Abstract
Abstract
Purpose: Somatic mosaic mutation in the PPM1D gene have been associated with risk of breast and ovarian cancer. Somatic mosaic mutations in blood cells may be associated with older age and chemotherapy exposure. We wanted to determine if somatic mosaic mutations in PPM1D and in other genes are associated with older age and repeated exposure to chemotherapy, rather than a contributor to risk of disease.
Experimental design: We used targeted capture and massively parallel genomic sequencing to sequence DNA from PBMCs from affected patients for PPM1D as well as 60 other DNA repair genes. For a number of samples with PPM1D mutations, we re-sequenced at greater depth on patients where PBMCs that were collected at diagnosis and recurrence.
Results: We identified somatic mosaic mutations in exon 6 of PPM1D in 4 out of 474 (0.8%) individuals that were newly diagnosed and had no previous chemotherapy, in 3 out of 29 (10%) individuals newly diagnosed but receiving chemotherapy and in 58 of 274 (21%) individuals with relapsed platinum resistant ovarian cancer (p<0.0001). The presence of PPM1D mutations in exon 6 was strongly associated with more advanced age (p=0.011, Wilcoxon test) and more than one chemotherapy regimen (p=0.026, Fisher's exact test). In paired blood samples from 13 patients, PPM1D mutations present at relapse were either not detected or detected at a lower percentage compared to blood obtained soon after diagnosis. Somatic mosaic mutations were also identified in TP53 in 7 of 274 (2.5%) women with relapsed platinum resistant cancer. In one of these cases, we had an earlier blood sample from diagnosis in which the mutation was not present at time near diagnosis.
Conclusion: We found that somatic mosaic PPM1D mutations in PMBCs are associated with advanced age and repeated exposure to chemotherapy. Mosaic mutations in other genes were not confirmed with the exception of TP53, for which mutations are also detectable after extensive treatment. It seems likely that mosaic PPM1D mutations in blood from cancer patients may be a result of selection by chemotherapy of age-induced somatic mutations during exposure to chemotherapy. Further studies are needed to determine the clinical significance of these mutations.
Citation Format: Maria I. Harrell, Barbara M. Norquist, Tom Walsh, Mark F. Brady, Ming K. Lee, Robert Hershberg, Kimberly R. Kalli, Heather Lankes, Eric Q. Konnick, Colin C. Pritchard, Bradley J. Monk, John K. Chan, Robert Burger, Scott H. Kaufmann, Michael J. Birrer, Elizabeth M. Swisher. Old age and chemotherapy contribute to the selection of PPM1D somatic mosaic mutations in ovarian cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr B71.