Top

Breast Cancer Research and Treatment

Published in:

01-05-2018 | Preclinical study

Identification and analysis of CHEK2 germline mutations in Chinese BRCA1/2-negative breast cancer patients

Authors: Zhenhua Fan, Tao Ouyang, Jinfeng Li, Tianfeng Wang, Zhaoqing Fan, Tie Fan, Benyao Lin, Ye Xu, Yuntao Xie

Published in: Breast Cancer Research and Treatment | Issue 1/2018

Abstract

Purpose

Cell-cycle-checkpoint kinase 2 (CHEK2) is an important moderate-penetrance breast cancer predisposition gene; however, recurrent CHEK2 mutations found in Caucasian women are very rare in Chinese population. We investigated the mutation spectrum and clinical relevance of CHEK2 germline mutations in Chinese breast cancer patients.

Methods

The entire coding regions and splicing sites of CHEK2 were screened in 7657 Chinese BRCA1/2-negative breast cancer patients, using 62-gene panel-based sequencing.

Results

Out of 7657 BRCA1/2-negative breast cancer patients, 26 (0.34%) carried CHEK2 pathogenic germline mutations. Most of these mutations (92.3%, 24/26) were nonsense or frameshift mutations; 84.6% (22/26) of them were in forkhead-associated (FHA) or kinase domains. Of the 18 types of CHEK2 mutations we found, 61.1% (11/18) of were novel mutations and two recurrent mutations (Y139X and R137X) were found in this cohort. Patients with CHEK2 mutations were significantly more likely to have family histories of breast and/or ovarian cancer (23.1% vs. 8.6%, p = 0.022) and family histories of any cancer (50.0% vs. 31.6%, p = 0.044); and were significantly more likely to have lymph node-positive (53.8% vs. 27.3%, p = 0.002) and progesterone receptor (PR)-positive (88.5% vs. 64.5%, p = 0.011) breast cancers.

Conclusions

Among Chinese breast cancer patients, the CHEK2 germline mutation rate is approximately 0.34% and two specific mutations (Y139X and R137X) are recurrent. Patients with CHEK2 mutations are significantly more likely to have family histories of cancer, and to develop lymph node-positive and/or PR-positive breast cancers.

Available only for authorised users

Bartek J, Falck J, Lukas J (2001) CHK2 kinase–a busy messenger. Nat Rev Mol Cell Biol 2(12):877–886. https://doi.org/10.1038/35103059 CrossRefPubMed

Bartek J, Lukas J (2003) Chk1 and Chk2 kinases in checkpoint control and cancer. Cancer Cell 3(5):421–429CrossRefPubMed

Antoni L, Sodha N, Collins I et al (2007) CHK2 kinase: cancer susceptibility and cancer therapy—two sides of the same coin? Nat Rev Cancer 7(12):925–936. https://doi.org/10.1038/nrc2251 CrossRefPubMed

Cybulski C, Wokolorczyk D, Jakubowska A et al (2011) Risk of breast cancer in women with a CHEK2 mutation with and without a family history of breast cancer. J Clin Oncol 29(28):3747–3752. https://doi.org/10.1200/jco.2010.34.0778 CrossRefPubMed

Weischer M, Bojesen SE, Ellervik C et al (2008) CHEK2*1100delC genotyping for clinical assessment of breast cancer risk: meta-analyses of 26,000 patient cases and 27,000 controls. J Clin Oncol 26(4):542–548. https://doi.org/10.1200/jco.2007.12.5922 CrossRefPubMed

Daly MB, Pilarski R, Berry M et al. (2017) NCCN Clinical practice guidelines in oncology. In: Genetic/Familial high-risk assessment: breast and ovarian version1.2018. Accessed 14 Nov 2017

Choi DH, Cho DY, Lee MH et al (2008) The CHEK2 1100delC mutation is not present in Korean patients with breast cancer cases tested for BRCA1 and BRCA2 mutation. Breast Cancer Res Treat 112(3):569–573. https://doi.org/10.1007/s10549-007-9878-z CrossRefPubMed

Liu Y, Liao J, Xu Y et al (2011) A recurrent CHEK2 p. H371Y mutation is associated with breast cancer risk in Chinese women. Hum Mutat 32(9):1000–1003. https://doi.org/10.1002/humu.21538 CrossRefPubMed

Mohamad S, Isa NM, Muhammad R et al (2015) Low prevalence of CHEK2 gene mutations in multiethnic cohorts of breast cancer patients in Malaysia. PLoS ONE 10(1):e0117104. https://doi.org/10.1371/journal.pone.0117104 CrossRefPubMedPubMedCentral

10.

Thirthagiri E, Cheong LS, Yip CH et al (2009) CHEK2*1100delC does not contribute to risk to breast cancer among Malay, Chinese and Indians in Malaysia. Fam Cancer 8(4):355–358. https://doi.org/10.1007/s10689-009-9244-x CrossRefPubMed

11.

Meijers-Heijboer H, van den Ouweland A, Klijn J et al (2002) Low-penetrance susceptibility to breast cancer due to CHEK2(*)1100delC in noncarriers of BRCA1 or BRCA2 mutations. Nat Genet 31(1):55–59. https://doi.org/10.1038/ng879 CrossRefPubMed

12.

