Genomic complexity profiling reveals that HORMAD1 overexpression contributes to homologous recombination deficiency in triple-negative breast cancers
A partir d'échantillons tumoraux prélevés sur plusieurs cohortes de patientes atteintes d'un cancer du sein triplement négatif, cette étude identifie une association entre l'expression d'un gène associé à la méiose (HORMAD1) et la réponse à une chimiothérapie à base de sels de platine
Triple-negative breast cancers (TNBCs) are characterised by a wide spectrum of genomic alterations, some of which might be caused by defects in DNA repair processes such as homologous recombination (HR). Despite this understanding, associating particular patterns of genomic instability with response to therapy has been challenging. Here, we show that Allelic-imbalanced Copy Number Aberrations (AiCNA) are more prevalent in TNBCs that respond to platinum-based chemotherapy, thus providing a candidate predictive biomarker for this disease. Furthermore, we show that a high level of AiCNA is linked with elevated expression of a meiosis-associated gene HORMAD1. Elevated HORMAD1 expression suppresses RAD51-dependent HR and drives the use of alternative forms of DNA repair, the generation of AiCNAs as well as sensitising cancer cells to HR targeting therapies. Our data therefore provides a mechanistic association between HORMAD1 expression, a specific pattern of genomic instability and an association with response to platinum-based chemotherapy in TNBC.
Cancer Discovery , résumé, 2015