- Volume 17 Issue 7
DOI QR Code
Novel Nonsense Variants c.58C>T (p.Q20X) and c.256G>T (p.E85X) in the CHEK2 Gene Identified in Breast Cancer Patients from Balochistan
- Baloch, Abdul Hameed (Faculty of Veterinary and Animal Sciences, Lasbela University of Agriculture, Water and Marine Sciences) ;
- Khosa, Ahmad Nawaz (Faculty of Veterinary and Animal Sciences, Lasbela University of Agriculture, Water and Marine Sciences) ;
- Bangulzai, Nasrullah (Faculty of Veterinary and Animal Sciences, Lasbela University of Agriculture, Water and Marine Sciences) ;
- Shuja, Jamila (Center for Nuclear Medicine and Radiotherapy (CENAR)) ;
- Naseeb, Hafiz Khush (Center for Nuclear Medicine and Radiotherapy (CENAR)) ;
- Jan, Mohammad (Faculty of Veterinary and Animal Sciences, Lasbela University of Agriculture, Water and Marine Sciences) ;
- Marghazani, Illahi Bakhsh (Faculty of Veterinary and Animal Sciences, Lasbela University of Agriculture, Water and Marine Sciences) ;
- Kakar, Masood-ul-Haq (Faculty of Veterinary and Animal Sciences, Lasbela University of Agriculture, Water and Marine Sciences) ;
- Baloch, Dost Mohammad (Faculty of Veterinary and Animal Sciences, Lasbela University of Agriculture, Water and Marine Sciences) ;
- Cheema, Abdul Majeed (Institute of Molecular Biology and Biotechnology, the University of Lahore) ;
- Ahmad, Jamil (Department of Biotechnology, Balochistan University of Information Technology, Engineering and Management Sciences)
- Published : 2016.07.01
Breast cancer is very common and the leading cause of cancer deaths among women globally. Hereditary cases account for 5-10% of the total burden and CHEK2, which plays crucial role in response to DNA damage to promote cell cycle arrest and repair or induce apoptosis, is considered as a moderate penetrance breast cancer risk gene. Our objective in the current study was to analyze mutations in related to breast cancer. A total of 271 individuals including breast cancer patients and normal subjects were enrolled and all 14 exons of CHEK2 were amplified and sequenced. The majority of the patients (>95%) were affected with invasive ductal carcinoma (IDC), 52.1% were diagnosed with grade III tumors and 56.2% and 27.5% with advanced stages III and IV. Two novel nonsense variants i.e. c.58C>T (P.Q20X) and c.256G>T (p.E85X) at exon 1 and 2 in two breast cancer patients were identified, both novel and not reported elsewhere.
Nonsense;breast cancer;CHEK2;Balochistan;novel variants
Supported by : International Agency for Research on Cancer (IARC)
- Willems PG (2007) Susceptibility genes in breast cancer: more is less? Clin Genet. 72, 493-6. https://doi.org/10.1111/j.1399-0004.2007.00909.x
- Panda S, Isbatan A, Adami GR (2008) Modification of the ATM/ ATR directed DNA damage response state with aging and long after hepatocyte senescence induction in vivo. Mech Ageing Dev, 129, 332-40. https://doi.org/10.1016/j.mad.2008.02.014
- Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D (2011) Global cancer statistics. CA Cancer J Clin, 61, 69-90. https://doi.org/10.3322/caac.20107
- Baloch AH, Daud S, Raheem N, et al (2014). Missense mutations (p.H371Y, p.D438Y) in gene CHEK2 are associated with breast cancer risk in women of Balochistan origin. Mol Biol Rep, 41, 1103-7. https://doi.org/10.1007/s11033-013-2956-x
- Meijers-Heijboer H, van den Ouweland A, Klijn J, et al (2002) CHEK2-Breast Cancer Consortium: Low-penetrance susceptibility to breast cancer due to CHEK2*1100delC in noncarriers of BRCA1 or BRCA2 mutations. Nat Genet, 31, 55-9. https://doi.org/10.1038/ng879
- Renwick A, Thompson D, Seal S, et al (2006). Breast Cancer Susceptibility Collaboration (UK), Easton DF, Stratton MR, Rahman N: ATM mutations that cause ataxia-telangiectasia are breast cancer susceptibility alleles. Nat Genet, 38, 873-875. https://doi.org/10.1038/ng1837
- Seal S, Thompson D, Renwick A, et al (2006). Truncating mutations in the Fanconi anemia J gene BRIP1 are lowpenetrance breast cancer susceptibility alleles. Nat Genet, 38, 1239-41. https://doi.org/10.1038/ng1902
- Rahman N, Seal S, Thompson D, et al (2007). PALB2, which encodes a BRCA2-interacting protein, is a breast cancer susceptibility gene. Nat Genet, 39, 165-167. https://doi.org/10.1038/ng1959
- Vahteristo P, Bartkova J, Eerola H, et al (2002). A CHEK2 genetic variant contributing to a substantial fraction of familial breast cancer. Am J Hum Genet, 71, 432-8. https://doi.org/10.1086/341943
- Oldenburg RA, Kroeze-Jansema K, Kraan J, et al (2003). The CHEK2*1100delC variant acts as a breast cancer risk modifier in non-BRCA1/BRCA2 multiple-case families. Cancer Res. 63, 8153-7.
