nach oben

Erschienen in:

03.01.2019 | Preclinical study

Prevalence and characterization of ATM germline mutations in Chinese BRCA1/2-negative breast cancer patients

verfasst von: Ziguo Yang, Tao Ouyang, Jinfeng Li, Tianfeng Wang, Zhaoqing Fan, Tie Fan, Benyao Lin, Juan Zhang, Yuntao Xie

Erschienen in: Breast Cancer Research and Treatment | Ausgabe 3/2019

Einloggen, um Zugang zu erhalten

Abstract

Purpose

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.

Methods

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.

Results

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).

Conclusions

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.

Nur mit Berechtigung zugänglich

Lavin MF (2008) Ataxia-telangiectasia: from a rare disorder to a paradigm for cell signalling and cancer. Nat Rev Mol Cell Biol 9(10):759–769. https://doi.org/10.1038/nrm2514 CrossRefPubMed

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):197–210CrossRefPubMed

Tung N, Domchek SM, Stadler Z et al (2016) Counselling framework for moderate-penetrance cancer-susceptibility mutations. Nat Rev Clin Oncol 13(9):581–588. https://doi.org/10.1038/nrclinonc.2016.90 CrossRefPubMedPubMedCentral

Easton DF, Pharoah PD, Antoniou AC et al (2015) Gene-panel sequencing and the prediction of breast-cancer risk. N Engl J Med 372(23):2243–2257. https://doi.org/10.1056/NEJMsr1501341 CrossRefPubMedPubMedCentral

Thompson ER, Rowley SM, Li N et al (2016) Panel testing for familial breast cancer: calibrating the tension between research and clinical care. J Clin Oncol 34(13):1455–1459. https://doi.org/10.1200/jco.2015.63.7454 CrossRefPubMed

Buys SS, Sandbach JF, Gammon A et al (2017) A study of over 35,000 women with breast cancer tested with a 25-gene panel of hereditary cancer genes. Cancer 123(10):1721–1730. https://doi.org/10.1002/cncr.30498 CrossRefPubMed

Couch FJ, Shimelis H, Hu C et al (2017) Associations between cancer predisposition testing panel genes and breast cancer. JAMA Oncol 3(9):1190–1196. https://doi.org/10.1001/jamaoncol.2017.0424 CrossRefPubMedPubMedCentral

Southey MC, Goldgar DE, Winqvist R et al (2016) PALB2, CHEK2 and ATM rare variants and cancer risk: data from COGS. J Med Genet 53(12):800–811. https://doi.org/10.1136/jmedgenet-2016-103839 CrossRefPubMed

Bernstein JL, Teraoka S, Southey MC et al (2006) Population-based estimates of breast cancer risks associated with ATM gene variants c.7271T> G and c.1066-6T> G (IVS10-6T> G) from the Breast Cancer Family Registry. Hum Mutat 27(11):1122–1128. https://doi.org/10.1002/humu.20415 CrossRefPubMed

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):205–215CrossRefPubMed

11.

Li J, Jing R, Wei H et al (2018) Germline mutations in 40 cancer susceptibility genes among Chinese patients with high hereditary risk breast cancer. Int J Cancer. https://doi.org/10.1002/ijc.31601 CrossRefPubMedPubMedCentral

12.

Bueno RC, Canevari RA, Villacis RA et al (2014) ATM down-regulation is associated with poor prognosis in sporadic breast carcinomas. Ann Oncol 25(1):69–75. https://doi.org/10.1093/annonc/mdt421 CrossRefPubMed

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 CrossRefPubMedPubMedCentral

14.

Sun J, Meng H, Yao L et al (2017) Germline mutations in cancer susceptibility genes in a large series of unselected breast cancer patients. Clin Cancer 23(20):6113–6119. https://doi.org/10.1158/1078-0432.ccr-16-3227 CrossRef

15.

Yao L, Liu Y, Li Z et al (2011) HER2 and response to anthracycline-based neoadjuvant chemotherapy in breast cancer. Ann Oncol 22(6):1326–1331. https://doi.org/10.1093/annonc/mdq612 CrossRefPubMed

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 CrossRefPubMedPubMedCentral

17.

Becker-Catania SG, Chen G, Hwang MJ et al (2000) Ataxia-telangiectasia: phenotype/genotype studies of ATM protein expression, mutations, and radiosensitivity. Mol Genet Metab 70(2):122–133. https://doi.org/10.1006/mgme.2000.2998 CrossRefPubMed

18.

Mitui M, Nahas SA, Du LT et al (2009) Functional and computational assessment of missense variants in the ataxia-telangiectasia mutated (ATM) gene: mutations with increased cancer risk. Hum Mutat 30(1):12–21. https://doi.org/10.1002/humu.20805 CrossRefPubMedPubMedCentral

19.

Ziv Y, Bar-Shira A, Pecker I et al (1997) Recombinant ATM protein complements the cellular A–T phenotype. Oncogene 15(2):159–167. https://doi.org/10.1038/sj.onc.1201319 CrossRefPubMed

20.

