Increasing evidence that germline mutations in<i>CHEK2</i>do not cause Li-Fraumeni syndrome

Sodha, Nayanta; Houlston, Richard S.; Bullock, Sarah; Yuille, Martin; Chu, Carol; Turner, Gwen; Eeles, Rosalind

doi:10.1002/humu.10136

Cited by 51 publications

(27 citation statements)

References 7 publications

(12 reference statements)

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“…The CHEK2:1100delC mutation was initially identified in a Li-Fraumeni syndrome family, 1 but the association between the 2 has not generally been verified in later studies. 15 The fact that this subject with osteosarcoma was mutation-negative further underscores the tenuous link between Li-Fraumeni syndrome and the CHEK2 gene. One proband had ovarian and thyroid cancer primaries in addition to breast cancer, but none of the 5 controls from the breast cancer case-control series with ovarian or thyroid cancer was positive, nor were the 6 breast cancer cases from the case-control series who also had ovarian, colon, or thyroid cancer.…”

mentioning

confidence: 83%

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

Pereira

Sigurdson

Doody

et al. 2004

Intl Journal of Cancer

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mentioning

confidence: 83%

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

Pereira

Sigurdson

Doody

et al. 2004

Intl Journal of Cancer

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“…The 1100delC mutation was also discovered in two breast cancer patients with a cancer family history not typical of LFS or LFL (Vahteristo et al, 2001). Screening of LFS or LFL families (Bougeard et al, 2001;Lee et al, 2001;Vahteristo et al, 2001;Sodha et al, 2002b) has revealed no or very rare individual missense variants in the CHEK2 gene and also the 1100delC variant has been found rare among LFS/LFL patients (Siddiqui et al, 2005). Although some of the variants identified in LFS/LFL families were also shown to have functional effect on CHEK2 (Lee et al, 2001) the evidence from different studies suggests that CHEK2 is not a predisposition gene to Li-Fraumeni 1100delC -a low-penetrance breast cancer predisposition allele Based on segregation analysis of data from both a population-based series of breast cancer cases and highrisk families in the UK Antoniou et al (2002) suggested that several common, low-penetrance genes with multiplicative effects on risk may account for the residual non-BRCA1/2 familial aggregation of breast cancer.…”

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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“…We have previously reported four rare, novel, germ line mutations in families with more than two breast cancer cases: delE161, R117G, R137Q, and R180H (9,11). To characterize these mutations, both bioinformatic and biochemical investigations were undertaken.…”

Section: Introductionmentioning

confidence: 99%

Rare Germ Line CHEK2 Variants Identified in Breast Cancer Families Encode Proteins That Show Impaired Activation

et al. 2006

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Germ line mutations in CHEK2, the gene that encodes the Chk2 serine/threonine kinase activated in response to DNA damage, have been found to confer an increased risk of some cancers. We have previously reported the presence of the common deleterious 1100delC and four rare CHEK2 mutations in inherited breast cancer. Here, we report that predictions made by bioinformatic analysis on the rare mutations indicate that two of these, delE161 (483-485delAGA) and R117G, are likely to be deleterious. We show that the proteins encoded by 1100delC and delE161 are both unstable and inefficiently phosphorylated at Thr 68 in response to DNA damage, a step necessary for the oligomerization of Chk2. Oligomerization is in turn necessary for additional phosphorylation and full activation of the protein. A second rare mutation, R117G, is phosphorylated at Thr 68 but fails to show a mobility shift on DNA damage, suggesting that it fails to become further phosphorylated and hence fully activated. Our results indicate that delE161 and R117G encode nonfunctional proteins and are therefore likely to be pathogenic. The findings from the biochemical analysis correlate well with predictions made by bioinformatics analysis. In addition, the results imply that these mutations, as well as 1100delC, cannot act in a dominant-negative manner to cause cancer, and tumorigenesis in association with these mutations may be due to haploinsufficiency. (Cancer Res 2006; 66(18): 8966-70)

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Increasing evidence that germline mutations inCHEK2do not cause Li-Fraumeni syndrome

Cited by 51 publications

References 7 publications

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

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

The CHEK2 gene and inherited breast cancer susceptibility

Rare Germ Line CHEK2 Variants Identified in Breast Cancer Families Encode Proteins That Show Impaired Activation

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