnosed with melanoma and bca, but not in her maternal aunt, affected with bca; her father, diagnosed with bca, was an obligate mutation carrier. PALB2 mutational analysis of 48 high-risk mbcs identified another truncating mutation, c.1984A>T (p.K662X), in a man diagnosed with breast, lung, and prostate cancer, and with family history of bca. Overall, 3/50 high-risk mbcs (6%) were carriers of PALB2 pathogenic mutations. Conclusions This study highlights the importance of a particular selection of pedigrees including mbc to better define the fraction of bca attributable to genetic predisposition. Our results add to the accumulating evidence that PALB2 is strongly involved in bca risk in both sexes. Consideration should be given to clinical testing for PALB2 in BRCA1/2– negative families, including not only multiple female bca cases, but also 1 or more members diagnosed with mbc or other cancers.