PPM1D Mutations in Circulating White Blood Cells Associated With Risk of Ovarian Cancer, Increased Mortality, and Risk of Breast Cancer
In a brief communication published in the Journal of the National Cancer Institute, Akbari et al reported finding a higher frequency of PPM1D mutations in circulating white blood cells from women with ovarian cancer vs controls, higher mortality associated with the mutation in women with ovarian cancer, and a greater risk of breast cancer in those carrying the mutation.
Study Details
In the study, the last exon of the PPM1D gene was sequenced in 1,295 ovarian cancer patients from the Familial Ovarian Tumor Study in Toronto and 834 control subjects without cancer who had attended a multimodal screening clinic at Women’s College Hospital in Toronto. The majority of case patients (81%) and control subjects (94%) were white.
Disease Associated With Mutation
A truncating PPM1D mutation was found in 20 case patients (1.5%) and 1 control subject (0.1%; odds ratio [OR] = 13.07, P < .001). None of the case patient mutation carriers had a BRCA1 or BRCA2 mutation. Compared with PPM1D-negative case patients, patients with PPM1D mutations had a higher mean age at ovarian cancer diagnosis (68 vs 57 years, P < .001), were more likely to have serous tumors (90% vs 57%, P = .002), and had significantly higher 12-year ovarian cancer–specific mortality (hazard ratio [HR] = 2.02, P = .007).
A family history of ovarian cancer was present in 1 of the 20 patients with PPM1D mutation. Three of the patients (15%) had a past history of breast cancer vs 29 (2.6%) of 1,129 noncarriers (OR = 6.69, P = .007), supporting the hypothesis that PPM1D mutations also predispose to breast cancer. The lifetime risks of ovarian or breast cancer among 54 female first-degree relatives of the 20 PPM1D mutation carriers were not significantly different from risks among 3,789 female first-degree relatives of 1,129 noncarrier ovarian cancer patients (HR = 1.32, P = .78), supporting the hypothesis that PPM1D mutations are not inherited. In contrast, relatives of BRCA1 or BRCA2 mutation carriers had 3- to 9-fold increased cancer risk.
The investigators noted: “The odds ratio of 13 for ovarian cancer corresponds to a lifetime risk of ovarian cancer of 15% to 20%, a level that justifies preventive salpingo-oophorectomy. All 20 PPM1D mutation carriers in our study experienced ovarian cancer after menopause. Approximately 1% of all ovarian cancers might be prevented through screening for PPM1D mutations in healthy women, but given the lack of familial segregation of mutations, identifying carriers eligible for surgical prevention would require population screening of a mutation with a prevalence estimated to be from one in 843 to one in 5,681.”
They concluded, “These observations suggest PPM1D mutations in the mosaic state predispose women to breast and ovarian cancer in the absence of a family history of cancer.”
Steven Narod, MD, of Women’s College Research Institute, Toronto, is the corresponding author for the Journal of the National Cancer Institute article.
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