- Dong X, Wang L, Taniguchi K, et al (2003). Mutations in CHEK2 associated with prostate cancer risk. Am J Hum Genet, 72, 270-80. https://doi.org/10.1086/346094
- Cybulski C, Gorski B, Huzarski T, et al (2004) CHEK2 is a multiorgan cancer susceptibility gene. Am J Hum Genet. 75, 1131-5. https://doi.org/10.1086/426403
- Nevanlinna H, Bartek J (2006) The CHEK2 gene and inherited breast cancer susceptibility. Oncogene, 25, 5912-9. https://doi.org/10.1038/sj.onc.1209877
- Walsh T, Casadei S, Lee MK, et al (2011). Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing. Proc Natl Acad Sci USA, 108, 18032-7. https://doi.org/10.1073/pnas.1115052108
- Zeng Y, Forbes KC, Wu Z, et al (1998). Replication checkpoint requires phosphorylation of the phosphatase Cdc25 by Cds1 or Chk1. Nature. 395, 507-10. https://doi.org/10.1038/26766
- Lee JS, Collins KM, Brown AL, Lee CH, Chung JH (2000). hCds1-mediated phosphorylation of BRCA1 regulates the DNA damage response. Nature, 404, 201-4. https://doi.org/10.1038/35004614
- Chehab NH, Malikzay A, Appel M, Halazonetis TD (2000). Chk2/hCds1 functions as a DNA damage checkpoint in G(1) by stabilizing p53. Genes Dev, 14, 278-288.
- Falck J, Mailand N, Syljuasen RG, et al (2001). The ATM-Chk2-Cdc25A checkpoint pathway guards against radioresistant DNA synthesis. Nature, 410, 842-7. https://doi.org/10.1038/35071124
- Matsuoka S, Rotman G, Ogawa A, et al (2000). Ataxia telangiectasia-mutated phosphorylates Chk2 in vivo and in vitro. Proc Natl Acad Sci USA. 97, 10389-94. https://doi.org/10.1073/pnas.190030497
- Bartek J, Lukas J (2003). Chk1 and Chk2 kinases in checkpoint control and cancer. Cancer Cell. 3, 421-9. https://doi.org/10.1016/S1535-6108(03)00110-7
- Wu X, Webster SR and Chen J (2001). Characterization of tumorassociated chk2 mutations. J Biol Chem, 276, 2971-74. https://doi.org/10.1074/jbc.M009727200
- Weischer M, Bojesen SE, Ellervik C, et al (2008). CHEK2_1100delC genotyping for clinical assessment of breast risk: meta analysis of 26,000 patient cases and 27,000 control. J Clin Oncol, 26, 542-8. https://doi.org/10.1200/JCO.2007.12.5922
- Fletcher O, Johnson N, Dos Santos Silva I, et al (2009). Family history, genetic testing, and clinical risk prediction: pooled analysis of CHEK2 1100delC in 1,828 bilateral breast cancers and 7,030 controls. Cancer Epidemiol Biomarkers Prev, 18, 230-4. https://doi.org/10.1158/1055-9965.EPI-08-0416
- Narod SA (2010) Testing for CHEK2 in the cancer genetics clinic: ready for prime time? Clin Genet, 78, 1-7.
