Allelic expression imbalance of PIK3CA mutations is frequent in breast cancer and prognostically significant
Year: 2021
Type: preprint
Abstract: PIK3CA mutations are the most common in breast cancer, particularly in the estrogen receptor positive cohort, but the benefit of PI3K inhibitors has had limited success compared with approaches targeting other less common mutations. We found allelic imbalances in the expression of PIK3CA in normal breast tissue and mapped a germline candidate regulatory variant. An imbalance was also frequently observed in the expression of the missense mutant and wild-type PIK3CA alleles in breast tumors from METABRIC and TCGA projects. Moreover, although 60% of tumors preferentially expressed the mutant allele, 10% did preferentially express the wild-type allele. Mechanistically, we show that these imbalances are more frequently due to regulatory variants in cis than altered copy-number and predict that somatic variants have a more significant role than germline ones. We further found that imbalanced allelic expression between mutant and wild-type alleles due to cis- regulatory variants associated with poor prognosis ( p =0.0081). Interestingly, ER + , PR + , and Her2 − tumors expressing very low levels of the mutant allele had the poorest prognosis (DSS <7.5yrs for ER + and PR + tumors and <5yrs for Her2 − tumors). Hence, our work provides compelling evidence to support the clinical utility of PIK3CA allelic expression in breast cancer in identifying this cohort of low mutant allele expressing patients of poorer prognosis, who will unlikely benefit from PI3K inhibitors. Furthermore, our work establishes a new model of differential regulation of critical cancer-promoting genes.
Authors: Lizelle Correia, Joana M. Xavier, Ramiro Magno, Bernardo P. de Almeida, Filipa Esteves, Isabel Duarte, Matthew Eldridge, Chong Sun, Astrid Bosma, Lorenza Mittempergher, Ana Marreiros, Rene Bernards, Carlos Caldas, Suet-Feung Chin, Ana-Teresa Maia
Institutions: Algarve Biomedical Center, University of Algarve, University of Cambridge, Cancer Research UK, The Netherlands Cancer Institute, Cambridge University Hospitals NHS Foundation Trust, National Institute for Health and Care Research, Cancer Research UK Cambridge Center, Addenbrooke's Hospital, NIHR Cambridge Biomedical Research Centre
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Funders: Cancer Research UK, National Institute for Health and Care Research, University of Cambridge, European Commission, Centro de Investigação em Tecnologias e Serviços de Saúde, Centro de Investigação em Biomedicina, Fundação para a Ciência e a Tecnologia, BC Cancer Agency, NIHR Cambridge Biomedical Research Centre, Cancer Research UK Cambridge Institute, University of Cambridge
Awards: G1483381719, G1516346500, G1690109813, G1763632427, Unveiling cis-regulatory variants role in breast cancer aetiology, G3207356259, G3802939133, G3840324753, G393177772, Genetic Control of Gene Expression in Cancer Risk, G5224927334, G564671996, G5702163051, G6459690456, G709051462, Centro de Investigação em Biomedicina, G778408385, Sem título, G8596289675
OpenAlex ID: W3134636404