A 10-gene signature associated with elevated levels of NCAPH identifies luminal A breast cancer patients with a risk of relapse

Abstract

Background Despite their generally favorable prognosis, luminal A tumors paradoxically pose the highest ten-year recurrence risk among breast cancers, with a quarter recurring within five years. Identifying such patients is crucial as long-term relapsers could benefit from extended hormone therapy, while early relapsers may require aggressive treatment. We propose a gene signature, sourced from genes such as NCAPH associated with luminal A breast cancer pathogenesis and poor prognosis, for improved stratification of these high-risk patients. Methods We used in vitro and in vivo mouse models to study the implication of NCAPH in breast cancer progression. We performed transcriptomic analysis from a backcross cohort of mice with breast tumors. Transcripts that were associated with high intratumoral Ncaph levels were used for a LASSO multivariate regression model in the human databases. Results We demonstrated that NCAPH participates in the pathogenesis of luminal breast cancer in vitro and in vivo using different mouse models. Transgenic mice overexpressing NCAPH generated breast tumors with a long latency, and in MMTV-NCAPHErbB2+ double-transgenic mice, the luminal tumors formed were more aggressive. In addition, high levels of Ncaph were associated with worse evolution and a poor response to chemotherapy in a cohort of genetically heterogeneous transgenic mice generated by backcrossing. Moreover, NCAPH levels were higher in patients with poor long-term evolution. Using LASSO multivariate regression, we identified a ten-gene risk score formed by a gene signature (Gene Signature for Luminal A 10 or GSLA10) that correlated with high intratumoral NCAPH expression and poor luminal A breast cancer evolution. This GSLA10 signature outperforms the Oncotype DX signature in distinguishing tumors with a poor outcome (previously categorized as luminal A by PAM50) in three independent human cohorts. Conclusions The GSLA10 signature assists in identifying patients with luminal A tumors exhibiting poor prognosis, who could thus potentially benefit from personalized treatment strategies.