Somatic mosaic mutations in PPM1D and TP53 in the blood of women with ovarian carcinoma

Elizabeth M. Swisher, Maria I. Harrell, Barbara M. Norquist, Tom Walsh, Mark Brady, Ming 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

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)370-372
Number of pages3
JournalJAMA oncology
Volume2
Issue number3
DOIs
StatePublished - Mar 1 2016

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Ovarian Neoplasms
Carcinoma
Mutation
Drug Therapy
Blood Cells
Lung Neoplasms
Odds Ratio
High-Throughput Nucleotide Sequencing
Clone Cells
Breast Neoplasms
Neoplasms

ASJC Scopus subject areas

  • Medicine(all)

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Swisher, E. M., Harrell, M. I., Norquist, B. M., Walsh, T., Brady, M., Lee, M., ... Birrer, M. J. (2016). Somatic mosaic mutations in PPM1D and TP53 in the blood of women with ovarian carcinoma. JAMA oncology, 2(3), 370-372. https://doi.org/10.1001/jamaoncol.2015.6053

Somatic mosaic mutations in PPM1D and TP53 in the blood of women with ovarian carcinoma. / Swisher, Elizabeth M.; Harrell, Maria I.; Norquist, Barbara M.; Walsh, Tom; Brady, Mark; Lee, Ming; Hershberg, Robert; Kalli, Kimberly R.; Lankes, Heather; Konnick, Eric Q.; Pritchard, Colin C.; Monk, Bradley J.; Chan, John K.; Burger, Robert; Kaufmann, Scott H; Birrer, Michael J.

In: JAMA oncology, Vol. 2, No. 3, 01.03.2016, p. 370-372.

Research output: Contribution to journalArticle

Swisher, EM, Harrell, MI, Norquist, BM, Walsh, T, Brady, M, Lee, M, Hershberg, R, Kalli, KR, Lankes, H, Konnick, EQ, Pritchard, CC, Monk, BJ, Chan, JK, Burger, R, Kaufmann, SH & Birrer, MJ 2016, 'Somatic mosaic mutations in PPM1D and TP53 in the blood of women with ovarian carcinoma', JAMA oncology, vol. 2, no. 3, pp. 370-372. https://doi.org/10.1001/jamaoncol.2015.6053
Swisher EM, Harrell MI, Norquist BM, Walsh T, Brady M, Lee M et al. Somatic mosaic mutations in PPM1D and TP53 in the blood of women with ovarian carcinoma. JAMA oncology. 2016 Mar 1;2(3):370-372. https://doi.org/10.1001/jamaoncol.2015.6053
Swisher, Elizabeth M. ; Harrell, Maria I. ; Norquist, Barbara M. ; Walsh, Tom ; Brady, Mark ; Lee, Ming ; Hershberg, Robert ; Kalli, Kimberly R. ; Lankes, Heather ; Konnick, Eric Q. ; Pritchard, Colin C. ; Monk, Bradley J. ; Chan, John K. ; Burger, Robert ; Kaufmann, Scott H ; Birrer, Michael J. / Somatic mosaic mutations in PPM1D and TP53 in the blood of women with ovarian carcinoma. In: JAMA oncology. 2016 ; Vol. 2, No. 3. pp. 370-372.
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abstract = "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.",
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T1 - Somatic mosaic mutations in PPM1D and TP53 in the blood of women with ovarian carcinoma

AU - Swisher, Elizabeth M.

AU - Harrell, Maria I.

AU - Norquist, Barbara M.

AU - Walsh, Tom

AU - Brady, Mark

AU - Lee, Ming

AU - Hershberg, Robert

AU - Kalli, Kimberly R.

AU - Lankes, Heather

AU - Konnick, Eric Q.

AU - Pritchard, Colin C.

AU - Monk, Bradley J.

AU - Chan, John K.

AU - Burger, Robert

AU - Kaufmann, Scott H

AU - Birrer, Michael J.

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N2 - 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.

AB - 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.

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