Hereditary cancer predispositions: Comparison of multigene panel sequencing on fresh‐frozen breast/ovarian tumor versus blood

• Published in: Clinical genetics Vol. 104; no. 1; pp. 107 - 113
• Main Authors: Schwartz, Mathias, Moncoutier, Virginie, Peytral, Adrien, Le Gall, Jessica, Suybeng, Voreak, Pagès, Mélanie, Masliah‐Planchon, Julien, Trabelsi‐Grati, Olfa, Melaabi, Samia, Callens, Céline, Bièche, Ivan, Delhomelle, Hélène, De Pauw, Antoine, Saule, Claire, Mouret‐Fourme, Emmanuelle, Gauthier‐Villars, Marion, Buecher, Bruno, Colas, Chrystelle, Stoppa‐Lyonnet, Dominique, Golmard, Lisa
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.07.2023
• Subjects: Blood; BRCA1 protein; BRCA1 Protein - genetics; BRCA2 protein; BRCA2 Protein - genetics; Breast; Breast Neoplasms - diagnosis; Breast Neoplasms - genetics; Copy number; Female; Gene frequency; Genes, BRCA2; Genetic Predisposition to Disease; Genomic instability; Germ-Line Mutation - genetics; HBOC; Heterozygosity; Humans; Loss of heterozygosity; MSH6; Ovarian cancer; Ovarian Neoplasms - diagnosis; Ovarian Neoplasms - genetics; PARPi; RAD51C; TP53; Tumors; MSH6; RAD51C; PARPi; TP53; HBOC
• ISSN: 0009-9163; 1399-0004; 1399-0004
• DOI: 10.1111/cge.14327

In breast or ovarian cancer (BC/OC) patients with evocative personal and/or family history, multigene panel sequencing is performed on blood to diagnose hereditary predispositions. Additionally, BRCA1/BRCA2 testing can be performed on tumor sample for therapeutic purpose. The accuracy of multigene panel tumor analysis on BC/OC to detect predisposing germline pathogenic variants (gPV) has not been precisely assessed. By comparing sequencing data from blood and fresh‐frozen tumor we show that tumor genomic instability causes pitfalls to consider when performing tumor testing to detect gPV. Even if loss of heterozygosity increases germline signal in most cases, somatic copy number variants (CNV) can mask germline CNV and collapse point gPV variant allele frequency (VAF). Moreover, VAF does not allow an accurate distinction between germline and somatic pathogenic variants.