Allelic expression imbalance of PIK3CA mutations is frequent in breast cancer and prognostically significant

Authors and affiliations:
Lizelle Correia^1*, Ramiro Magno^2*, Joana M. Xavier² , Bernardo P. de Almeida¹, Isabel Duarte² , Filipa Esteves^1,3, Marinella Ghezzo² , Matthew Eldridge⁴ , Chong Sun⁵, Astrid Bosma⁵ , Lorenza Mittempergher⁵ , Ana Marreiros¹, Rene Bernards⁵ , Carlos Caldas^4,6,7, Suet-Feung Chin ^4,6 and Ana-Teresa Maia ^1,2

* Equal contribution

¹ Faculty of Medicine and Biomedical Sciences (FMCB), Universidade do Algarve, Faro, Portugal.

² Center for Research in Health Technologies and Information Systems (CINTESIS), Universidade do Algarve, Faro, Portugal.

³ ProRegeM-PhD Program in Mechanisms of Disease and Regenerative Medicine, Universidade do Algarve, Faro, Portugal.

⁴ Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Robinson Way, Cambridge, UK.

⁵ Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam, The Netherlands.

⁶ Department of Oncology, University of Cambridge, Cambridge, UK.

⁷ Cancer Research UK Cambridge Cancer Centre, Cambridge, UK.

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 a frequent allelic expression imbalance between the missense mutant and wild-type PIK3CA alleles in breast tumors from the METABRIC (70.2%) and the TCGA (60.1%) projects. When considering the mechanisms controlling allelic expression, 27.7% and 11.8% of tumors showed imbalance due to regulatory variants in cis, in the two studies respectively. Furthermore, preferential expression of the mutant allele due to cis-regulatory variation is associated with poor prognosis in the METABRIC tumors (P = 0.031). Interestingly, ER−, PR−, and HER2+ tumors showed significant preferential expression of the mutated allele in both datasets. Our work provides compelling evidence to support the clinical utility of PIK3CA allelic expression in breast cancer in identifying patients of poorer prognosis, and those with low expression of the mutated allele, who will unlikely benefit from PI3K inhibitors. Furthermore, our work proposes a model of differential regulation of a critical cancer-promoting gene in breast cancer.

Journal: npj Breast Cancer

Link: https://www.nature.com/articles/s41523-022-00435-9