Differences in cancer prevalence among CHEK2 carriers identified via multi-gene panel testing

Sutcliffe, E; Stettner, Amy; Miller, Stacey A.; Solomon, Sheila; Marshall, Megan L.; Roberts, Maegan E.; Susswein, Lisa R.; Arvai, Kevin J.; Klein, Rachel T.; Murphy, Patricia D.; Hruska, Kathleen S.

doi:10.1016/j.cancergen.2020.07.001

Cited by 25 publications

(22 citation statements)

References 39 publications

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“…Aloraifi and colleagues performed a meta-analysis of protein-truncating variants in moderate-risk breast cancer genes in 2015 and cited only 12 out of 54 published CHEK2 analyses (22%) that had performed full gene scanning [ 113 ]. Recently, a spectrum of CHEK2 pathogenic/likely pathogenic variants identified in 2508 carriers analyzed by GeneDx in the USA was published by Sutcliffe and colleagues [ 114 ]. They showed that nearly 95% of all carriers have some of the 18 variants detected more than 10 times, while the remaining approximately 5% of individuals carried one of the 101 rare germline variants including 17 large intragenic rearrangements.…”

Section: Germline Chek2 Variantsmentioning

confidence: 99%

“…A full gene analysis was largely introduced with NGS panels. However, the identification of copy number variations (CNV), which represent a substantial fraction of CHEK2 germline mutations (exon 9–10 deletions (denoted also 5395del) in Slavic populations [ 115 ] and US patients [ 114 ] and exons 2–3 and 6 in Greece [ 116 ]), is still not a golden standard. Besides, pseudogene sequences homologous to exons 10–14 limited analyses in early NGS studies [ 117 , 118 ].…”

Section: Germline Chek2 Variantsmentioning

confidence: 99%

“…Besides a handful of exceptions [ 21 , 115 , 123 ], however, the published studies have only analyzed a single or a few variants, and their results were mutually concordant only in part. Therefore, a systematic analysis of CHEK2 VUS is highly desirable as rare missense variants or small in-frame deletions are frequent and they may represent 25–50% of all germline CHEK2 alterations [ 114 , 115 , 122 , 126 , 127 ].…”

Section: Germline Chek2 Variantsmentioning

confidence: 99%

“…The relatively high frequency of germline CHEK2 mutations in some populations and the dispensability of CHK2 for normal development results in identification of recessive homozygotes or compound heterozygotes carrying CHEK2 mutations at both alleles. Sutcliffe and colleagues reported 32 (1.3%) homozygotes among 2508 identified CHEK2 mutation carriers [ 114 ]. The most frequent ones were c.1100delC and p.I157T homozygotes, of whom 66% and 60% were diagnosed with BC, respectively.…”

Section: Germline Chek2 Variantsmentioning

confidence: 99%

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CHEK2 Germline Variants in Cancer Predisposition: Stalemate Rather than Checkmate

Stolařová

Kleiblová

Janatová

et al. 2020

Cells

141

101

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Germline alterations in many genes coding for proteins regulating DNA repair and DNA damage response (DDR) to DNA double-strand breaks (DDSB) have been recognized as pathogenic factors in hereditary cancer predisposition. The ATM-CHEK2-p53 axis has been documented as a backbone for DDR and hypothesized as a barrier against cancer initiation. However, although CHK2 kinase coded by the CHEK2 gene expedites the DDR signal, its function in activation of p53-dependent cell cycle arrest is dispensable. CHEK2 mutations rank among the most frequent germline alterations revealed by germline genetic testing for various hereditary cancer predispositions, but their interpretation is not trivial. From the perspective of interpretation of germline CHEK2 variants, we review the current knowledge related to the structure of the CHEK2 gene, the function of CHK2 kinase, and the clinical significance of CHEK2 germline mutations in patients with hereditary breast, prostate, kidney, thyroid, and colon cancers.

