Whole genome sequencing (WGS) brings comprehensive insights to cancer genome interpretation. To explore clinical value of WGS, the authors sequenced 254 triple negative breast cancers (TNBC) with associated treatment and outcome data collected between 2010-2015 via the population-based Sweden Cancerome Analysis Network-Breast (SCAN-B) project. Applying the HRDetect mutational-signature-based algorithm to classify tumors, 59% were predicted to have Homologous-recombination-repair deficiency (HRDetect-high): 67% explained by germline/somatic mutations of BRCA1/BRCA2, BRCA1 promoter hypermethylation, RAD51C hypermethylation or biallelic loss of PALB2. A novel mechanism of BRCA1 abrogation was discovered via germline SINE-VNTR-Alu retrotransposition. Finally, the authors concluded that new treatment options need to be considered for now-discernible HRDetect-intermediate and HRDetect-low categories. This population-based study advocates for WGS of TNBC to better inform trial stratification and improve clinical decision-making.

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