Frequency of CHEK2*1100delC in New York breast cancer cases and controls

Offit, Kenneth; Pierce, Heather; Kirchhoff, Tomas; Kolachana, Prema; Rapaport, Beth; Gregersen, Peter K.; Johnson, Steven B.; Yossepowitch, Orit; Huang, Helen J.; Satagopan, Jaya M.; Robson, Mark E.; Scheuer, Lauren; Nafa, Khédoudja; Ellis, Nathan A.

doi:10.1186/1471-2350-4-1

Cited by 107 publications

(81 citation statements)

References 7 publications

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“…11 The prevalence of the 1100delC variant varies among populations. The frequency in other Northern European populations is approximately 1%, 11 comparable to the frequency in Finland but a lower frequency has been reported in a New York study, 24 and the variant was not found among 400 familial breast cancer patients or 400 healthy controls in a Spanish study. 25 The markedly elevated frequency of 1100delC in breast cancer cases with a strong family history suggests this mutation acts as a low-penetrance breast cancer susceptibility allele whose risk may be modified by other low penetrance breast cancer susceptibility alleles, as suggested by recent genetic epidemiological models.…”

Section: Frequency Of the I157t Variant In Breast Cancer Patientsmentioning

confidence: 78%

CHEK2 variant I157T may be associated with increased breast cancer risk

Kilpivaara

Vahteristo

Falck

et al. 2004

Intl Journal of Cancer

140

129

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Cell cycle checkpoint kinase 2 (CHEK2) is a transducer of cellular responses to DNA damage. The CHEK2 1100delC has previously been shown to be a low-penetrance breast cancer susceptibility allele. We have evaluated the role of another CHEK2 variant, I157T in the FHA domain of the gene, for association with breast cancer. I157T was found at a significantly higher frequency in the population- CHEK2 is a checkpoint kinase that plays an important role in the DNA-damage signaling network. 1 The CHEK2 protein consists of an N-terminal SQ/TQ-rich region, an FHA (fork head associated) domain and a Ser/Thr kinase domain, all of which are characteristic for the CHEK2/Rad53/Cds1 family of proteins. 2 In response to ionizing radiation-induced DNA damage, ATM (ataxia telangiectasia mutated) phosphorylates CHEK2 at multiple sites in the SQ/TQ region. 1,3 Once activated, CHEK2 is capable of phosphorylating several substrates including BRCA1, Cdc25A, Cdc25C and p53, contributing to checkpoint activation and cell cycle arrest. 1 Germ line mutations or variants in the CHEK2 gene have been reported in cancer families or patients. 4 -9 Most notably, a protein truncating mutation in exon 10 in the kinase domain of CHEK2, 1100delC that abolishes the kinase function of the CHEK2 protein, 10 has been recently shown to be strongly associated with familial breast cancer. 11,12 Another variant, I157T (470 T3 C) in the FHA domain has been previously detected in families with classical or variant Li-Fraumeni syndrome (LFS), 4 -6 in breast cancer families and patients as well as in the normal Finnish population 5,13 but its association with breast cancer risk has not been studied previously. Functional studies have indicated that the binding of p53, 14 BRCA1 15 and Cdc25A 16 by CHEK2 is deleteriously affected by the I157T mutation. We have analyzed the frequency of the I157T variant among unselected as well as familial breast cancer patients and healthy population controls. MATERIAL AND METHODS PatientsThe frequency of the I157T variant was analyzed in a series of 1,035 breast cancer patients unselected for family history, in a series of 507 patients selected for a positive family history, and in 1885 healthy population controls from the Finnish Red Cross Blood Transfusion Service. These series were used previously to determine the frequency of the CHEK2 1100delC mutation in exon 10. 12 The population based series was drawn from the Helsinki (N ϭ 627) and Tampere (N ϭ 408) University Hospitals and covers 82% (87% in Helsinki and 75% in Tampere) of all newly diagnosed breast cancer patients in these hospital districts over the period 1997-1999. 17 The familial breast cancer series includes 507 breast cancer patients (index cases of the families) from 507 BRCA1/2 mutation-negative families identified by screening of family history at the Helsinki University Central Hospital. The screening for BRCA1 and BRCA2 mutations has been described previously. 5,18 -20 This familial series includes 216 breast cancer patients with a stronger family histo...

