CHEK2 mutation in a patient with pancreatic adenocarcinoma—a rare case report

Vittal, Anusha; Saha, Debbie; Samanta, Ipsita; Kasi, Anup

doi:10.21037/acr-20-83

Cited by 4 publications

(3 citation statements)

References 19 publications

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“…CHEK2 is a multi-organ cancer predisposition gene playing an important role in cell cycle regulation and DNA damage repair, two processes involved in cancer development and response to treatment (Cybulski et al 2004 ). Recently, the Cancer Genome Atlas (TCGA) Research Network reported that CHEK2 mutations were observed in 0.7% of PanC patients (Vittal et al 2021 ). CHEK2 mutations are rare and associated with modest penetrance, so very large sample sizes are needed to identify significant relative risks (Cybulski et al 2004 ); in addition, the presence of many VUS makes sometimes it difficult to reach a conclusive genetic interpretation.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of inherited germline mutations in cancer susceptibility genes among pancreatic cancer patients: a single-center study

Tavano

Gioffreda

Fontana

et al. 2023

Mol Med

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Background Germline mutations in cancer susceptibility genes were identified in pancreatic cancer (PanC) patients with a sporadic disease and in those unselected for family cancer history. Methods With the aim to determine the prevalence of germline predisposition genes mutations in PanC, and to evaluate whether they were associated with the presence of PanC, we profiled a custom AmpliSeq panel of 27 cancer susceptibility genes in 47 PanC patients and 51 control subjects by using the Ion Torrent PGM system. Results Multigene panel testing identified a total of 31 variants in 27 PanC (57.4%), including variants with pathogenic/likely pathogenic effect, those of uncertain significance, and variants whose clinical significance remains currently undefined. Five patients carried more than one variant in the same gene or in different genes. Eight patients (17.0%) had at least one pathogenic/likely pathogenic variant in four main genes: CFTR (10.6%), BRCA2 (8.5%), ATM and CHEK2 (2.1%). Pathogenic/likely pathogenic mutation were identified in patients with positive PanC family history (20%) or in patients without first-degree relatives affected by PanC (13.6%). All the BRCA2 mutation carriers were unselected PanC patients. The presence of mutations in BRCA2 was significantly associated with an increased occurrence of PanC and with positive family history for endometrial cancer (p = 0.018). Conclusions This study confirmed the potential remarkable contribution of BRCA2 in assessing the presence of PanC. Overall our findings supported the recommendation of offering the germline testing to all the PanC patients with the intent to reduce the number of underdiagnosed carriers of mutations in predisposition genes, and not to preclude their relatives from the opportunity to benefit from surveillance programs.

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Section: Discussionmentioning

confidence: 99%

Evaluation of inherited germline mutations in cancer susceptibility genes among pancreatic cancer patients: a single-center study

Tavano

Gioffreda

Fontana

et al. 2023

Mol Med

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“…67,90 The missense variant I157T and germline mutations in CHK2 gene are involved in the development of colon cancer and pancreatic cancer. 68,69 PTEN inhibits Akt function which leads to the restriction of Mdm2 to enter into cytoplasm that eventually promotes p53 activation. Functional variations and nonsense mutations in PTEN gene were observed in gastric cancer.…”

Section: Genementioning

confidence: 99%

“…The germline mutations in CHK2 were observed in biliary cancer and the missense variants were observed in gastric cancer 67,90 . The missense variant I157T and germline mutations in CHK2 gene are involved in the development of colon cancer and pancreatic cancer 68,69 . PTEN inhibits Akt function which leads to the restriction of Mdm2 to enter into cytoplasm that eventually promotes p53 activation.…”

Section: P53‐mdm2 Axis Dynamicsmentioning

confidence: 99%

Working title: Molecular involvement of p53‐MDM2 interactome in gastrointestinal cancers

