Chemotherapy Linked To PPM1D Mutations in Ovarian Cancer Patients

Chemotherapy may play a role in the development of somatic mosaic mutations in the peripheral blood mononuclear cells of ovarian cancer patients

medwireNews: US researchers have questioned the purported relationship between somatic mosaic mutations in the p53-inducible protein phosphatase gene PPM1D and a predisposition to cancer, finding that the genetic markers are associated with ovarian cancer patient age and history of chemotherapy.

Previously, somatic mosaic mutations in PPM1D have been detected in peripheral blood mononuclear cells (PBMCs) of patients with breast and ovarian cancer, and hypothesized to reflect an underlying repair defect associated with cancer development, explain Elizabeth Swisher, from the University of Washington Medical Center in Seattle, and co-workers.

And although a cause and effect relationship has not yet been demonstrated between somatic mosaic mutations in PPM1D and future cancer risk, the team notes that risk-reducing salpingo-oophorectomy has been suggested as an option for patients with this biomarker.

In the current study, massively parallel sequencing of 65 genes in PBMCs from 412 patients with primary ovarian cancer and 274 patients with relapsed disease detected somatic mosaic mutations in PPM1D in 69 patients and in TP53 in 11 patients.

PPM1D somatic mosaic mutations were significantly associated with a history of chemotherapy and, for patients who had received chemotherapy, their age at the time their blood was drawn, the researchers report in JAMA Oncology.

For the relapsed ovarian cancer patients, PPM1D mutations were associated with the number of chemotherapy regimens, so that the biomarker was detected in 15.2% of 138 women who received one regimen compared with 26.9% of the 130 patients who had received two regimens.

And 5.1% of the relapsed patients had multiple PPM1D mutations whereas none of the patients with a primary tumour had more than one.

By contrast, the presence of TP53 somatic mutations was not associated with prior chemotherapy. Such mutations were detected in 1.2% of 326 women with ovarian cancer not exposed to chemotherapy and 2.6% of patients with recurrent platinum-resistant tumours. Nor was there a significant difference in the age of patients with and without TP53 somatic mosaic mutations.

However, the researchers observe that two patients developed TP53 mutations after prolonged chemotherapy, “suggesting that there may be an effect of extended chemotherapy on somatic TP53 mutations, although that effect was not detected in the larger cohort.”

Elizabeth Swisher et al conclude: “Given the relationship between prior chemotherapy, age, and somatic mosaic mutations inPPM1D, long-term prospective studies appear to be required to determine whether PPM1D or TP53 somatic mosaic mutations by themselves actually confer an increased risk of primary or secondary neoplasms.”

They add: “Care should be taken to control for chemotherapy exposure and age at blood draw when testing the association of somatic mosaic mutations in PBMCs with cancer risk.”

Reference

Swisher EM, Harrell MI, Norquist BM, et al. Somatic mosaic mutations inPPM1DandTP53in the blood of women with ovarian carcinoma. JAMA Oncol 2016; Advance online publication 4 February.doi:10.1001/jamaoncol.2015.6053

medwireNews (www.medwireNews.com) is an independent medical news service provided by Springer Healthcare Limited. © Springer Healthcare Ltd; 2016