Current gene panels account for nearly all homologous recombination repair-associated multiple-case breast cancer families

Thibaut S Matis,Patricia N Tonin,Alexandre Orthwein,Bouchra Labraki,Paz Polak,Nadia Zayed,William D Foulkes,Barbara Rivera,Yuval Tabach,Anne-Marie Mes-Masson,Manon De Ladurantaye,Nancy Hamel,Zaki El Haffaf,José Camacho Valenzuela,Adrienne Atayan,Théophane A Matis

doi:10.1038/s41523-021-00315-8

Abstract

It was hypothesized that variants in underexplored homologous recombination repair (HR) genes could explain unsolved multiple-case breast cancer (BC) families. We investigated HR deficiency (HRD)-associated mutational signatures and second hits in tumor DNA from familial BC cases. No candidates genes were associated with HRD in 38 probands previously tested negative with gene panels. We conclude it is unlikely that unknown HRD-associated genes explain a large fraction of unsolved familial BC.

Highlights

Many multiple-case breast cancer (BC) families remain unexplained by a pathogenic variant, despite routine clinical testing of an increasing number of recognized BC susceptibility genes (BCSGs)
We showed that using sequencing of paired tumor and normal tissues we can detect these HRDassociated mutational signatures as well as second hits[6,7]
We showed that inactivation of RAD51C, RAD51D, PALB2, and BARD1 are all associated with elevated signature 3 (Sig 3) levels, indicating that germline pathogenic variants (GPVs) in these genes lead to BRCA-like/homologous repair deficiency (HRD) cancers

Summary

Priortising variants via Tumor features

The pipeline was optimized for archival formalin-fixed paraffinembedded (FFPE) tumor tissues. Given that WES is not ideally suited to detect large genomic events, we considered the 7 tumors (18%) that were called positive by both tools for further analysis (Fig. 2) This percentage is within the range of detection reported by other HRD studies[7,9,10,11]. We cannot exclude the possibility that variants were missed for technical reasons given the age of some of the FFPE material, as one-quarter of our cases were diagnosed more than 10 years prior to analysis, which likely affected the quality of DNA for analysis This limitation would not be as relevant for somatic testing of freshly processed tissues in a clinical context. We must look elsewhere to find the missing inherited susceptibility present in these families

METHODS

Findings

CODE AVAILABILITY