Abstract
BRCA1/2 variants are prognostic biomarkers for hereditary breast and/or ovarian cancer (HBOC) syndrome and predictive biomarkers for PARP inhibition. In this study, we benchmarked the classification of BRCA1/2 variants from patients with HBOC-related cancer using MH BRCA, a novel computational technology that combines the ACMG guidelines with expert-curated variant annotations. Evaluation of BRCA1/2 variants (n = 1040) taken from four HBOC studies showed strong concordance within the pathogenic (98.1%) subset. Comparison of MH BRCA’s ACMG classification to ClinVar submitter content from ENIGMA, the international consortium of investigators on the clinical significance of BRCA1/2 variants, the ARUP laboratories, a clinical testing lab of the University of UTAH, and the German Cancer Consortium showed 99.98% concordance (4975 out of 4976 variants) in the pathogenic subset. In our patient cohort, refinement of patients with variants of unknown significance reduced the uncertainty of cancer-predisposing syndromes by 64.7% and identified three cases with potential family risk to HBOC due to a likely pathogenic variant BRCA1 p.V1653L (NM_007294.3:c.4957G > T; rs80357261). To assess whether classification results predict PARP inhibitor efficacy, contextualization with functional impact information on DNA repair activity were performed, using MH Guide. We found a strong correlation between treatment efficacy association and MH BRCA classifications. Importantly, low efficacy to PARP inhibition was predicted in 3.95% of pathogenic variants from four examined HBOC studies and our patient cohort, indicating the clinical relevance of the consolidated variant interpretation.
Highlights
Deleterious BRCA1/2 variants have emerged as critical prognostic and predictive biomarkers for DeleteriousBRCA1/2 have as critical prognostic andmachinery predictive[1], biomarkers for deficiency in DNA damagevariants repair by the emerged homologous recombination (HR) deficiency in DNA damage repair by the homologous recombination machinery [1], for patients with hereditary breast and/or ovarian cancer syndrome (HBOC) and for sporadic for patients with the hereditary breastthe and/or cancerpolymerase syndrome (PARP)(HBOC)family and for sporadic cases [2,3,4]
We focused retrospectively on 346 patients (334 with breast and/or ovarian cancer sequenced at at the Yamanashi Central Hospital (YCH) with the purpose and 12 with prostate cancer) sequenced to compare our BRCA1/2 variant interpretation provided by the current clinical workflow with those provided through reanalysis with the Molecular Health (MH) BRCA technology and to evaluate the predicted response
BRCA1/2 variant analyzed for predicted treatment response to PARP inhibition in MH Guide
Summary
Deleterious BRCA1/2 variants have emerged as critical prognostic and predictive biomarkers for DeleteriousBRCA1/2 have as critical prognostic andmachinery predictive[1], biomarkers for deficiency in DNA damagevariants repair by the emerged homologous recombination (HR) deficiency in DNA damage repair by the homologous recombination machinery [1], for patients with hereditary breast and/or ovarian cancer syndrome (HBOC) and for sporadic for patients with the hereditary breastthe and/or cancerpolymerase syndrome (PARP)(HBOC)family and for sporadic cases [2,3,4]. BRCA1/2 have as critical prognostic andmachinery predictive[1], biomarkers for deficiency in DNA damagevariants repair by the emerged homologous recombination (HR). Deficiency in DNA damage repair by the homologous recombination machinery [1], for patients with hereditary breast and/or ovarian cancer syndrome (HBOC) and for sporadic for patients with the hereditary breastthe and/or cancerpolymerase syndrome (PARP). Poly ovarian (ADP-ribose) of proteins has cases established [2,3,4]. PARPs are involved in DNA repairhas of been established as an important therapeutic target [5,6,7,8]. DNA breaks and inhibitionHR of PARP function based on concept of synthetic lethality lethality in cancers with simultaneous deficiency [9]. Despite the utility of platinum sensitivity and BRCA1/2 as predictors of treatment response, there is an urgent needand forBRCA1/2 greater variants as predictors of treatment response, there is an urgent need for greater resolution in the resolution in the predictive capacity of individual BRCA1/2 variants to understand the determinants predictive variants to determinants of response related of responsecapacity related of to individual the degree BRCA1/2 of HR deficiency
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