- Le Calvez-Kelm F, Lesueur F, Damiola F, et al (2011). Rare, evolutionarily unlikely missense substitutions in CHEK2 contribute to breast cancer susceptibility: results from a breast cancer family registry case-control mutationscreening study. Breast Cancer Res, 13, 6.
- Available online: Globocan (2012). http://globocan.iarc.fr/Default.aspx.
- Curado MP, Edwards B, Shin HR, et al (2007)\ eds. Cancer incidence in five continents. Vol. IX. Lyon, France: International Agency for Research on Cancer, 2007. (IARC scientific publications no. 160.) (Accessed December 27, 2007, at http://www-dep.iarc.fr/.)
- Hortobagyi GN, de la Garza Salazar J, Pritchard K, et al (2005). ABREAST investigators: the global breast cancer burden: variations in epidemiology and survival. Clin Breast Cancer, 6, 391-401 https://doi.org/10.3816/CBC.2005.n.043
- Ries LAG, Eisner MP, Kosary CL (2003) Cancer Statistics Review, 1975-2000. Bethesda, MD. National Cancer Institute.
- Rowan T. Chlebowski, Lewis H, et al (2009). Breast cancer after use of estrogen plus progestin in postmenopausal women. N Engl J Med, 360, 573-87. https://doi.org/10.1056/NEJMoa0807684
- Chlebowski RT, Kuller LH, Prentice RL, et al (2009). Breast cancer after use of estrogen plus progestin in postmenopausal women. N Engl J Med, 360, 573-587. https://doi.org/10.1056/NEJMoa0807684
- Gathani T, Ali R, Balkwill A, et al (2014) Ethnic differences in breast cancer incidence in England are due to differences in known risk factors for the disease: prospective study. Br J Cancer, 110, 224-9. https://doi.org/10.1038/bjc.2013.632
- Meijers-Heijboer H, van den Ouweland A, Klijn J, et al (2002). CHEK2-Breast Cancer Consortium. Low-penetrance susceptibility to breast cancer due to CHEK2*1100delC in noncarriers of BRCA1 or BRCA2 mutations. Nat Genet, 31, 55-9. https://doi.org/10.1038/ng879
- Cristofanilli M, Gonzalez-Angulo A, Sneige N, et al (2005) Invasive lobular carcinoma classic type: response to primary chemotherapy and survival outcomes. J Clin Oncol, 23, 41-8. https://doi.org/10.1200/JCO.2005.03.111
- Ludwig J (2008) Personalized therapy of sarcomas: integration of biomarkers for improved diagnosis, prognosis, and therapy Sselection. Curr Oncol Rep, 10, 329-37. https://doi.org/10.1007/s11912-008-0051-6
- Baloch A.H, Shuja J, Daud S, et al (2013) Various aspects, patterns and risk factors in breast cancer patients of balochistan. Asian Pac J Cancer Prev, 13, 4013-6.
- Desrichard A., Bidet Y., Uhrhammaer N, Bignon Yves-J (2011). CHEK2 contribution to hereditary breast cancer in non-BRCA families. Breast Cancer Res, 13, 119 https://doi.org/10.1186/bcr3062
- Mohamad S, Nurismah Md Isa1 N, Muhammad R, et al (2015). Prevalence of CHEK2 gene mutations in multiethnic cohorts of breast cancer patients in Malaysia. PLoS One, 10, 117104.
- Kuusisto KM, Bebel A, Vihinen M, et al (2011) Screening for BRCA1, BRCA2, CHEK2, PALB2, BRIP1, RAD50, and CDH1 mutations in high-risk Finnish BRCA1/2-founder mutation negative breast and/or ovarian cancer individuals. Breast Cancer Res, 13, R20. https://doi.org/10.1186/bcr2832
- Staalesen V, Falck J, Geisler S, et al (2004). Alternative splicing and mutation status of CHEK2 in stage III breast cancer. Oncogene, 23, 8535-44. https://doi.org/10.1038/sj.onc.1207928
- Chrisanthar R, Knappskog S, Lokkevik E, et al (2008). CHEK2 Mutations affecting kinase activity together with mutations in tp53indicate a functional pathway associated with resistance to epirubicin in primary breast cancer. PLoS One, 3, 3062. https://doi.org/10.1371/journal.pone.0003062