Ploidy and large-scale genomic instability consistently identify basal-like breast carcinomas with BRCA1/2 inactivation.

By T. Popova, Elodie Manié, Guillaume Rieunier, V. Caux‐Moncoutier, Carole Tirapo, T. Dubois, O. Delattre, B. Sigal‐Zafrani, M. Bollet, M. Longy and 5 more. Cancer Research, 2012

618 citations recorded by the source corpus.

BRCA1 inactivation is a frequent event in basal-like breast carcinomas (BLC). However, BRCA1 can be inactivated by multiple mechanisms and determining its status is not a trivial issue. As an alternate approach, we profiled 65 BLC cases using single-nucleotide polymorphism arrays to define a signature of BRCA1-associated genomic instability. Large-scale state transitions (LST), defined as chromosomal break between adjacent regions of at least 10 Mb, were found to be a robust indicator of BRCA1 status in this setting. Two major ploidy-specific cutoffs in LST distributions were sufficient to distinguish highly rearranged BLCs with 85% of proven BRCA1-inactivated cases from less rearranged BLCs devoid of proven BRCA1-inactivated cases. The genomic signature we defined was validated in a second independent series of 55 primary BLC cases and 17 BLC-derived tumor cell lines. High numbers of LSTs resembling BRCA1-inactivated BLC were observed in 4 primary BLC cases and 2 BLC cell lines that harbored BRCA2 mutations. Overall, the genomic signature we defined predicted BRCA1/2 inactivation in BLCs with 100% sensitivity and 90% specificity (97% accuracy). This assay may ease the challenge of selecting patients for genetic testing or recruitment to clinical trials of novel emerging therapies that target DNA repair deficiencies in cancer.

Subfields: Genetics, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/4731b2eb6bf1fc1346cbef0269221a1e19004ae4

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Citations in the corpus

Homologous Recombination Deficiency (HRD) Score Predicts Response to Platinum-Containing Neoadjuvant Chemotherapy in Patients with Triple-Negative Breast Cancer (2016, background): “The combined cisplatin cohort was not used in the development of theHRD score,HRD threshold, or any of the individual components of the HRD score (LOH, TAI, LST), butwere the first two cohorts inwhich TAIwas tested.”
Homologous recombination deficiency: Exploiting the fundamental vulnerability of ovarian cancer (2015, background): “These include (i) the whole-genome tumor LOH score (54), (ii) the telomeric allelic imbalance (TAI) score (55), and (iii) the large-scale state transitions (LST) score, which quantifies chromosomal breaks between adjacent regions of at least 10 Mb (56).”
Repair Pathway Choices and Consequences at the Double-Strand Break (2015, neutral): “heterozygosity (LOH) profiling have detected specific mutation profiles indicative of a HR defect [96–98].”
Genomic and Molecular Landscape of DNA Damage Repair Deficiency across The Cancer Genome Atlas (2018, positive): “We calculated a HRD score, combined from HRD-LOH (Abkevich et al., 2012), LST (large-scale state transitions) (Popova et al., 2012), and NtAI (number of telomeric allelic imbalances) scores (Birkbak et al., 2012), for all PanCanAtlas samples using SCNA calls generated from ABSOLUTE (Figure S4B).”