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

BackgroundPPM1D (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.MethodsWe 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.ResultsA 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.ConclusionsWe 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

Prevalence and clinical implications of germline predisposition gene mutations in patients with acute myeloid leukemia

Abstract Acute myeloid leukemia (AML) is one of the most common types of leukemia. With the recent advances in sequencing technology and the growing body of knowledge on the genetics of AML, there is increasing concern about cancer predisposing germline mutations as well as somatic mutations. As familial cases sharing germline mutations are constantly reported, germline predisposition gene mutations in patients with AML are gaining attention. We performed genomic sequencing of Korean patients diagnosed with AML to identify the prevalence and characteristics of germline predisposition mutations. Among 180 patients, germline predisposition mutations were identified in 13 patients (13/180, 7.2%, eight adults and five children). Germline mutations of BLM, BRCA1, BRCA2, CTC1, DDX41, ERCC4, ERCC6, FANCI, FANCM, PALB2, and SBDS were identified. Most of the mutations are in genes involved in DNA repair and genomic stability maintenance. Patients harboring germline mutations tended to have earlier onset of AML (p = 0.005), however, the presence of germline mutations did not showed significant association with other clinical characteristics or treatment outcome. Since each mutation was rare, further study with a larger number of cases would be needed to establish the effect of the mutations

Targeted next generation sequencing can serve as an alternative to conventional tests in myeloid neoplasms.

The 2016 World Health Organization classification introduced a number of genes with somatic mutations and a category for germline predisposition syndromes in myeloid neoplasms. We have designed a comprehensive next-generation sequencing assay to detect somatic mutations, translocations, and germline mutations in a single assay and have evaluated its clinical utility in patients with myeloid neoplasms. Extensive and specified bioinformatics analyses were undertaken to detect single nucleotide variations, FLT3 internal tandem duplication, genic copy number variations, and chromosomal copy number variations. This enabled us to maximize the clinical utility of the assay, and we concluded that, as a single assay, it can be a good supplement for many conventional tests, including Sanger sequencing, RT-PCR, and cytogenetics. Of note, we found that 8.4-11.6% of patients with acute myeloid leukemia and 12.9% of patients with myeloproliferative neoplasms had germline mutations, and most were heterozygous carriers for autosomal recessive marrow failure syndromes. These patients often did not respond to standard chemotherapy, suggesting that germline predisposition may have distinct and significant clinical implications