Yedla,

Bhamidipati,

Syed

et al. 2024

Cell Biochemistry & Function

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The interaction between murine double minute 2 (MDM2) and p53, marked by transcriptional induction and feedback inhibition, orchestrates a functional loop dictating cellular fate. The functional loop comprising p53‐MDM2 axis is made up of an interactome consisting of approximately 81 proteins, which are spatio‐temporally regulated and involved in DNA repair mechanisms. Biochemical and genetic alterations of the interactome result in dysregulation of the p53‐mdm2 axis that leads to gastrointestinal (GI) cancers. A large subset of interactome is well known and it consists of proteins that either stabilize p53 or MDM2 and proteins that target the p53‐MDM2 complex for ubiquitin‐mediated destruction. Upstream signaling events brought about by growth factors and chemical messengers invoke a wide variety of posttranslational modifications in p53‐MDM2 axis. Biochemical changes in the transactivation domain of p53 impact the energy landscape, induce conformational switching, alter interaction potential and could change solubility of p53 to redefine its co‐localization, translocation and activity. A diverse set of chemical compounds mimic physiological effectors and simulate biochemical modifications of the p53‐MDM2 interactome. p53‐MDM2 interactome plays a crucial role in DNA damage and repair process. Genetic aberrations in the interactome, have resulted in cancers of GI tract (pancreas, liver, colorectal, gastric, biliary, and esophageal). We present in this article a review of the overall changes in the p53‐MDM2 interactors and the effectors that form an epicenter for the development of next‐generation molecules for understanding and targeting GI cancers.

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ENIGMACHEK2gether Project: A Comprehensive Study Identifies Functionally ImpairedCHEK2Germline Missense Variants Associated with Increased Breast Cancer Risk

Stolařová

Kleiblová

Zemánková

et al. 2023

Clinical Cancer Research

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Purpose: Germline pathogenic variants in CHEK2 confer moderately elevated breast cancer risk (odds ratio, OR ∼ 2.5), qualifying carriers for enhanced breast cancer screening. Besides pathogenic variants, dozens of missense CHEK2 variants of uncertain significance (VUS) have been identified, hampering the clinical utility of germline genetic testing (GGT). Experimental Design: We collected 460 CHEK2 missense VUS identified by the ENIGMA consortium in 15 countries. Their functional characterization was performed using CHEK2-complementation assays quantifying KAP1 phosphorylation and CHK2 autophosphorylation in human RPE1–CHEK2-knockout cells. Concordant results in both functional assays were used to categorize CHEK2 VUS from 12 ENIGMA case–control datasets, including 73,048 female patients with breast cancer and 88,658 ethnicity-matched controls. Results: A total of 430/460 VUS were successfully analyzed, of which 340 (79.1%) were concordant in both functional assays and categorized as functionally impaired (N = 102), functionally intermediate (N = 12), or functionally wild-type (WT)–like (N = 226). We then examined their association with breast cancer risk in the case–control analysis. The OR and 95% CI (confidence intervals) for carriers of functionally impaired, intermediate, and WT-like variants were 2.83 (95% CI, 2.35–3.41), 1.57 (95% CI, 1.41–1.75), and 1.19 (95% CI, 1.08–1.31), respectively. The meta-analysis of population-specific datasets showed similar results. Conclusions: We determined the functional consequences for the majority of CHEK2 missense VUS found in patients with breast cancer (3,660/4,436; 82.5%). Carriers of functionally impaired missense variants accounted for 0.5% of patients with breast cancer and were associated with a moderate risk similar to that of truncating CHEK2 variants. In contrast, 2.2% of all patients with breast cancer carried functionally wild-type/intermediate missense variants with no clinically relevant breast cancer risk in heterozygous carriers.

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CHEK2 mutation in a patient with pancreatic adenocarcinoma—a rare case report

Cited by 4 publications

References 19 publications

Evaluation of inherited germline mutations in cancer susceptibility genes among pancreatic cancer patients: a single-center study

Evaluation of inherited germline mutations in cancer susceptibility genes among pancreatic cancer patients: a single-center study

Working title: Molecular involvement of p53‐MDM2 interactome in gastrointestinal cancers

ENIGMACHEK2gether Project: A Comprehensive Study Identifies Functionally ImpairedCHEK2Germline Missense Variants Associated with Increased Breast Cancer Risk

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