Weischer M, Bojesen SE, Tybjaerg-Hansen A et al (2007) Increased risk of breast cancer associated with CHEK2*1100delC. J Clin Oncol 25(1):57–63. https://doi.org/10.1200/jco.2005.05.5160 CrossRefPubMed

13.

de Bock GH, Schutte M, Krol-Warmerdam EM et al (2004) Tumour characteristics and prognosis of breast cancer patients carrying the germline CHEK2*1100delC variant. J Med Genet 41(10):731–735. https://doi.org/10.1136/jmg.2004.019737 CrossRefPubMedPubMedCentral

14.

Cybulski C, Gorski B, Huzarski T et al (2006) CHEK2-positive breast cancers in young Polish women. Clin Cancer Res 12(16):4832–4835. https://doi.org/10.1158/1078-0432.ccr-06-0158 CrossRefPubMed

15.

Cybulski C, Gorski B, Huzarski T et al (2004) CHEK2 is a multiorgan cancer susceptibility gene. Am J Hum Genet 75(6):1131–1135. https://doi.org/10.1086/426403 CrossRefPubMedPubMedCentral

16.

Nevanlinna H, Bartek J (2006) The CHEK2 gene and inherited breast cancer susceptibility. Oncogene 25(43):5912–5919. https://doi.org/10.1038/sj.onc.1209877 CrossRefPubMed

17.

Kilpivaara O, Vahteristo P, Falck J et al (2004) CHEK2 variant I157T may be associated with increased breast cancer risk. Int J Cancer 111(4):543–547. https://doi.org/10.1002/ijc.20299 CrossRefPubMed

18.

Shaag A, Walsh T, Renbaum P et al (2005) Functional and genomic approaches reveal an ancient CHEK2 allele associated with breast cancer in the Ashkenazi Jewish population. Hum Mol Genet 14(4):555–563. https://doi.org/10.1093/hmg/ddi052 CrossRefPubMed

19.

Walsh T, Mandell JB, Norquist BM et al (2017) Genetic predisposition to breast cancer due to mutations other than BRCA1 and BRCA2 founder Alleles among Ashkenazi Jewish Women. JAMA Oncol. https://doi.org/10.1001/jamaoncol.2017.1996

20.

Chen W, Yurong S, Liansheng N (2008) Breast cancer low-penetrance allele 1100delC in the CHEK2 gene: not present in the Chinese familial breast cancer population. Adv Ther 25(5):496–501. https://doi.org/10.1007/s12325-008-0057-3 CrossRefPubMed

21.

Song CG, Hu Z, Yuan WT et al (2006) CHEK2 c.1100delC may not contribute to genetic background of hereditary breast cancer from Shanghai of China. Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese. J Med Genet 23(4):443–445

22.

Wang N, Ding H, Liu C et al (2015) A novel recurrent CHEK2 Y390C mutation identified in high-risk Chinese breast cancer patients impairs its activity and is associated with increased breast cancer risk. Oncogene 34(40):5198–5205. https://doi.org/10.1038/onc.2014.443 CrossRefPubMed

23.

Xie Y, Li G, Chen M et al (2017) Mutation screening of 10 cancer susceptibility genes in unselected breast cancer patients. Clin Genet. https://doi.org/10.1111/cge.13063

24.

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 Res. https://doi.org/10.1158/1078-0432.ccr-16-3227

25.

Yao L, Sun J, Zhang J et al (2016) Breast cancer risk in Chinese women with BRCA1 or BRCA2 mutations. Breast Cancer Research Treat 156(3):441–445. https://doi.org/10.1007/s10549-016-3766-3 CrossRef

26.

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

27.

Roeb W, Higgins J, King MC (2012) Response to DNA damage of CHEK2 missense mutations in familial breast cancer. Hum Mol Genet 21(12):2738–2744. https://doi.org/10.1093/hmg/dds101 CrossRefPubMedPubMedCentral

28.

Schwarz JK, Lovly CM, Piwnica-Worms H (2003) Regulation of the Chk2 protein kinase by oligomerization-mediated cis- and trans-phosphorylation. Mol Cancer Res 1(8):598–609PubMed

29.

Desrichard A, Bidet Y, Uhrhammer N et al (2011) CHEK2 contribution to hereditary breast cancer in non-BRCA families. Breast Cancer Res 13(6):R119. https://doi.org/10.1186/bcr3062 CrossRefPubMedPubMedCentral

30.

Falck J, Mailand N, Syljuasen RG et al (2001) The ATM-Chk2-Cdc25A checkpoint pathway guards against radioresistant DNA synthesis. Nature 410(6830):842–847. https://doi.org/10.1038/35071124 CrossRefPubMed

31.

Falck J, Lukas C, Protopopova M et al (2001) Functional impact of concomitant versus alternative defects in the Chk2-p53 tumour suppressor pathway. Oncogene 20(39):5503–5510. https://doi.org/10.1038/sj.onc.1204811 CrossRefPubMed

32.

