Abstract:Background:PPM1D (WIP1) negatively regulates by dephosphorylation many proteins including p53 tumour suppressor. The truncating mutations (nonsense and frameshift) in exon 6 of PPM1D were found recently in blood cells of patients with breast, ovarian or colorectal cancer. These mutants code for gain-of-function PPM1D with retained phosphatase activity. Their significance in carcinogenesis is unknown.Methods:The exon 6 of PPM1D was sequenced in blood DNA of 543 non-small-cell lung cancer patients (NSCLC). The f… Show more
“…These observations suggest that PPM1D somatic mosaic mutations reflect prior chemotherapy exposure. Consistent with this suggestion, all 26 patients with lung cancer and OC with a PPM1D mutation previously identified by Akbari et al 2 and Zajkowicz et al 3 also had received chemotherapy before PPM1D sequencing. It is possible that there may also be a rare, second group of younger, chemotherapy-naive patients with a more dominant PPM1D clone (eg, patients 11–13 in eTable 2 in the Supplement), but the clinical significance of that finding requires additional investigation.…”
Section: Discussionsupporting
confidence: 67%
“…2 Somatic mosaic PPM1D mutations have also been reported in lung cancer. 3 Although it has been assumed that the presence of these mutations might reflect an underlying repair defect that contributes to cancer predisposition, our results suggest that this association between PPM1D mutations and solid tumors might have been confounded by prior chemotherapy. In particular, we observe a stepwise increase in the incidence of PPM1D somatic mosaic mutations between patients with OC without prior chemotherapy, patients with newly diagnosed OC but prior chemotherapy exposure, and patients previously treated extensively for OC (Table).…”
Section: Discussionmentioning
confidence: 59%
“…Somatic mosaic PPM1D mutations have also been reported in lung cancer. 3 Whether PPMID mutations reflect an underlying cancer predisposition or consequence of cancer therapy is unclear. Here we investigated whether PPM1D somatic mosaic mutations reflect a previously unrecognized association with prior chemotherapy and whether similar mutations also occur in other genes associated with OC.…”
IMPORTANCE
Somatic mosaic mutations in PPM1D have been reported in patients with breast cancer, lung cancer, and ovarian cancer (OC), but cause or effect has not been established.
OBSERVATIONS
To test the hypothesis that somatic mosaic mutations are associated with chemotherapy exposure, we used massively parallel sequencing to quantitate mutations in peripheral blood mononuclear cells (PBMCs) of 686 women with primary OC (n = 412) or relapsed OC (n = 274). The frequency of somatic mosaic PPM1D mutations in PBMCs was significantly associated with prior chemotherapy (P < .001), and, in patients exposed to chemotherapy, with older age at blood draw (recurrent OC odds ratio [OR], 17.24; 95%CI, 6.80–43.69; and primary OC postchemotherapy OR, 4.82; 95%CI, 1.43–16.18). In contrast, somatic mosaic mutations in TP53 were not significantly associated with chemotherapy or age. In sequential PBMC samples harvested from 13 patients with OC near diagnosis and after a median of 2 different chemotherapy regimens, somatic mosaic PPM1D mutations increased in 11 individuals (84.6%) and TP53 mutations appeared in 2 (15.4%).
CONCLUSIONS AND RELEVANCE
Chemotherapy exposure and age influence the accumulation of PPM1D-mutated PBMC clones. 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.
“…These observations suggest that PPM1D somatic mosaic mutations reflect prior chemotherapy exposure. Consistent with this suggestion, all 26 patients with lung cancer and OC with a PPM1D mutation previously identified by Akbari et al 2 and Zajkowicz et al 3 also had received chemotherapy before PPM1D sequencing. It is possible that there may also be a rare, second group of younger, chemotherapy-naive patients with a more dominant PPM1D clone (eg, patients 11–13 in eTable 2 in the Supplement), but the clinical significance of that finding requires additional investigation.…”
Section: Discussionsupporting
confidence: 67%
“…2 Somatic mosaic PPM1D mutations have also been reported in lung cancer. 3 Although it has been assumed that the presence of these mutations might reflect an underlying repair defect that contributes to cancer predisposition, our results suggest that this association between PPM1D mutations and solid tumors might have been confounded by prior chemotherapy. In particular, we observe a stepwise increase in the incidence of PPM1D somatic mosaic mutations between patients with OC without prior chemotherapy, patients with newly diagnosed OC but prior chemotherapy exposure, and patients previously treated extensively for OC (Table).…”
Section: Discussionmentioning
confidence: 59%
“…Somatic mosaic PPM1D mutations have also been reported in lung cancer. 3 Whether PPMID mutations reflect an underlying cancer predisposition or consequence of cancer therapy is unclear. Here we investigated whether PPM1D somatic mosaic mutations reflect a previously unrecognized association with prior chemotherapy and whether similar mutations also occur in other genes associated with OC.…”
IMPORTANCE
Somatic mosaic mutations in PPM1D have been reported in patients with breast cancer, lung cancer, and ovarian cancer (OC), but cause or effect has not been established.
