Gene panel sequencing in familial breast/ovarian cancer patients identifies multiple novel mutations also in genes others than BRCA1/2

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• 作者：Cornelia Kraus ; Juliane Hoyer ; Georgia Vasileiou ; Marius Wunderle ; Michael P. Lux ; Peter A. Fasching ; Mandy Krumbiegel ; Steffen Uebe ; Miriam Reuter ; Matthias W. Beckmann and André ; Reis
• 刊名：International Journal of Cancer
• 出版年：2017
• 出版时间：1 January 2017
• 年：2017
• 卷：140
• 期：1
• 页码：95-102
• 全文大小：305K
• ISSN：1097-0215

文摘

Breast and ovarian cancer (BC/OC) predisposition has been attributed to a number of high- and moderate to low-penetrance susceptibility genes. With the advent of next generation sequencing (NGS) simultaneous testing of these genes has become feasible. In this monocentric study, we report results of panel-based screening of 14 BC/OC susceptibility genes (BRCA1, BRCA2, RAD51C, RAD51D, CHEK2, PALB2, ATM, NBN, CDH1, TP53, MLH1, MSH2, MSH6 and PMS2) in a group of 581 consecutive individuals from a German population with BC and/or OC fulfilling diagnostic criteria for BRCA1 and BRCA2 testing including 179 with a triple-negative tumor. Altogether we identified 106 deleterious mutations in 105 (18%) patients in 10 different genes, including seven different exon deletions. Of these 106 mutations, 16 (15%) were novel and only six were found in BRCA1/2. To further characterize mutations located in or nearby splicing consensus sites we performed RT-PCR analysis which allowed confirmation of pathogenicity in 7 of 9 mutations analyzed. In PALB2, we identified a deleterious variant in six cases. All but one were associated with early onset BC and a positive family history indicating that penetrance for PALB2 mutations is comparable to BRCA2. Overall, extended testing beyond BRCA1/2 identified a deleterious mutation in further 6% of patients. As a downside, 89 variants of uncertain significance were identified highlighting the need for comprehensive variant databases. In conclusion, panel testing yields more accurate information on genetic cancer risk than assessing BRCA1/2 alone and wide-spread testing will help improve penetrance assessment of variants in these risk genes.