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Section: Frequency Of the I157t Variant In Breast Cancer Patientsmentioning

confidence: 78%

CHEK2 variant I157T may be associated with increased breast cancer risk

Kilpivaara

Vahteristo

Falck

et al. 2004

Intl Journal of Cancer

140

129

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“…Highest population frequencies have been found in the Netherlands (1.3-1.6%) and in Finland Kleibl et al, 2005), Italy (0.11%, Caligo et al, 2004), USA (0.3-0.4%, Offit et al, 2003;Friedrichsen et al, 2004) and Canada (0.2%, Bernstein et al, 2006); the variant has not been detected in the Spanish population (Osorio et al, 2004).…”

Section: Chek2 In Li-fraumeni Syndromementioning

confidence: 99%

The CHEK2 gene and inherited breast cancer susceptibility

2006

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Checkpoint kinase 2 (CHEK2, Chk2) emerges as an important signal transducer of cellular responses to DNA damage and a candidate tumor suppressor whose defects contribute to molecular pathogenesis of diverse types of human malignancies, both sporadic and hereditary. Here, we briefly outline the molecular properties, regulation and physiological role of CHEK2, and review in more detail its defects that predispose to tumors, with particular emphasis on familial breast cancer. The frequency, penetrance and epidemiological as well as clinical significance of the two most studied breast cancerpredisposing variants of the CHEK2 gene, 1100delC and I157T, are highlighted in more depth, and additional CHEK2 mutations and their cancer relevance are discussed as well. These recent findings are considered also from a broader perspective of CHEK2 as the integral component of the ataxia telangiectasia-mutated-CHEK2-p53 pathway within the genome integrity maintenance system and a barrier against tumor progression. Finally, the potential value of information about the CHEK2 status in family counseling and optimizition of individualized cancer treatment is discussed.

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“…After the BRCA1 and BRCA2 proteins were cloned and their association with family breast cancer was detected (Miki Y et al, 1994;Wooster R et al, 1995), greater emphasis was placed on the candidate gene of breast cancer. The cell cycle-checkpoint kinase 2 gene, or CHEK2, was widely researched as a strong candidate gene for breast cancer susceptibility (Vahteristo et al, 2002;Sodha et al, 2002;Offit et al, 2003;CHEK2 Breast Cancer Consortium, 2004;Dufault et al, 2004;Friedrichsen et al, 2004;Mateus Pereira et al, 2004;Baeyens et al, 2005;Kleibl et al, 2005;Rashid et al, 2005;Bernstein et al, 2006;Einarsdóttir et al, 2006;Cybulski et al, 2007;Weischer et al, 2007;Zhang et al, 2008;Fletcher et al, 2009;McInerney et al, 2010;Iniesta et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

CHEK2 1100delC Variant and Breast Cancer Risk in Caucasians: A Meta-analysis Based on 25 Studies with 29,154 Cases and 37,064 Controls

Yang

Zhang²,

Wang³

et al. 2012

Asian Pacific Journal of Cancer Prevention

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Links between the CHEK2 1100delC heterozygote and breast cancer risk have been extensively explored. However, both positive and negative associations with this variant have been reported in individual studies. For a detailed assessment of the CHEK2 1100delC heterozygote and breast cancer risk, relevant studies published as recently as May 2012 were identified using PUBMED and EMBASE and selected using a priori defined criteria. The strength of the relationship between the CHEK2 1100delC variant and breast cancer risks was assessed by odds ratios (ORs) under the fixed effects model. A total of 29,154 cases and 37,064 controls from 25 case-control studies were identified in this meta-analysis. The CHEK2 1100delC heterozygote was more frequently detected in cases than in controls (1.34% versus 0.44%

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Frequency of CHEK2*1100delC in New York breast cancer cases and controls

Cited by 107 publications

References 7 publications

CHEK2 variant I157T may be associated with increased breast cancer risk

CHEK2 variant I157T may be associated with increased breast cancer risk

The CHEK2 gene and inherited breast cancer susceptibility

CHEK2 1100delC Variant and Breast Cancer Risk in Caucasians: A Meta-analysis Based on 25 Studies with 29,154 Cases and 37,064 Controls

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