PPM1D

Overview

PPM1D (protein phosphatase Mg2+/Mn2+-dependent 1D, also known as Wip1) encodes a serine/threonine phosphatase that negatively regulates the DNA damage response by dephosphorylating ATM, p53, and H2AX. Truncating mutations in exon 6 are a recurrent form of clonal hematopoiesis (CH), particularly enriched after cytotoxic chemotherapy or radiation, and can confound tumor-tissue sequencing when blood-based contamination is not controlled.

Alterations observed in the corpus

  • Clonal hematopoiesis variant enriched after prior systemic therapy: PPM1D truncating variants (alongside CHEK2 variants) are flagged as clonal-hematopoiesis (CH) mutations enriched after prior systemic therapy in a large multi-cancer real-world dataset (MSK-CHORD), encompassing LUAD, BRCA, and PRAD patients. PMID:39506116
  • Single frameshift mutation identified in the sinonasal adenoid cystic carcinoma cohort; PPM1D (Wip1 phosphatase) is a known oncogene that restrains p53 activity PMID:24418857
  • PPM1D identified as one of seven significantly mutated genes (SMGs, q<0.1) in the TCGA PTC cohort (n=402 exome-sequenced tumors); DNA-repair SMG co-occurring with MAPK-pathway drivers; DNA-repair mutations associated with higher mutation density (p=0.022) and high-risk patients (p=0.018). PMID:25417114
  • Appeared in nonleukemic rising clones during decitabine-induced remission in TP53-mutant AML/MDS, consistent with clonal hematopoiesis of indeterminate potential PMID:27959731

Cancer types (linked)

  • LUAD / BRCA / PRAD: PPM1D CH variants appear in tumor-sequencing data from multiple cancer types within MSK-CHORD, reflecting the pan-cancer nature of therapy-related clonal hematopoiesis rather than a somatic tumor driver role. PMID:39506116

Co-occurrence and mutual exclusivity

  • Co-flagged with CHEK2 as a clonal-hematopoiesis marker enriched in patients who have received prior systemic therapy. PMID:39506116

Therapeutic relevance

  • PPM1D CH variants are a biomarker of prior therapy exposure rather than a therapeutic target in the current corpus. Their enrichment after treatment may complicate interpretation of tumor NGS panels that do not have matched germline comparators.

Open questions

  • The degree to which PPM1D CH variants in MSK-CHORD are tumor-derived versus blood-contamination artifacts remains to be formally quantified; the paper identifies the association but does not resolve the source. PMID:39506116

Sources

This page was processed by crosslinker on 2026-05-04. - PMID:24418857

This page was processed by wiki-cli on 2026-05-09. - PMID:25417114

This page was processed by entity-page-writer on 2026-05-15. - PMID:27959731

This page was processed by entity-page-writer on 2026-05-15.