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Background   PPM1D  (Protein phosphatase magnesium-dependent 1δ) is known as a damage response regulator, a part of the p53 negative feedback loop. Truncating mutations of  PPM1D , resulting in overexpression, are frequently found in the blood of patients with breast or ovarian cancer. To identify whether the  PPM1D  mutation predisposes patients to such cancers or if it results from the cancer and therapy, somatic  PPM1D  mutations in association with previous cancer and chemotherapy need to be explored.    Methods  We performed next-generation sequencing (NGS) analysis of blood samples from patients suspected to have hereditary cancer. We grouped the patients according to their diagnoses and history of chemotherapy. For the patients with  PPM1D  mutations in blood, tumor tissue specimens were examined for the  PPM1D  mutation using conventional sequencing.    Results  A total of 1,195 patients, including 719 patients with breast cancer and 240 with ovarian cancer, were tested, and four (~0.3%) had the truncating mutation in  PPM1D . All truncating mutations were in exon 6, in mosaic form, with a mean allele fraction of 11.15%. While 395 out of the 1,195 patients had undergone chemotherapy, the four with the truncating mutation had a history of cisplatin-based chemotherapy. No corresponding mutations were identified in the tumor tissues.    Conclusions  We investigated the frequency of the somatic mosaic  PPM1D  mutation, in patients with breast or ovarian cancer, which is suggested to be low and related to a history of cisplatin-based chemotherapy. It may be a marker of previous exposure to selective pressure for cells with an impaired DNA damage response.

Somatic mosaic truncating mutations of PPM1D in blood can result from expansion of a mutant clone under selective pressure of chemotherapy