Response to DNA damage of CHEK2 missense mutations in familial breast cancer

Roeb, Wendy; Higgins, John; King, Mary Claire

doi:10.1093/hmg/dds101

Cited by 76 publications

(93 citation statements)

References 31 publications

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“…One mutation was the CHEK2 c.1100delC founder mutation, and the other mutation, p.I157T, is a missense mutation that has been demonstrated to be damaging through functional assays 17 .…”

Section: Resultsmentioning

confidence: 99%

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BRCA1, TP53, and CHEK2 germline mutations in uterine serous carcinoma

Pennington

Walsh

Liu

et al. 2012

Cancer

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104

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Background Uterine serous carcinoma (USC) is not recognized as part of any defined hereditary cancer syndrome, and its association with hereditary breast and ovarian carcinoma and Lynch syndrome are uncertain. Methods Using targeted capture and massively parallel genomic sequencing, we assessed 151 subjects with USC for germline mutations in 30 tumor suppressor genes, including BRCA1, BRCA2, the DNA mismatch repair genes (MLH1, MSH2, MSH6, PMS2), TP53, and ten other genes in the Fanconi anemia (FA)-BRCA pathway. Ten cases with <10% serous histology were also assessed. Results Seven subjects (4.6%) carried germline loss-of-function mutations: three (2.0%) in BRCA1, two (1.3%) in TP53, and two (1.3%) in CHEK2. One subject with <10% serous histology had an MSH6 mutation. Subjects with MSH6 and TP53 mutations had neither personal nor family histories suggestive of Lynch or Li-Fraumeni syndromes. Of the 22 women with USC and a personal history of breast carcinoma, the frequency of BRCA1 mutations was 9%, compared to 0.9% in 119 women with no such history. Conclusions Approximately 5% of women with USC have germline mutations in three different tumor suppressor genes: BRCA1, CHEK2, and TP53. Mutations in DNA mismatch repair genes that cause Lynch syndrome are rare in USC. The germline BRCA1 mutation rate in USC subjects of 2% is higher than expected in a non-founder population, suggesting that USC is associated with hereditary breast and ovarian carcinoma in a small proportion of cases. Women with USC and breast cancer should be offered genetic testing for BRCA1 and BRCA2 mutations.

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“…One mutation was the CHEK2 c.1100delC founder mutation, and the other mutation, p.I157T, is a missense mutation that has been demonstrated to be damaging through functional assays 17 .…”

Section: Resultsmentioning

confidence: 99%

“… † previously demonstrated to be damaging (http://research.nhgri.nih.gov/bic/) ‡ previously demonstrated to be damaging (http://www-p53.iarc.fr/) ⋄ previously demonstrated to be damaging 17 …”

Section: Tablementioning

confidence: 99%

BRCA1, TP53, and CHEK2 germline mutations in uterine serous carcinoma

Pennington

Walsh

Liu

et al. 2012

Cancer

Self Cite

104

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“…A mutation in the CHEK2 gene leads to a decrease in the DNA repair and may increase the risk of cancer [3,4]. Mutation analyses indicate that CHEK2 acts as the multiorgan cancer susceptibility gene contributing to the development of numerous cancers, including breast, colorectal, prostate, ovarian, thyroid and kidney cancer [2].…”

Section: Introductionmentioning

confidence: 99%

A Comparison between <b><i>CHEK2</i></b>*1100delC/I157T Mutation Carrier and Noncarrier Breast Cancer Patients: A Clinicopathological Analysis

Huszno

Budryk

Kołosza³

et al. 2016

Oncology

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Objective: The suppressor gene CHEK2 encodes a cell cycle checkpoint kinase, involved in cell cycle regulation, apoptosis and response to DNA damage. The aim of this study was to analyze the differences between CHEK2 mutation carriers (CHEK2*1100delC/I157T) and noncarriers with respect to clinicopathological factors. Methods: We reviewed the medical records of 100 early breast cancer patients (46 mutation carriers and 54 noncarriers) who were treated with chemotherapy, hormonotherapy or trastuzumab. Results:CHEK2 mutation carriers were older (>65 years) than noncarriers (17 vs. 7%; p = 0.215). Twenty-five (54%) of them had a history of cancer in the family. Gastric cancer in the family history was detected in 11% of mutation carriers and in 2% of noncarriers (p = 0.092). There was a trend for more frequent lymph node metastases in patients without the mutation in comparison to mutation carriers (46 vs. 28%; p = 0.098). Luminal B type breast cancer was detected more often in carriers (39 vs. 20%; p = 0.048). Breast-conserving treatment was also conducted more often in mutation carriers (57 vs. 31%; p = 0.015). Histologic grades G1/G2 were detected more frequently in mutation carriers (82 vs. 70%; p = 0.212). Conclusion: Mutation carriers were characterized by older age, a history of gastric cancer in the family, locally advanced disease, lower histologic grade and luminal B type breast cancer.

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“…In addition to in silico predictions, CHEK2 p.(T476M) was found to be damaging in a functional assay for CHEK2 variants and was weighted more strongly towards being pathogenic. [44] After weighting carriers, we found 9.1% of the replication series of pancreatic cancer cases, unselected for family history, carried a variant with potential medical impact.…”

Section: Pancreatic Cancer Unselected For Family Historymentioning

confidence: 98%

Universal Panel Testing of Pancreatic Cancer Cases for Cancer Predisposition

Young

Thompson

Neklason

et al. 2017

Preprint

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Background and AimsGenes associated with hereditary breast and ovarian cancer (HBOC) and colorectal cancer (CRC) susceptibility have been shown to play a role in pancreatic cancer susceptibility. Germline genetic testing of pancreatic cancer cases could be beneficial for at-risk relatives with pathogenic variants in established HBOC and CRC genes, but it is unclear what proportion of pancreatic cancer cases harbor pathogenic variants in these genes.Methods66 pancreatic cancer cases, unselected for family history and diagnosed at the Huntsman Cancer Hospital (HCH), were sequenced on a custom 34-gene panel including known HBOC and CRC genes. A second set of 156 unselected HCH pancreatic cancer cases were sequenced on an expanded 59-gene panel (n=95) or with a custom 14-gene clinical panel (n=61). Sequencing data from both sets of pancreatic cancer cases, the pancreatic cancer cases of the Cancer Genome Atlas (TCGA), and an unselected pancreatic cancer screen from the Mayo Clinic were combined in a meta-analysis to estimate the proportion of carriers with pathogenic and variants of uncertain significance.ResultsApproximately 8.9% of unselected pancreatic cancer cases at the HCH carried a variant with potential HBOC or CRC screening recommendations. A meta-analysis of unselected pancreatic cancer cases revealed that approximately 10.5% carry a pathogenic variant or HiP-VUS.ConclusionWith the inclusion of both HBOC and CRC susceptibility genes in a panel test, unselected pancreatic cancer cases have a high enough percentage of carriers to rationalize genetic testing for identification of variants that could be further used in cascade testing of healthy relatives to increase HBOC and CRC surveillance measures.

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Response to DNA damage of CHEK2 missense mutations in familial breast cancer

Cited by 76 publications

References 31 publications

BRCA1, TP53, and CHEK2 germline mutations in uterine serous carcinoma

BRCA1, TP53, and CHEK2 germline mutations in uterine serous carcinoma

A Comparison between <b><i>CHEK2</i></b>*1100delC/I157T Mutation Carrier and Noncarrier Breast Cancer Patients: A Clinicopathological Analysis

Universal Panel Testing of Pancreatic Cancer Cases for Cancer Predisposition

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