Buzin CH, Gatti RA, Nguyen VQ et al (2003) Comprehensive scanning of the ATM gene with DOVAM-S. Hum Mutat 21(2):123–131. https://doi.org/10.1002/humu.10158 CrossRefPubMed

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 CrossRefPubMed

22.

Nakamura K, Du L, Tunuguntla R et al (2012) Functional characterization and targeted correction of ATM mutations identified in Japanese patients with ataxia-telangiectasia. Hum Mutat 33(1):198–208. https://doi.org/10.1002/humu.21632 CrossRefPubMed

23.

Kurian AW, Hare EE, Mills MA et al (2014) Clinical evaluation of a multiple-gene sequencing panel for hereditary cancer risk assessment. J Clin Oncol 32(19):2001–2009. https://doi.org/10.1200/jco.2013.53.6607 CrossRefPubMedPubMedCentral

24.

Micol R, Ben Slama L, Suarez F et al (2011) Morbidity and mortality from ataxia-telangiectasia are associated with ATM genotype. J Allergy Clin Immunol 128(2):382–389.e381. https://doi.org/10.1016/j.jaci.2011.03.052 CrossRefPubMed

25.

Lin CH, Lin WC, Wang CH et al (2010) Child with ataxia telangiectasia developing acute myeloid leukemia. J Clin Oncol 28(14):e213–e214. https://doi.org/10.1200/jco.2009.25.5067 CrossRefPubMed

26.

Jacquemin V, Rieunier G, Jacob S et al (2012) Underexpression and abnormal localization of ATM products in ataxia telangiectasia patients bearing ATM missense mutations. Eur J Hum Genet 20(3):305–312. https://doi.org/10.1038/ejhg.2011.196 CrossRefPubMed

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):257–264CrossRef

28.

Susswein LR, Marshall ML, Nusbaum R et al (2016) Pathogenic and likely pathogenic variant prevalence among the first 10,000 patients referred for next-generation cancer panel testing. Genet Med 18(8):823–832. https://doi.org/10.1038/gim.2015.166 CrossRefPubMed

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):40–44PubMedPubMedCentral

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):479–487CrossRefPubMed

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 CrossRefPubMed

32.

Barone G, Groom A, Reiman A et al (2009) Modeling ATM mutant proteins from missense changes confirms retained kinase activity. Hum Mutat 30(8):1222–1230. https://doi.org/10.1002/humu.21034 CrossRefPubMed

33.

Zhang J, Sun J, Chen J et al (2016) Comprehensive analysis of BRCA1 and BRCA2 germline mutations in a large cohort of 5931 Chinese women with breast cancer. Breast Cancer Res Treat 158(3):455–462. https://doi.org/10.1007/s10549-016-3902-0 CrossRefPubMed

34.

Thorstenson YR, Roxas A, Kroiss R et al (2003) Contributions of ATM mutations to familial breast and ovarian cancer. Cancer Res 63(12):3325–3333PubMed

35.

Renwick A, Thompson D, Seal S et al (2006) ATM mutations that cause ataxia-telangiectasia are breast cancer susceptibility alleles. Nat Genet 38(8):873–875. https://doi.org/10.1038/ng1837 CrossRefPubMed

36.

Thompson D, Duedal S, Kirner J et al (2005) Cancer risks and mortality in heterozygous ATM mutation carriers. J Natl Cancer Inst 97(11):813–822. https://doi.org/10.1093/jnci/dji141 CrossRefPubMed

37.

Decker B, Allen J, Luccarini C et al (2017) Rare, protein-truncating variants in ATM, CHEK2 and PALB2, but not XRCC2, are associated with increased breast cancer risks. J Med Genet 54(11):732–741. https://doi.org/10.1136/jmedgenet-2017-104588 CrossRefPubMed

38.

Lu HM, Li S, Black MH et al (2018) Association of breast and ovarian cancers with predisposition genes identified by large-scale sequencing. JAMA Oncol. https://doi.org/10.1001/jamaoncol.2018.2956 CrossRefPubMedPubMedCentral

39.

van Os NJ, Roeleveld N, Weemaes CM et al (2016) Health risks for ataxia-telangiectasia mutated heterozygotes: a systematic review, meta-analysis and evidence-based guideline. Clin Genet 90(2):105–117. https://doi.org/10.1111/cge.12710 CrossRefPubMed

40.

Marabelli M, Cheng SC, Parmigiani G (2016) Penetrance of ATM gene mutations in breast cancer: a meta-analysis of different measures of risk. Genet Epidemiol 40(5):425–431. https://doi.org/10.1002/gepi.21971 CrossRefPubMedPubMedCentral

41.

Swift M, Lukin JL (2008) Breast cancer incidence and the effect of cigarette smoking in heterozygous carriers of mutations in the ataxia-telangiectasia gene. Cancer Epidemiol Biomark Prev 17(11):3188–3192. https://doi.org/10.1158/1055-9965.Epi-08-0414 CrossRef

42.

Dombernowsky SL, Weischer M, Allin KH et al (2008) Risk of cancer by ATM missense mutations in the general population. J Clin Oncol 26(18):3057–3062. https://doi.org/10.1200/jco.2007.14.6613 CrossRefPubMed

43.

