<i>CHEK2</i>:1100delC and female breast cancer in the United States

Pereira, Lutécia; Sigurdson, Alice J.; Doody, Michele M.; Pineda, Marbin; Alexander, Bruce H.; Greene, Mark H.; Struewing, Jeffery P.

doi:10.1002/ijc.20439

Cited by 19 publications

(11 citation statements)

References 14 publications

(3 reference statements)

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“…Among cases, CHEK2 ‐1100delC was restricted to African–Americans, Caucasians and Latino populations, but it was not detected among Japanese or native Hawaiian groups. This is consistent with previous findings that the population frequency of this allele is variable according to geographic location ranging from 0.3 to 0.7% within the US49, 51, 52 to 1.2–1.6% within the Netherlands 9. To our knowledge this is the first report to show an increased risk of breast cancer associated with the 1100delC allele in the African–American population, as well as to demonstrate that it is infrequent among Asian, Latina and Hawaiian populations underscoring the importance of studying variants across multiple populations.…”

Section: Resultssupporting

confidence: 93%

Genetic and functional analysis of CHEK2 (CHK2) variants in multiethnic cohorts

Bell

Kim

Godwin

et al. 2007

Intl Journal of Cancer

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The CHEK2-1100delC mutation is recurrent in the population and is a moderate risk factor for breast cancer. To identify additional CHEK2 mutations potentially contributing to breast cancer susceptibility, we sequenced 248 cases with early-onset disease; functionally characterized new variants and conducted a populationbased case-control analysis to evaluate their contribution to breast cancer risk. We identified 1 additional null mutation and 5 missense variants in the germline of cancer patients. In vitro, the CHEK2-H143Y variant resulted in gross protein destabilization, while others had variable suppression of in vitro kinase activity using BRCA1 as a substrate. The germline CHEK2-1100delC mutation was present among 8/1,646 (0.5%) sporadic, 2/400 (0.5%) early-onset and 3/302 (1%) familial breast cancer cases, but undetectable amongst 2,105 multiethnic controls, including 633 from the US. CHEK2-positive breast cancer families also carried a deleterious BRCA1 mutation. 1100delC appears to be the only recurrent CHEK2 mutation associated with a potentially significant contribution to breast cancer risk in the general population. Another recurrent mutation with attenuated in vitro function, CHEK2-P85L, is not associated with increased breast cancer susceptibility, but exhibits a striking difference in frequency across populations with different ancestral histories. These observations illustrate the importance of genotyping ethnically diverse groups when assessing the impact of low-penetrance susceptibility alleles on population risk. Our findings highlight the notion that clinical testing for rare missense mutations within CHEK2 may have limited value in predicting breast cancer risk, but that testing for the 1100delC variant may be valuable in phenotypically-and geographically-selected populations. ' 2007 Wiley-Liss, Inc.Key words: CHEK2; susceptibility; breast; cancer; mutation The highly penetrant breast cancer susceptibility genes BRCA1 and BRCA2 have been linked to 80% of familial breast cancer, 1,2 but to only 10% of cases without a strong family history. [3][4][5]

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Section: Resultssupporting

confidence: 93%

Genetic and functional analysis of CHEK2 (CHK2) variants in multiethnic cohorts

Bell

Kim

Godwin

et al. 2007

Intl Journal of Cancer

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“…In our material the CHEK2 1100delC carriers were markedly younger at diagnosis compared to non-carriers, even though the difference was of borderline significance in the two groups of breast cancer cases and the material small. Several previous studies support this finding including the large pooled analysis where mutation prevalence decreased with increasing age at diagnosis [ 9 , 10 , 15 , 24 - 26 ]. Other studies have found a modest, non-significant, difference regarding age at onset and there are also negative studies including the original Dutch study [ 7 , 8 , 16 , 27 , 28 ].…”

Section: Discussionsupporting

confidence: 72%

“…In the original studies from Finland and the Netherlands the prevalence in familial breast cancer was 3.1–5.5 % [ 7 , 8 ]. The highest prevalence of CHEK2 1100delC has been reported in familial non- BRCA1/2 families also harboring colon cancer cases (18%) and in some highly selected high-risk breast cancer families (9–11%) [ 9 , 15 , 16 ]. The prevalence varies according to ethnicity and in studies mainly from Central and southern Europe, the variant, even in high-risk families, is very rare (<1%) [ 17 - 20 ].…”

Section: Discussionmentioning

confidence: 99%

CHEK2 1100delC is prevalent in Swedish early onset familial breast cancer

Margolin

Eiberg²,

Lindblom

et al. 2007

BMC Cancer

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“…Another study in the US confirmed the rare frequency of this allele in America (1.1%); however, this allele has been correlated with a risk of breast cancer 14. Similar results were obtained in South America, as the allele was also rarely observed in Brazil 15.…”

Section: Chek2*1100delcsupporting

confidence: 61%

Current perspectives on CHEK2 mutations in breast cancer

Apostolou¹,

Papasotiriou²

2017

BCTT

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Checkpoint kinase 2 (CHEK2) is a serine/threonine kinase which is activated upon DNA damage and is implicated in pathways that govern DNA repair, cell cycle arrest or apoptosis in response to the initial damage. Loss of kinase function has been correlated with different types of cancer, mainly breast cancer. CHEK2 functionality is affected by different missense or deleterious mutations. CHEK2*1100delC and I157T are most studied in populations all over the world. Although these variants have been identified in patients with breast cancer, their frequency raises doubts about their importance as risk factors. The present article reviews the recent advances in research on CHEK2 mutations, focusing on breast cancer, based on the latest experimental data.

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CHEK2:1100delC and female breast cancer in the United States

Cited by 19 publications

References 14 publications

Genetic and functional analysis of CHEK2 (CHK2) variants in multiethnic cohorts

Genetic and functional analysis of CHEK2 (CHK2) variants in multiethnic cohorts

CHEK2 1100delC is prevalent in Swedish early onset familial breast cancer

Current perspectives on CHEK2 mutations in breast cancer

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