Background: Identification of germline mutations in hereditary breast cancer (HBC) genes can impact breast cancer (BC) therapy and risk management of family members. In addition, tumour sequencing can reveal clinically relevant somatic features, such as homologous recombination deficiency (HRD) and mutational signatures, which are not discernible by germline sequencing that can further inform treatment decisions.
Methods: 650 consecutive patients presenting with non-metastatic BC (invasive BC, high-grade DCIS and pleomorphic LCIS) were recruited in two phases between 12/06/2020 to 22/03/2023. In phase one, 157 participants underwent combined germline and somatic whole genome sequencing (WGS) while for phase two, 495 participants underwent only germline whole exome sequencing.
Pathogenic variants were interrogated in BRCA1, BRCA2, PALB2, ATM, CHEK2, BARD1, BRIP1, RAD51B, RAD51C, RAD51D, MLH1, MSH2, MSH6, PMS2, CDH1, PTEN, STK11, TP53 and NTHL1. HRD score was calculated using HRDetect (Nat Med 2017;23:517). For BCs showing a high HRDetect score (>0.75), all HBC gene promoter CpG islands were assessed for hypermethylation using the Twist NGS Methylation system. Mutational signatures were calculated from somatic mutations identified from whole genome sequenced BCs using the DeconstructSig package in R (Genome Biol. 2016;17:31).
Results: All BRCA1, BRCA2 and PALB2 mutation positive tumours demonstrated high HRDetect scores, indicative of a role in pathogenesis, while a PMS mutation positive tumour exhibited a low HRD score, suggestive of a “passenger” mutation. In phase one participants without a germline pathogenic variant, 16% (18/117 invasive and 3/13 DCIS) had an HRDetect score of >0.7 indicative of a HR defect and potentially “BRCA-like”.
Conclusion: Tumour sequencing confirmed HBC genes that were ‘driver’ mutations and identified three times as many cases than germline testing alone (16% versus 5.4%) who might be eligible for HR repair defect targeted therapy.