Identification and analysis of CHEK2 germline mutations in Chinese BRCA1/2-negative breast cancer patients

Ouyang, Tao; Li, Jinfeng; Wang, Tianfeng; Fan, Zhaoqing; Fan, Tie; Lin, Benyao; Xu, Ye; Xie, Yuntao

doi:10.1007/s10549-018-4673-6

Cited by 10 publications

(11 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…A strongly increased frequency of second cancers of various origin in CHEK2 mutation carriers and tumors in their relatives corresponds to documented multiorgan cancer susceptibility in CHEK2 mutations carriers and indicates that family cancer history associated with CHEK2 mutations must be reconsidered to facilitate the selection of potential CHEK2 mutation carriers for genetic analyses.…”

Section: Discussionsupporting

confidence: 83%

“…The effect of coincidental alterations in other moderatepenetrance CPG with CHEK2 mutations are unknown; however, the influence of a polygenic risk score on c.1100delC penetrance has been recently documented. 56 A strongly increased frequency of second cancers of various origin in CHEK2 mutation carriers and tumors in their relatives corresponds to documented multiorgan cancer susceptibility in CHEK2 mutations carriers 5,25 and indicates that family cancer history associated with CHEK2 mutations must be reconsidered to facilitate the selection of potential CHEK2 mutation carriers for genetic analyses.…”

Section: Discussionmentioning

confidence: 99%

“…Our analysis confirmed proposed "CHEK2 mutation-specific" tumor phenotype, characterized by premenopausal, ductal, grade 2, luminal A or luminal B/HER2-negative tumors, reported in other studies. 25,26,46,55 These tumor characteristics lost in carriers of coincidental BRCA1/BRCA2 mutations having a stronger effect on tumor phenotype. Nurmi et al 42 identified an additive effect of mutations in moderate-penetrance genes, including CHEK2, increasing BC risk in Finnish BRCA1/BRCA2 mutation carriers.…”

Section: Discussionmentioning

confidence: 99%

“…Only few early studies analyzed the entire CHEK2 coding sequence and revealed that c.1100delC and p.I157T represent only a fraction of CHEK2 variants in BC patients . Recent panel NGS analyses in large cohorts have shown that the CHEK2 mutation rate is one of the highest among non‐ BRCA1/BRCA2 genes in BC in individuals of Ashkenazi Jewish or European ancestry . However, the classification of most missense variants remains uncertain, their assessment is problematic, and nearly one‐third of CHEK2 variants are reported discordantly …”

Section: Introductionmentioning

confidence: 99%

“…[19][20][21][22] Recent panel NGS analyses in large cohorts have shown that the CHEK2 mutation rate is one of the highest among non-BRCA1/BRCA2 genes in BC in individuals of Ashkenazi Jewish or European ancestry. [23][24][25][26] However, the classification of most missense variants remains uncertain, 27 their assessment is problematic, 4 and nearly one-third of CHEK2 variants are reported discordantly. 28 In contrast to BC, the association of CHEK2 germline variants with OC risk is disputable.…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

Identification of deleterious germline CHEK2 mutations and their association with breast and ovarian cancer