OBSERVATIONS
To test the hypothesis that somatic mosaic mutations are associated with chemotherapy exposure, we used massively parallel sequencing to quantitate mutations in peripheral blood mononuclear cells (PBMCs) of 686 women with primary OC (n = 412) or relapsed OC (n = 274). The frequency of somatic mosaic PPM1D mutations in PBMCs was significantly associated with prior chemotherapy (P < .001), and, in patients exposed to chemotherapy, with older age at blood draw (recurrent OC odds ratio [OR], 17.24; 95%CI, 6.80–43.69; and primary OC postchemotherapy OR, 4.82; 95%CI, 1.43–16.18). In contrast, somatic mosaic mutations in TP53 were not significantly associated with chemotherapy or age. In sequential PBMC samples harvested from 13 patients with OC near diagnosis and after a median of 2 different chemotherapy regimens, somatic mosaic PPM1D mutations increased in 11 individuals (84.6%) and TP53 mutations appeared in 2 (15.4%).
CONCLUSIONS AND RELEVANCE
Chemotherapy exposure and age influence the accumulation of PPM1D-mutated PBMC clones. 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.
“…249 Similarly, somatic mutations in PPM1D, a serine/threonine phosphatase that negatively regulates p53, 250 have been found in blood of patients with breast, ovarian, and lung cancer. [251][252][253][254] In ovarian cancer, the frequency of PPM1D mutations in blood was significantly associated with prior chemotherapy, and the variant allele frequency increased during chemotherapy. 251 These data suggest a model in which hematopoietic progenitor cells carrying mutations in the TP53 pathway undergo selective pressure by cytotoxic therapy, ultimately leading to t-AML.…”
Section: Therapy-related Aml Biology Of T-amlmentioning
The first edition of the European LeukemiaNet (ELN) recommendations for diagnosis and management of acute myeloid leukemia (AML) in adults, published in 2010, has found broad acceptance by physicians and investigators caring for patients with AML. Recent advances, for example, in the discovery of the genomic landscape of the disease, in the development of assays for genetic testing and for detecting minimal residual disease (MRD), as well as in the development of novel antileukemic agents, prompted an international panel to provide updated evidence- and expert opinion-based recommendations. The recommendations include a revised version of the ELN genetic categories, a proposal for a response category based on MRD status, and criteria for progressive disease
“…Besides breast and ovarian cancer, this type of mutations has been found in brainstem gliomas, lung adenocarcinoma, and prostate cancer [61–67]. WIP1 truncating mutations are considerably less common than PPM1D amplifications (usually below 1%) and their occurrence was reported to further increase after chemotherapy [66]. Although gain-of-function mutations in PPM1D efficiently suppress p53 function, their pathogenic role in cancer development still needs to be experimentally tested.Fig.…”
Section: Wip1 Phosphatase As An Oncogenementioning
DNA damage response (DDR) pathway protects cells from genome instability and prevents cancer development. Tumor suppressor p53 is a key molecule that interconnects DDR, cell cycle checkpoints, and cell fate decisions in the presence of genotoxic stress. Inactivating mutations in TP53 and other genes implicated in DDR potentiate cancer development and also influence the sensitivity of cancer cells to treatment. Protein phosphatase 2C delta (referred to as WIP1) is a negative regulator of DDR and has been proposed as potential pharmaceutical target. Until recently, exploitation of WIP1 inhibition for suppression of cancer cell growth was compromised by the lack of selective small-molecule inhibitors effective at cellular and organismal levels. Here, we review recent advances in development of WIP1 inhibitors and discuss their potential use in cancer treatment.
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