Optimized Detection of Homologous Recombination Deficiency Improves the Prediction of Clinical Outcomes in Cancer

Overview

Journal NPJ Precis Oncol

Publisher Springer Nature

Specialty Oncology

Date 2022 Dec 29

PMID 36581696

Authors

Fernando Perez-Villatoro

Jaana Oikkonen

Julia Casado

Anastasiya Chernenko

Doga C Gulhan

Manuela Tumiati

Yilin Li

Kari Lavikka

Sakari Hietanen

Johanna Hynninen

Ulla-Maija Haltia

Jaakko S Tyrmi

Hannele Laivuori

Panagiotis A Konstantinopoulos

Sampsa Hautaniemi

Liisa Kauppi

Anniina Farkkila

Affiliations

Soon will be listed here.

Abstract

Homologous recombination DNA-repair deficiency (HRD) is a common driver of genomic instability and confers a therapeutic vulnerability in cancer. The accurate detection of somatic allelic imbalances (AIs) has been limited by methods focused on BRCA1/2 mutations and using mixtures of cancer types. Using pan-cancer data, we revealed distinct patterns of AIs in high-grade serous ovarian cancer (HGSC). We used machine learning and statistics to generate improved criteria to identify HRD in HGSC (ovaHRDscar). ovaHRDscar significantly predicted clinical outcomes in three independent patient cohorts with higher precision than previous methods. Characterization of 98 spatiotemporally distinct metastatic samples revealed low intra-patient variation and indicated the primary tumor as the preferred site for clinical sampling in HGSC. Further, our approach improved the prediction of clinical outcomes in triple-negative breast cancer (tnbcHRDscar), validated in two independent patient cohorts. In conclusion, our tumor-specific, systematic approach has the potential to improve patient selection for HR-targeted therapies.

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