Somatic mutations in LRRK2 identify a subset of invasive mammary carcinomas associated with high mutation burden

Edgardo R Parrilla Castellar 1, Jennifer K Plichta 2, Richard Davis 3, Claudia Gonzalez-Hunt 4, Laurie H Sanders 5

Affiliations

PMID: 32931768
DOI: 10.1016/j.ajpath.2020.08.010

Abstract

Mutations in the LRRK2 gene are the most common cause of familial Parkinson's disease (PD). While LRRK2-related PD patients have a heightened risk of certain non-skin cancers, including breast cancer, it is unknown whether LRRK2 somatic mutations occur and are associated with breast cancer. The objective of this study was to evaluate the occurrence of LRRK2 somatic mutations in breast cancer and the clinicopathologic features associated with LRRK2-mutated tumors. Using The Cancer Genome Atlas (TCGA-BRCA), somatic LRRK2 DNA sequence information was obtained for 93 cases, of which 17 cases (18%) with 18 mutations were identified. LRRK2-mutated mammary carcinomas are enriched with stop-gain, truncating mutations predicted to result in loss-of-function; missense mutations frequently targeted the GTPase and kinase domains. Tumors displayed predominantly high-grade morphology with abundant granular eosinophilic cytoplasm, resembling mitochondria-rich apocrine-like carcinomas. Exploration of the genomic landscape of LRRK2-mutated carcinomas yielded frequent TP53 deactivation and a remarkably high tumor mutation burden. Importantly, breast cancers with LRRK2 mutations are associated with reduced patient survival compared to the TGCA-BRCA cohort. These findings for the first time show that somatic LRRK2 mutations occur frequently in breast cancer and the high mutation burden seen in this subset of tumors suggest that LRRK2 mutations may herald benefit from immune checkpoint inhibition.