Detectible Mosaic Truncating PPM1D Mutations, Age and Breast Cancer Risk

Overview

Journal J Hum Genet

Specialty Genetics

Date 2019 Mar 10

PMID 30850729

Citations 4

Authors

Mitchell J Machiela

Timothy A Myers

Christopher J Lyons

Roelof Koster

William D Figg Jr

Leandro M Colli

Lea Jessop

Thomas U Ahearn

Neal D Freedman

Montserrat Garcia-Closas

Stephen J Chanock

Affiliations

Soon will be listed here.

Abstract

Mosaic protein truncating variants (PTVs) in the phosphatase, Mg2+/Mn2+dependent 1D (PPM1D) gene in blood-derived DNA have been associated with increased risk of breast cancer. We analyzed PPM1D PTVs in blood from 3817 breast cancer cases and 3058 controls by deep sequencing of a previously defined region in exon 6 of PPM1D. We identified 50 of 6875 (0.73%) participants having a mosaic PPM1D PTV. We observed a higher frequency of mosaic PPM1D PTVs with increasing age (P = 2.9 × 10). We did not observe an overall association between PPM1D PTVs and increased breast cancer risk (OR = 1.51, 95% CI = 0.84-2.71). Evidence for an association was observed in a subset of cases with DNA collected 1-year or more before breast cancer diagnosis (OR = 3.44, 95% CI = 1.62-7.30, P-value = 0.001); however, no significant association was observed for the larger series of cases with DNA collected post diagnosis (OR = 1.01, 95% CI = 0.51-2.01, P-value = 0.98). Our study indicates that the PPM1D PTVs are present at higher rates than previously reported and the frequency of PPM1D PTVs increases with age. We observed limited evidence for an association between mosaic PPM1D PTVs and breast cancer risk, suggesting mosaic PPM1D PTVs in the blood likely do not influence risk of breast cancer.

Citing Articles

Jansen-de Vries syndrome: Expansion of the PPM1D clinical and phenotypic spectrum in 34 families.

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PMID: 37183572 PMC: 10330231. DOI: 10.1002/ajmg.a.63226.

Clonal hematopoiesis due to mosaic chromosomal alterations: Impact on disease risk and mortality.

Hubbard A, Brown D, Machiela M Leuk Res. 2023; 126:107022.

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PPM1D in Solid and Hematologic Malignancies: Friend and Foe?.

Zhang L, Hsu J, Goodell M Mol Cancer Res. 2022; 20(9):1365-1378.

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Large-scale analysis of acquired chromosomal alterations in non-tumor samples from patients with cancer.

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