Germline mutations in PPP2R1B in patients with a personal and family history of cancer.

An estimated 5%-10% of cancer results from an underlying genetic predisposition. For the majority of familial cases, the genes in question remain unknown, suggesting a critical need to identify new cancer predisposition genes. Members of the protein phosphatase 2A (PP2A) family exist as trimeric holoenzymes and are vital negative regulators of multiple oncogenic pathways. PP2A inhibition by somatic mutation, loss of expression, and upregulation of its exogenous inhibitors in tumors has been well described. However, it remains unknown whether germline loss of any PP2A subunits results in a predisposition to cancer in humans. In this study, we identified 9 cancer patients with germline loss-of-function (LOF) variants in PPP2R1B (Aβ), the β isoform of the PP2A scaffold subunit. All 4 patients for whom documentation was available also had a family history of cancer, including multiple indicators of hereditary cancer. Overexpression of these mutant forms of Aβ resulted in truncated proteins that were rapidly turned over. Characterization of an additional missense germline Aβ variant, R233C, which is also recurrently mutated at the somatic level, showed disruption of PP2A catalytic subunit binding, resulting in loss of phosphatase activity. An analysis of Aβ expression among multiple breast cancer cohorts (the most highly represented cancer among the Aβ germline patients) revealed that somatic, heterozygous loss of Aβ was a frequent event in this disease, and decreased Aβ expression correlated with shorter disease-free and overall survival. Furthermore, Aβ levels were significantly lower in multiple histological subtypes of both in situ and malignant breast cancer compared with adjacent normal breast tissue, suggesting that Aβ loss is an early event in breast cancer development. Together, these results highlight a role for Aβ as a predisposition gene in breast cancer and potentially additional cancers.