Identifying Transcripts with Tandem Duplications from RNA‐Sequencing Data to Predict BRCA1‐Type Primary Breast Cancer

Shuoying Qu, John W.M. Martens*, Antoinette Hollestelle, Marcel Smid

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

Patients with cancers that are deficient for homologous recombination repair (HRD) may benefit from PARP inhibitor treatment. Therefore, methods that identify such cancers are crucial. Using whole genome sequencing data, specific genomic scars derived from somatic mutations and genomic rearrangements can identify HRD tumors, with only BRCA1‐like HRD cancers profoundly displaying small (< 10 kb) tandem duplications (TDs). In this manuscript we describe a method of detecting BRCA1‐type HRD in breast cancer (BC) solely from RNA sequencing data by identifying TDs surfacing in transcribed genes. We find that the number of identified TDs (TD‐score) is significantly higher in BRCA1‐type vs. BRCA2‐type BCs, or vs. HR‐proficient BCs (p = 2.4 × 10−6 and p = 2.7 × 10−12, respectively). A TD‐score ≥ 2 shows an 88.2% sensitivity (30 out of 34) to detect a BRCA1‐ type BC, with a specificity of 64.7% (143 out of 221). Pathway enrichment analyses showed genes implicated in cancer to be affected by TDs of which PTEN was found significantly more frequently affected by a TD in BRCA1‐type BC. In conclusion, we here describe a novel method to identify TDs in transcripts and classify BRCA1‐type BCs with high sensitivity.

Original languageEnglish
Article number753
JournalCancers
Volume14
Issue number3
DOIs
Publication statusPublished - 31 Jan 2022

Bibliographical note

Funding Information:
Acknowledgments: This work was made possible through the ICGC Breast Cancer Working group by the Breast Cancer Somatic Genetics Study (BASIS) and the Hartwig Medical Foundation. Partic‐ ipating institutes are Institut Jules Bordet (Belgium), Institut National Du Cancer Gip (France), Oslo Universitetssykehus Hf (Norway), Max Iv Laboratory, Lund University (Sweden), Academisch Medisch Centrum Bij De Universiteit Van Amsterdam, Stichting Radboud Universiteit, Erasmus Universitair Medisch Centrum Rotterdam, Stichting Het Nederlands Kanker Instituut‐Antoni Van Leeuwenhoek Ziekenhuis (The Netherlands), Cancer Research, The University Of Cambridge, The Institute Of Cancer Research: Royal Cancer Hospital.Germany: European Molecular Biology Labor‐ atory (UK), Dana‐Farber Cancer Institute Inc, Sloan‐Kettering Institute For Cancer Research Corpo‐ ration (USA). We acknowledge the clinical networks across ICGC and the hospitals who provided samples and data to the consortium. We thank the patients and their families for their participation in the BASIS project.

Funding Information:
This work was made possible through the ICGC Breast Cancer Working group by the Breast Cancer Somatic Genetics Study (BASIS) and the Hartwig Medical Foundation. Partic-ipating institutes are Institut Jules Bordet (Belgium), Institut National Du Cancer Gip (France), Oslo Universitetssykehus Hf (Norway), Max Iv Laboratory, Lund University (Sweden), Academisch Medisch Centrum Bij De Universiteit Van Amsterdam, Stichting Radboud Universiteit, Erasmus Universitair Medisch Centrum Rotterdam, Stichting Het Nederlands Kanker Instituut?Antoni Van Leeuwenhoek Ziekenhuis (The Netherlands), Cancer Research, The University Of Cambridge, The Institute Of Cancer Research: Royal Cancer Hospital.Germany: European Molecular Biology Laboratory (UK), Dana?Farber Cancer Institute Inc, Sloan?Kettering Institute For Cancer Research Corporation (USA). We acknowledge the clinical networks across ICGC and the hospitals who provided samples and data to the consortium. We thank the patients and their families for their participation in the BASIS project.

Publisher Copyright:
© 2022 by the authors. Licensee MDPI, Basel, Switzerland.

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