Kleiblová

Stolařová

Křížová

et al. 2019

Intl Journal of Cancer

View full text Add to dashboard Cite

Germline mutations in checkpoint kinase 2 (CHEK2), a multiple cancer‐predisposing gene, increase breast cancer (BC) risk; however, risk estimates differ substantially in published studies. We analyzed germline CHEK2 variants in 1,928 high‐risk Czech breast/ovarian cancer (BC/OC) patients and 3,360 population‐matched controls (PMCs). For a functional classification of VUS, we developed a complementation assay in human nontransformed RPE1‐CHEK2‐knockout cells quantifying CHK2‐specific phosphorylation of endogenous protein KAP1. We identified 10 truncations in 46 (2.39%) patients and in 11 (0.33%) PMC (p = 1.1 × 10−14). Two types of large intragenic rearrangements (LGR) were found in 20/46 mutation carriers. Truncations significantly increased unilateral BC risk (OR = 7.94; 95%CI 3.90–17.47; p = 1.1 × 10−14) and were more frequent in patients with bilateral BC (4/149; 2.68%; p = 0.003), double primary BC/OC (3/79; 3.80%; p = 0.004), male BC (3/48; 6.25%; p = 8.6 × 10−4), but not with OC (3/354; 0.85%; p = 0.14). Additionally, we found 26 missense VUS in 88 (4.56%) patients and 131 (3.90%) PMC (p = 0.22). Using our functional assay, 11 variants identified in 15 (0.78%) patients and 6 (0.18%) PMC were scored deleterious (p = 0.002). Frequencies of functionally intermediate and neutral variants did not differ between patients and PMC. Functionally deleterious CHEK2 missense variants significantly increased BC risk (OR = 3.90; 95%CI 1.24–13.35; p = 0.009) and marginally OC risk (OR = 4.77; 95%CI 0.77–22.47; p = 0.047); however, carriers low frequency will require evaluation in larger studies. Our study highlights importance of LGR detection for CHEK2 analysis, careful consideration of ethnicity in both cases and controls for risk estimates, and demonstrates promising potential of newly developed human nontransformed cell line assay for functional CHEK2 VUS classification.

show abstract

Section: Discussionsupporting

confidence: 83%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Identification of deleterious germline CHEK2 mutations and their association with breast and ovarian cancer

Kleiblová

Stolařová

Křížová

et al. 2019

Intl Journal of Cancer

View full text Add to dashboard Cite

show abstract

A novel CHEK2 variant identified by next generation sequencing in an Indian family with hereditary breast cancer syndrome

et al. 2019

View full text Add to dashboard Cite

Identification of CHEK2 Germline Mutations in BRCA1/2- and PALB2-Negative Breast and Ovarian Cancer Patients

et al. 2022

View full text Add to dashboard Cite

Introduction: The CHEK2 gene is known to be an important signal transducer involved in DNA repair, apoptosis, or cell cycle arrest in response to DNA damage. The mutations in this gene have been associated with a wide range of cancers, both sporadic and hereditary. Germline CHEK2 mutations are linked to an increased risk of breast cancer. Therefore, the aim of this study was to identify the prevalence of CHEK2 variants in BRCA1/2 and PALB2 negative early-onset patients with breast cancer and/or ovarian cancer in a Turkish population for the first time. Methods: The study included 95 patients with BRCA1/2 and PALB2 negative early-onset breast cancer and/or ovarian cancer and also 60 unaffected women. All the intron/exon boundaries and coding exons of CHEK2 were subjected to mutational analysis by heteroduplex analysis and DNA sequencing. Results: A total of 16 CHEK2 variants were found in breast cancer patients within the Turkish population. CHEK2 c.1100delC mutation studied in the CHEK2 gene most frequently was not detected in our study. The prevalence of variants of uncertain significance in CHEK2 was found to be 7.3% (n= 7) in BRCA1/2 and PALB2 mutation negative Turkish patients with early-onset breast and/or ovarian cancer. Discussion/Conclusion: The present study may shed light on alternative variations that could be significant for understanding the prevalence and clinical suitability of the CHEK2 gene.

show abstract

Identification and analysis of CHEK2 germline mutations in Chinese BRCA1/2-negative breast cancer patients

Cited by 10 publications

References 44 publications

Identification of deleterious germline CHEK2 mutations and their association with breast and ovarian cancer

Identification of deleterious germline CHEK2 mutations and their association with breast and ovarian cancer

A novel CHEK2 variant identified by next generation sequencing in an Indian family with hereditary breast cancer syndrome

Identification of <b><i>CHEK2</i></b> Germline Mutations in <b><i>BRCA1/2-</i></b> and <b><i>PALB2</i></b>-Negative Breast and Ovarian Cancer Patients

Contact Info

Product

Resources

About