Association of Germline CHEK2 Gene Variants with Risk and Prognosis of Non-Hodgkin Lymphoma

Havránek, Ondřej; Kleiblová, Petra; Hojný, J.; Lhota, Filip; Souček, Pavel; Trněný, Marek; Kleibl, Zdeněk

doi:10.1371/journal.pone.0140819

Cited by 35 publications

(24 citation statements)

References 46 publications

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“…Until 2015, mutation analyses of the entire CHEK2 coding sequence in BC patients were performed by a high‐resolution melting analysis (HRMA) of all coding exons. LGRs were analyzed by a multiplex ligation‐dependent probe amplification (MLPA), as described previously . All OC patients’ samples, samples from BC patients enrolled since 2015, and samples from all identified CHEK2 variant carriers were analyzed by a CZECANCA panel (CZEch CAncer paNel for Clinical Application; custom‐made SeqCap EZ choice panel, Roche) targeting 219 genes with MiSeq (Illumina) NGS as described recently .…”

Section: Methodsmentioning

confidence: 99%

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

Kleiblová

Stolařová

Křížová

et al. 2019

Intl Journal of Cancer

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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.

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Section: Methodsmentioning

confidence: 99%

“…LGRs were analyzed by a multiplex ligation-dependent probe amplification (MLPA), as described previously. 33 34 The coverage uniformity enabled to evaluate CNVs at 100× average coverage. CHEK2 variants identified in patients were also sequenced at the mRNA (cDNA) level to determine a potential impact on splicing.…”

Section: Mutation Analysesmentioning

confidence: 99%

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

Kleiblová

Stolařová

Křížová

et al. 2019

Intl Journal of Cancer

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“…Cell cycle checkpoint kinase 2 (CHEK2) has been identified as a type of serine/threonine protein kinase, located in chromosome 22 q12.1 of humans and yeast. It has been confirmed as an important mediator of the DNA damage response pathway, and as a susceptibility gene in several types of cancer (16,17). As a tumor suppressor gene, CHEK2 is vital for the induction of cell cycle arrest and cell apoptosis following DNA damage.…”

Section: Introductionmentioning

confidence: 99%

Associations between mutations of the cell cycle checkpoint kinase 2 gene and gastric carcinogenesis

Hong

Shi

Zhang

et al. 2017

Molecular Medicine Reports

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Gastric cancer is the most common malignant tumor of the digestive system. The etiology of gastric cancer is complex, and susceptibility at the genetic level remains to be fully elucidated in genetic investigations. In the present study, mutations of the cell cycle checkpoint kinase 2 (CHEK2) gene and its association with gastric cancer were examined. Reverse transcription‑quantitative polymerase chain reaction technology was used to detect the expression of CHEK2 and it was found that the expression of CHEK2 was low in gastric cancer. Using sequencing analysis, it was found that the low expression level of CHEK2 was associated with expression of its mutation. The present study also established a CHEK2‑overexpressing mutant and confirmed that CHEK2 promoted gastric cancer cell proliferation. Overexpression of the CHEK2 mutation was confirmed to promote cancer cell migration and invasion. Furthermore, western blot analysis results revealed that overexpression of the CHEK2 mutation downregulated E‑cadherin and upregulated vimentin expression, indicating the mechanism underlying the altered biological behavior. These results suggested that there was a correlation between mutation of the CHEK2 gene and gastric cancer, and provided an experimental basis for antitumor drug investigation and development according to its mutation target.

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“…Contrasting the risk assessments of single amino acid substitutions of the CHEK2, it has been estimated that the 1100delC-variant confers a two-fold elevated risk of both breast cancer [ 3 ] and prostate cancer [ 1 ]. Further, another deletion variant in Eastern Europe (5395 bp deletion) has also been linked to increased breast cancer risk [ 1 , 4 , 5 ] and several germline truncating variants have been linked to Non-Hodgkin lymphoma [ 6 ].…”

Section: Discussionmentioning

confidence: 99%

“…Unlike single amino acid substitutions, the 1100delC truncation variant has been associated with an increased risk for cancer of the breast and prostate [ 1 , 3 ]. Also, a larger 5395 bp germline deletion observed in individuals of Eastern European descent, has been linked to increased risk of breast cancer [ 1 , 4 , 5 ], and recently several germline truncating CHEK2 mutations were linked to risk of Non-Hodgkin Lymphoma [ 6 ]. Taken together, these, and other data clearly indicates CHEK2 to be a multi-cancer susceptibility gene, with truncating mutation being of particular importance for some cancer types [ 7 ].…”

Section: Introductionmentioning

confidence: 99%

Prevalence of the CHEK2 R95* germline mutation

Knappskog

Leirvaag

Gansmo

et al. 2016

Hered Cancer Clin Pract

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BackgroundWhile germline CHEK2 mutations have been linked to a moderately elevated cancer risk, to date, a limited number of such mutations have been identified. Recently, we reported a germline nonsense mutation (C283T; R95*), introducing an early stop-codon, in two Norwegian patients diagnosed with locally advanced breast cancer. Both patients were resistant to anthracycline therapy, resembling what has been observed for TP53 mutations.MethodsIn the present study, we screened a large population based sample, including 3748 non-cancer individuals and 7081 incident cancer cases (breast cancer, n = 1717; prostate cancer n = 2501, lung cancer n = 1331 and colorectal cancer n = 1532), for the distribution of CHEK2 R95*.ResultsWe found that 12 individuals (0.11 %) carried the R95* variant: 4 non-cancer individuals (0.11 %), 4 breast cancer cases (0.23 %), and 4 prostate cancer cases (0.16 %). Although the low number of observations precluded formal statistical assessment, our data may indicate an elevated risk for breast (OR: 2.19, 95 % CI: 0.55–8.75) and prostate cancer (OR: 1.5, 95 % CI: 0.36–6.00) associated with CHEK2 R95*. By mining international databanks, we found no individuals carrying the R95* mutation, indicating it to be restricted to the Norwegian population.ConclusionWe provide proof-of-concept that previously unknown CHEK2 germline mutations may be present in certain populations. Notably, germline mutations in tumours are in general missed by contemporary massive parallel sequencing strategies, since tumour mutations are usually filtered against the germline. The fact that the CHEK2 R95* mutation may be associated with resistance to anthracyclines in cancer patients emphasizes its possible clinical importance.

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Association of Germline CHEK2 Gene Variants with Risk and Prognosis of Non-Hodgkin Lymphoma

Cited by 35 publications

References 46 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

Associations between mutations of the cell cycle checkpoint kinase 2 gene and gastric carcinogenesis

Prevalence of the CHEK2 R95* germline mutation

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