Gene panel sequencing in familial breast/ovarian cancer patients identifies multiple novel mutations also in genes others than BRCA1/2.
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.
Institute of Human Genetics, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany.
Cornelia
C
Kraus
Institute of Human Genetics, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany.
Juliane
J
Hoyer
Institute of Human Genetics, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany.
Georgia
G
Vasileiou
Department of Gynecology and Obstetrics, University Hospital Erlangen, Comprehensive Cancer Center Erlangen-EMN, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany.
Marius
M
Wunderle
Department of Gynecology and Obstetrics, University Hospital Erlangen, Comprehensive Cancer Center Erlangen-EMN, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany.
Michael P
MP
Lux
Department of Gynecology and Obstetrics, University Hospital Erlangen, Comprehensive Cancer Center Erlangen-EMN, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany.
Peter A
http://orcid.org/0000-0003-4885-8471
PA
Fasching
Institute of Human Genetics, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany.
Mandy
M
Krumbiegel
Institute of Human Genetics, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany.
Steffen
S
Uebe
Institute of Human Genetics, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany.
Miriam
M
Reuter
Department of Gynecology and Obstetrics, University Hospital Erlangen, Comprehensive Cancer Center Erlangen-EMN, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany.
Matthias W
MW
Beckmann
Institute of Human Genetics, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany.
André
A
Reis
D017668:Age of Onset; D019313:BRCA1 Protein / Q000235:genetics; D024682:BRCA2 Protein; D001943:Breast Neoplasms / Q000235:genetics*; D000076164:Fanconi Anemia Complementation Group N Protein; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005858:Germany; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006801:Humans; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics; D010051:Ovarian Neoplasms / Q000235:genetics*; D017422:Sequence Analysis, DNA / Q000379:methods*; D025521:Tumor Suppressor Proteins / Q000235:genetics; D044465:White People / Q000235:genetics
D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D024682:BRCA2 Protein; C551750:BRCA2 protein, human; D000076164:Fanconi Anemia Complementation Group N Protein; D009687:Nuclear Proteins; C512790:PALB2 protein, human; D025521:Tumor Suppressor Proteins
breast cancer; gene panel; next generation sequencing; non-BRCA1/2; ovarian cancer