Prevalence and characterization of ATM germline mutations in Chinese BRCA1/2-negative breast cancer patients
- 67 Downloads
The ataxia telangiectasia-mutated (ATM) gene is a moderate susceptibility gene for breast cancer. However, little is known about the breast cancer phenotypes associated with ATM mutation. We therefore investigated the spectrum and clinical characteristics of ATM germline mutations in Chinese breast cancer patients.
A multi-gene panel was performed to screen for ATM germline mutations in 7657 BRCA1/2-negative breast cancer patients. All deleterious mutations were validated by independent polymerase chain reaction (PCR)-Sanger sequencing.
A total of 31 pathogenic mutations in the ATM gene across 30 carriers were identified, and the ATM mutation rate was 0.4% (30/7,657) in this cohort. The majority of the mutations (90.3%, 28/31) were nonsense or frameshift mutations. Of the total ATM mutations, 61.3% (19/31) were novel mutations and 13 recurrent mutations were found. ATM mutations carriers were significantly more likely to have a family history of breast and/or ovarian cancer (26.7% in carriers vs. 8.6% in non-carriers, p < 0.001), as well as a family history of any cancer (60.0% in carriers vs. 31.5% in non-carriers, p = 0.001). In addition, ATM mutations carriers were significantly more likely to have oestrogen receptor (ER)-positive (p = 0.011), progesterone receptor (PR)-positive (p = 0.040), and lymph node-positive breast cancer (p = 0.034).
The prevalence of the ATM mutation is approximately 0.4% in Chinese BRCA1/2-negative breast cancer. ATM mutation carriers are significantly more likely to have a family history of cancer and to develop ER- and/or PR-positive breast cancer or lymph node-positive breast cancer.
KeywordsATM gene Germline mutation Breast cancer Chinese population
The ataxia telangiectasia-mutated gene
One-way analysis of variance
DNA double-strand break
Human epidermal growth factor receptor 2
Poly (ADP-ribose) polymerase
Polymerase chain reaction
Triple-negative breast cancer
This study was supported by the National Natural Science Foundation of China (81772824, 81773209 and 81372832).
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
The study was conducted in accordance with Helsinki Declaration, and was approved by the Research Ethics Committee of Peking University Cancer Hospital.
Written informed consent was obtained from all participants.
- 2.Shiloh Y, Ziv Y (2013) The ATM protein kinase: regulating the cellular response to genotoxic stress, and more. Nat Rev Mol Cell Biol 14(4):197–210Google Scholar
- 10.Chenevix-Trench G, Spurdle AB, Gatei M et al (2002) Dominant negative ATM mutations in breast cancer families. J Natl Cancer Inst 94(3):205–215Google Scholar
- 13.Feng X, Li H, Dean M et al (2015) Low ATM protein expression in malignant tumor as well as cancer-associated stroma are independent prognostic factors in a retrospective study of early-stage hormone-negative breast cancer. Breast Cancer Res 17:65. https://doi.org/10.1186/s13058-015-0575-2 Google Scholar
- 16.Richards S, Aziz N, Bale S et al (2015) Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 17(5):405–424. https://doi.org/10.1038/gim.2015.30 Google Scholar
- 21.Keimling M, Volcic M, Csernok A et al (2011) Functional characterization connects individual patient mutations in ataxia telangiectasia mutated (ATM) with dysfunction of specific DNA double-strand break-repair signaling pathways. FASEB J 25(11):3849–3860. https://doi.org/10.1096/fj.11-185546 Google Scholar
- 27.Magliozzi M, Piane M, Torrente I et al (2006) DHPLC screening of ATM gene in Italian patients affected by ataxia-telangiectasia: fourteen novel ATM mutations. Dis Mark 22(4):257–264Google Scholar
- 29.Telatar M, Wang Z, Udar N et al (1996) Ataxia-telangiectasia: mutations in ATM cDNA detected by protein-truncation screening. Am J Hum Genet 59(1):40–44Google Scholar
- 30.Teraoka SN, Malone KE, Doody DR et al (2001) Increased frequency of ATM mutations in breast carcinoma patients with early onset disease and positive family history. Cancer 92(3):479–487Google Scholar
- 31.Laake K, Jansen L, Hahnemann JM et al (2000) Characterization of ATM mutations in 41 Nordic families with ataxia telangiectasia. Hum Mutat 16(3):232–246. https://doi.org/10.1002/1098-1004(200009)16:3%3C232::aid-humu6%3E3.0.co;2-l Google Scholar
- 34.Thorstenson YR, Roxas A, Kroiss R et al (2003) Contributions of ATM mutations to familial breast and ovarian cancer. Cancer Res 63(12):3325–3333Google Scholar
- 44.Daly MB, Pilarski R, Berry M et al NCCN Clinical practice guidelines in oncology. In: Genetic/Familial high-risk assessment: breast and ovarian version1.2018. Accessed 17 June 2018Google Scholar
- 51.Bang YJ, Im SA, Lee KW et al (2015) Randomized, double-blind phase II trial with prospective classification by atm protein level to evaluate the efficacy and tolerability of olaparib plus paclitaxel in patients with recurrent or metastatic gastric cancer. J Clin Oncol 33(33):3858–3865. https://doi.org/10.1200/jco.2014.60.0320 Google Scholar