PPM1D – Hereditary Breast Carcinoma

Hereditary breast carcinoma is characterized by early-onset breast malignancy in multiple family members and is most often driven by pathogenic germline variants in DNA repair genes. While BRCA1 and BRCA2 account for the majority of high-penetrance cases, additional moderate- and low-penetrance genes contribute to familial risk. Among these, PPM1D—encoding the Wip1 phosphatase—has been proposed as a breast cancer susceptibility gene (PMID:30552672).

PPM1D functions as a serine/threonine phosphatase that negatively regulates the p53-mediated DNA damage response by dephosphorylating Ser15 of p53 and Thr68 of the checkpoint kinase Chk2, restoring cells to a pre-stress state. Truncating mutations in the last exon of PPM1D produce stable gain-of-function proteins with enhanced phosphatase activity, thereby attenuating p53 and checkpoint signaling and promoting genomic instability.

Despite its mechanistic plausibility, germline PPM1D variants have not been definitively associated with familial breast carcinoma. In a large review of hereditary breast cancer predisposition, PPM1D was listed among low-penetrance genes without supporting proband-level data or segregation analyses (PMID:30552672). No pathogenic familial PPM1D variants have been described in hereditary breast carcinoma pedigrees.

Somatic and mosaic germline studies in other cancers identify recurrent PPM1D variants, including the hotspot truncating variant c.1654C>T (p.Arg552Ter) which confers gain-of-function activity in vitro (PMID:23907125). However, these findings have not translated into clinically actionable germline risk alleles for hereditary breast cancer.

Functional assays support an oncogenic role for PPM1D: overexpression of wild-type Wip1 suppresses Chk2 Thr68 phosphorylation and checkpoint activation (PMID:16798742), while Wip1-deficient mouse models exhibit enhanced DNA damage signaling and resistance to Atm-deficiency phenotypes (PMID:20118229). These data underscore a gain-of-function mechanism but remain indirect with respect to hereditary breast carcinoma.

No studies to date dispute the potential involvement of PPM1D in breast cancer risk, but the absence of familial segregation and case-control data limits clinical validity. Additional large-scale sequencing of familial breast cancer cohorts and functional characterization of germline PPM1D variants are required.

Key Take-home: PPM1D demonstrates a plausible oncogenic mechanism via p53 pathway suppression, but current evidence for a hereditary breast carcinoma association is limited, and PPM1D is not recommended for routine germline testing pending further validation.

References

• Journal of cellular physiology • 2019 • Hereditary breast cancer; Genetic penetrance and current status with BRCA. PMID:30552672
• Cell cycle (Georgetown, Tex.) • 2013 • Genetic variants and mutations of PPM1D control the response to DNA damage. PMID:23907125
• The Journal of biological chemistry • 2006 • Intrinsic kinase activity and SQ/TQ domain of Chk2 kinase as well as N-terminal domain of Wip1 phosphatase are required for regulation of Chk2 by Wip1. PMID:16798742
• The Journal of biological chemistry • 2010 • Wild-type p53-induced phosphatase 1 dephosphorylates histone variant gamma-H2AX and suppresses DNA double strand break repair. PMID:20118229

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