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Section: Germline Chek2 Variantsmentioning

confidence: 99%

Section: Germline Chek2 Variantsmentioning

confidence: 99%

Section: Germline Chek2 Variantsmentioning

confidence: 99%

Section: Germline Chek2 Variantsmentioning

confidence: 99%

See 2 more Smart Citations

CHEK2 Germline Variants in Cancer Predisposition: Stalemate Rather than Checkmate

Stolařová

Kleiblová

Janatová

et al. 2020

Cells

141

101

View full text Add to dashboard Cite

show abstract

“…Sutcliffe et al [ 37 ] analyzed different phenotypes of CHEK2 mutation associated with the occurrence of various malignancies. PVs in CHEK2 mutation were analyzed in 2508 patients (93% females; 83% Caucasians).…”

Section: Resultsmentioning

confidence: 99%

Recent Insights on Genetic Testing in Primary Prostate Cancer

2021

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Prostate cancer (PCa) is one of the most common cancers in developed countries. The results of large trials indicate that the proportion of PCa attributable to hereditary factors is as high as 15%, highlighting the importance of genetic testing. Despite improved understanding of the prevalence of pathogenic variants among men with PCa, it remains unclear which men will most benefit from genetic testing. In this review, we summarize recent evidence on genetic testing in primary PCa and its impact on routine clinical practice. We outline current guideline recommendations on genetic testing, most importantly, for mutations in BRCA1/2, MMR, CHEK2, PALB2, and HOXB13 genes, as well as various single nucleotide polymorphisms associated with an increased risk of developing PCa. The implementation of genetic testing in clinical practice, especially in young patients with aggressive tumors or those with positive family history, represents a new challenge for the coming years and will identify men with pathogenic variants who may benefit from early screening/intervention and specific therapeutic options. Key PointsGenetic testing is an important part of personalized diagnosis and treatment of prostate cancer (PCa).Recent clinical studies have highlighted specific genes (e.g., BRCA 1/2, PALB2, CHEK, HOXB13) and single nucleotide polymorphisms as special genes of interest.One future goal of genetic testing is to detect men harboring an increased risk of lethal PCa.

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The CHK2 kinase is recurrently mutated and functionally impaired in the germline of pediatric cancer patients

Wagener

Walter

Auer

et al. 2022

Intl Journal of Cancer

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Predisposing CHEK2 germline variants are associated with various adult‐type malignancies, whereas their impact on cancer susceptibility in childhood cancer is unclear. To understand the frequency of germline variants in the CHEK2 gene and their impact on pediatric malignancies, we used whole‐exome sequencing to search for CHEK2 variants in the germlines of 418 children diagnosed with cancer in our clinics. Moreover, we performed functional analysis of the pathogenic CHEK2 variants to analyze the effect of the alterations on CHK2 protein function. We detected a CHEK2 germline variant in 32/418 (7.7%) pediatric cancer patients and 46.8% of them had leukemia. Functional analysis of the pathogenic variants revealed that 5 pathogenic variants impaired CHK2 protein function. 6/32 patients carried one of these clearly damaging CHEK2 variants and two of them harbored a matching family history of cancer. In conclusion, we detected germline CHEK2 variants in 7.7% of all pediatric cancer patients, of which a minority but still relevant fraction of approximately 20% had a profound impact on protein expression or its phosphorylation after irradiation‐induced DNA damage. Accordingly, we conclude that CHEK2 variants increase the risk for not only adult‐onset but also pediatric cancer.

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Differences in cancer prevalence among CHEK2 carriers identified via multi-gene panel testing

Cited by 25 publications

References 39 publications

CHEK2 Germline Variants in Cancer Predisposition: Stalemate Rather than Checkmate

CHEK2 Germline Variants in Cancer Predisposition: Stalemate Rather than Checkmate

Recent Insights on Genetic Testing in Primary Prostate Cancer

The CHK2 kinase is recurrently mutated and functionally impaired in the germline of pediatric cancer patients

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