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. https://doi.org/10.1136/jmedgenet-2017-104588

33.

Leedom TP, LaDuca H, McFarland R et al (2016) Breast cancer risk is similar for CHEK2 founder and non-founder mutation carriers. Cancer Genet 209(9):403–407. https://doi.org/10.1016/j.cancergen.2016.08.005 CrossRefPubMed

34.

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

35.

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 CrossRefPubMed

36.

Hallamies S, Pelttari LM, Poikonen-Saksela P et al (2017) CHEK2 c.1100delC mutation is associated with an increased risk for male breast cancer in finnish patient population. BMC Cancer 17(1):620. https://doi.org/10.1186/s12885-017-3631-8 CrossRefPubMedPubMedCentral

37.

Wasielewski M, den Bakker MA, van den Ouweland A et al (2009) CHEK2 1100delC and male breast cancer in the Netherlands. Breast Cancer Res Treat 116(2):397–400. https://doi.org/10.1007/s10549-008-0162-7 CrossRefPubMed

38.

Naslund-Koch C, Nordestgaard BG, Bojesen SE (2016) Increased risk for other cancers in addition to breast cancer for CHEK2*1100delC heterozygotes estimated From the copenhagen general population study. J Clin Oncol 34(11):1208–1216. https://doi.org/10.1200/jco.2015.63.3594 CrossRefPubMed

39.

Weischer M, Nordestgaard BG, Pharoah P et al (2012) CHEK2*1100delC heterozygosity in women with breast cancer associated with early death, breast cancer-specific death, and increased risk of a second breast cancer. J Clin Oncol 30(35):4308–4316. https://doi.org/10.1200/jco.2012.42.7336 CrossRefPubMedPubMedCentral

40.

Huszno J, Budryk M, Kolosza Z et al (2016) A comparison between CHEK2*1100delC/I157T mutation carrier and noncarrier breast cancer patients: a clinicopathological analysis. Oncol 90(4):193–198. https://doi.org/10.1159/000444326 CrossRef

41.

Schmidt MK, Hogervorst F, van Hien R et al (2016) Age- and Tumor Subtype-Specific Breast Cancer Risk Estimates for CHEK2*1100delC Carriers. J Clin Oncol 34(23):2750–2760. https://doi.org/10.1200/jco.2016.66.5844 CrossRefPubMedPubMedCentral

42.

Nagel JH, Peeters JK, Smid M et al (2012) Gene expression profiling assigns CHEK2 1100delC breast cancers to the luminal intrinsic subtypes. Breast Cancer Res Treat 132(2):439–448. https://doi.org/10.1007/s10549-011-1588-x CrossRefPubMed

43.

Baloch AH, Khosa AN, Bangulzai N et al (2016) Novel Nonsense Variants c.58C>T (p. Q20X) and c.256G>T (p.E85X) in the CHEK2 Gene Identified dentified in Breast Cancer Patients from Balochistan. Asian Pac J Cancer Prev 17(3):1089–1092CrossRefPubMed

44.

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

45.

Friedrichsen DM, Malone KE, Doody DR et al (2004) Frequency of CHEK2 mutations in a population based, case-control study of breast cancer in young women. Breast Cancer Res 6(6):R629–635. https://doi.org/10.1186/bcr933 CrossRefPubMedPubMedCentral

46.

Sodha N, Mantoni TS, Tavtigian SV et al (2006) Rare germ line CHEK2 variants identified in breast cancer families encode proteins that show impaired activation. Cancer Res 66(18):8966–8970. https://doi.org/10.1158/0008-5472.can-06-1990 CrossRefPubMed

47.

Tung N, Lin NU, Kidd J et al (2016) Frequency of Germline mutations in 25 cancer susceptibility genes in a sequential series of patients with breast cancer. J Clin Oncol 34(13):1460–1468. https://doi.org/10.1200/jco.2015.65.0747 CrossRefPubMedPubMedCentral

Title: Identification and analysis of CHEK2 germline mutations in Chinese BRCA1/2-negative breast cancer patients
Authors: Zhenhua Fan
Tao Ouyang
Jinfeng Li
Tianfeng Wang
Zhaoqing Fan
Tie Fan
Benyao Lin
Ye Xu
Yuntao Xie
Publication date: 01-05-2018
Publisher: Springer US
Published in: Breast Cancer Research and Treatment / Issue 1/2018
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI: https://doi.org/10.1007/s10549-018-4673-6

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2018

Digital image analysis of Ki67 proliferation index in breast cancer using virtual dual staining on whole tissue sections: clinical validation and inter-platform agreement

Associations of coffee consumption and caffeine intake with mammographic breast density

Surveillance for cancer recurrence in long-term young breast cancer survivors randomly selected from a statewide cancer registry

GATA-3 is superior to GCDFP-15 and mammaglobin to identify primary and metastatic breast cancer

Circulating free DNA integrity and concentration as independent prognostic markers in metastatic breast cancer

Detailed information about chemotherapy in breast control arm might affect cognitive sequelae compared with endocrine therapy patients

Keynote webinar | Spotlight on antibody–drug conjugates in cancer