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

Mathias Schwartz; Virginie Moncoutier; Adrien Peytral; Jessica Le Gall; Voreak Suybeng; Mélanie Pagès; Julien Masliah-Planchon; Olfa Trabelsi-Grati; Samia Melaabi; Céline Callens; Ivan Bièche; Hélène Delhomelle; Antoine De Pauw; Claire Saule; Emmanuelle Mouret-Fourme; Marion Gauthier-Villars; Bruno Buecher; Chrystelle Colas; Dominique Stoppa-Lyonnet; Lisa Golmard

doi:10.1111/cge.14327

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

Clin Genet. 2023 Jul;104(1):107-113. doi: 10.1111/cge.14327. Epub 2023 Mar 27.

Authors

Mathias Schwartz^{1

2}, Virginie Moncoutier^{1

2}, Adrien Peytral^{1

2}, Jessica Le Gall^{1

2}, Voreak Suybeng^{1

2}, Mélanie Pagès^{1

2}, Julien Masliah-Planchon^{1

2}, Olfa Trabelsi-Grati^{1

2}, Samia Melaabi^{1

2}, Céline Callens^{1

2}, Ivan Bièche^{1

3}, Hélène Delhomelle^{1

2}, Antoine De Pauw^{1

2}, Claire Saule^{1

2}, Emmanuelle Mouret-Fourme^{1

2}, Marion Gauthier-Villars^{1

2}, Bruno Buecher^{1

2}, Chrystelle Colas^{1

2

4}, Dominique Stoppa-Lyonnet^{1

3

4}, Lisa Golmard^{1

2}

Affiliations

¹ Department of Genetics, Institut Curie, Paris, France.
² Paris Sciences Lettres Research University, Paris, France.
³ Paris-Cité University, Paris, France.
⁴ Cancer, Heterogeneity, Instability and Plasticity, INSERM U830, Institut Curie, Paris, France.

PMID: 36974006
DOI: 10.1111/cge.14327

Abstract

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.

Keywords: HBOC; MSH6; PARPi; RAD51C; TP53.

MeSH terms

BRCA1 Protein / genetics
BRCA2 Protein / genetics
Breast Neoplasms* / diagnosis
Breast Neoplasms* / genetics
Female
Genes, BRCA2
Genetic Predisposition to Disease
Germ-Line Mutation / genetics
Humans
Ovarian Neoplasms* / diagnosis
Ovarian Neoplasms* / genetics

Substances

BRCA1 Protein
BRCA2 Protein