Helgason H, Rafnar T, Olafsdottir HS et al (2015) Loss-of-function variants in ATM confer risk of gastric cancer. Nat Genet 47(8):906–910. https://doi.org/10.1038/ng.3342 CrossRefPubMed

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 2018

45.

Renault AL, Mebirouk N, Fuhrmann L et al (2018) Morphology and genomic hallmarks of breast tumours developed by ATM deleterious variant carriers. Breast Cancer Res 20(1):28. https://doi.org/10.1186/s13058-018-0951-9 CrossRefPubMedPubMedCentral

46.

Choi M, Kipps T, Kurzrock R (2016) ATM Mutations in cancer: therapeutic implications. Mol Cancer Ther 15(8):1781–1791. https://doi.org/10.1158/1535-7163.Mct-15-0945 CrossRefPubMed

47.

Williamson CT, Muzik H, Turhan AG et al (2010) ATM deficiency sensitizes mantle cell lymphoma cells to poly(ADP-ribose) polymerase-1 inhibitors. Mol Cancer Ther 9(2):347–357. https://doi.org/10.1158/1535-7163.Mct-09-0872 CrossRefPubMedPubMedCentral

48.

Kubota E, Williamson CT, Ye R et al (2014) Low ATM protein expression and depletion of p53 correlates with olaparib sensitivity in gastric cancer cell lines. Cell Cycle 13(13):2129–2137. https://doi.org/10.4161/cc.29212 CrossRefPubMedPubMedCentral

49.

Gilardini Montani MS, Prodosmo A, Stagni V et al (2013) ATM-depletion in breast cancer cells confers sensitivity to PARP inhibition. J Exp Clin Cancer Res 32:95. https://doi.org/10.1186/1756-9966-32-95 CrossRefPubMedPubMedCentral

50.

Weston VJ, Oldreive CE, Skowronska A et al (2010) The PARP inhibitor olaparib induces significant killing of ATM-deficient lymphoid tumor cells in vitro and in vivo. Blood 116(22):4578–4587. https://doi.org/10.1182/blood-2010-01-265769 CrossRefPubMed

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 CrossRefPubMed

52.

Mateo J, Carreira S, Sandhu S et al (2015) DNA-Repair defects and olaparib in metastatic prostate cancer. N Engl J Med 373(18):1697–1708. https://doi.org/10.1056/NEJMoa1506859 CrossRefPubMedPubMedCentral

Titel: Prevalence and characterization of ATM germline mutations in Chinese BRCA1/2-negative breast cancer patients
verfasst von: Ziguo Yang
Tao Ouyang
Jinfeng Li
Tianfeng Wang
Zhaoqing Fan
Tie Fan
Benyao Lin
Juan Zhang
Yuntao Xie
Publikationsdatum: 03.01.2019
Verlag: Springer US
Erschienen in: Breast Cancer Research and Treatment / Ausgabe 3/2019
Print ISSN: 0167-6806
Elektronische ISSN: 1573-7217
DOI: https://doi.org/10.1007/s10549-018-05124-5

Neu im Fachgebiet Onkologie

19.04.2024 | EAU 2024 | Kongressbericht | Nachrichten

Live-Webinar: Aktuelle Leitlinien bei Herz-Kreislauf-Erkrankungen

Springer Medizin

Prevalence and characterization of ATM germline mutations in Chinese BRCA1/2-negative breast cancer patients

Abstract

Purpose

Methods

Results

Conclusions

Neu im Fachgebiet Onkologie

Prostatakarzinom: EU initiiert neues Screeningkonzept

Blasenkarzinom – Biomarker statt Zytologie?

Stereotaktische Radiatio schlägt konventionelle Bestrahlung

Adjuvante Brustkrebstherapie: Doppelt hält besser

Update Onkologie

Live-Webinar: Aktuelle Leitlinien bei Herz-Kreislauf-Erkrankungen

Springer Medizin

Abstract

Purpose

Methods

Results

Conclusions

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 3/2019

National consensus recommendations on patient-centered care for ductal carcinoma in situ

A common Chk1-dependent phenotype of DNA double-strand break suppression in two distinct radioresistant cancer types

Comparative efficacy of palbociclib, ribociclib and abemaciclib for ER+ metastatic breast cancer: an adjusted indirect analysis of randomized controlled trials

Palbociclib and endocrine therapy in heavily pretreated hormone receptor-positive HER2-negative advanced breast cancer: the UK Compassionate Access Programme experience

Epithelial-to-mesenchymal transition status of primary breast carcinomas and its correlation with metastatic behavior

Efficacy and safety of dasatinib with trastuzumab and paclitaxel in first line HER2-positive metastatic breast cancer: results from the phase II GEICAM/2010-04 study

Neu im Fachgebiet Onkologie

Prostatakarzinom: EU initiiert neues Screeningkonzept

Blasenkarzinom – Biomarker statt Zytologie?

Stereotaktische Radiatio schlägt konventionelle Bestrahlung

Adjuvante Brustkrebstherapie: Doppelt hält besser

Update Onkologie