Evidence against a major genetic basis for combined breast and colorectal cancer susceptibility

Brinkman, Hannah R.; Barwell, Julian; Rose, Steven J; Tinworth, Lorna; Sodha, Nayanta; Langman, Caroline; Brooks, Lucy; Payne, Stewart J.; Fisher, Samantha; Rowan, Andrew; Tomlinson, Ian; Hodgson, Shirley

doi:10.1111/j.1399-0004.2006.00711.x

Cited by 3 publications

(2 citation statements)

References 28 publications

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“…9,10 The CHEK2 Y390C variant was previously reported in a female patient who was diagnosed with colorectal cancer and endometrial cancer at 58 years and breast cancer at 63-year old. 40 The daughter of this patient was also diagnosed with breast cancer, suggesting that this variant might cause hereditary breast cancer. Importantly, our study provided additional evidence of four more incidences of familiar breast/ovarian cancers with this genotype.…”

Section: Discussionmentioning

confidence: 89%

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

et al. 2015

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Certain predisposition factors such as BRCA1/2 and CHEK2 mutations cause familial breast cancers that occur early. In China, breast cancers are diagnosed at relatively younger age, and higher percentage of patients are diagnosed before 40 years, than that in Caucasians. However, the prevalence for BRCA1/2 mutations and reported CHEK2 germline mutations is much lower or absent in Chinese population, arguing for the need to study other novel risk alleles among Chinese breast cancer patients. In this study, we searched for CHEK2 mutations in young, high-risk breast cancer patients in China and detected a missense variant Y390C (1169A > G) in 12 of 150 patients (8.0%) and 2 in 250 healthy controls (0.8%, P = 0.0002). Four of the Y390C carriers have family history of breast and/or ovarian cancer. In patients without family history, Y390C carriers tend to develop breast cancer early, before 35 years of age. The codon change at Y390, a highly conserved residue located in CHEK2's kinase domain, appeared to significantly impair CHEK2 activity. Functional analysis suggested that the CHEK2 Y390C mutation is deleterious as judged by the mutant protein's inability to inactivate CDC25A or to activate p53 after DNA damage. Cells expressing the CHEK2 Y390C variant showed impaired p21 and Puma expression after DNA damage, and the deregulated cell cycle checkpoint and apoptotic response may help conserve mutations and therefore contribute to tumorigeneisis. Taken together, our results not only identified a novel CHEK2 allele that is associated with cancer families and confers increased breast cancer risk, but also showed that this allele significantly impairs CHEK2 function during DNA damage response. Our results provide further insight on how the function of such an important cancer gene may be impaired by existing mutations to facilitate tumorigenesis. It also offers a new subject for breast cancer monitoring, prevention and management.

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Section: Discussionmentioning

confidence: 89%

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

et al. 2015

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“…Brinkmann et al. studied 97 case‐control pairs in patients with a history of breast and colorectal cancer. Using microsatellite instability analysis for the monomorphic mononucleotide markers BAT25 and BAT26 they detected no microsatellite instability in all 97 breast cancer tissue samples in the study.…”

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confidence: 99%

Loss of Mismatch Repair Protein Expression in Breast Carcinoma in Patients with Lynch Syndrome: Report of Two Cases

2013

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Prognostic Significance of CHEK2 Mutation in Progression of Breast Cancer

Ansari

Shahrabi

Khosravi

et al. 2019

Laboratory Medicine

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Breast cancer (BC) is one of the most common cancers among women; genetic mutations reflect the development of this disease. Mutations in cell signaling factors can be the main cause of BC development. In this study, we focused on mutations in checkpoint kinase 2 (CHEK2) and their impact as a prognostic factor in the pathogenesis of BC. CHEK2 is controlled in cell signaling pathways through the influence of upstream genes. Also, several downstream genes are regulated by CHEK2. In addition, mutations in CHEK2 lead to resistance of BC cells to chemotherapy and metastasis of cancer cells to other parts of the body. Finally, detection of mutations in CHEK2 can be used as a prognostic factor for patient response to treatment and for targeting downstream molecules of CHEK2 that are involved in the proliferation of breast tumor cells. Mutations such as c.1100delC and I157T can distinguish which patients are susceptible to metastasis.

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Evidence against a major genetic basis for combined breast and colorectal cancer susceptibility

Cited by 3 publications

References 28 publications

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

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

Loss of Mismatch Repair Protein Expression in Breast Carcinoma in Patients with Lynch Syndrome: Report of Two Cases

Prognostic Significance of CHEK2 Mutation in Progression of Breast Cancer

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