Common clonal origin of chronic myelomonocytic leukemia and B-cell acute lymphoblastic leukemia in a patient with a germline <i>CHEK2</i> variant

Bazinet, Alexandre; Heath, John A.; Chong, Anne‐Sophie; Simo‐Cheyou, Estelle R.; Worme, Samantha; Polo, Barbara Rivera; Foulkes, William D.; Caplan, Stephen; Johnson, Nathalie A.; Orthwein, Alexandre; Mercier, François

doi:10.1101/mcs.a006090

Cited by 4 publications

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“…This study provides additional evidence for associations of cancers that have not been documented in the OMIM database but were reported in previous literature, including ATM with gastric and pancreatic cancer, 53,54 MSH6 with bladder cancer, 55 and CHEK2 with leukemia. [56][57][58] Notably, a recent study 59 suggested that loss of CHEK2 function increased the risk of clonal hematopoiesis of indeterminate potential, which was a risk factor for hematological malignant neoplasms. 60 Furthermore, it was found that prior cancer therapies could increase the risk of clonal hematopoiesis of indeterminate potential.…”

Section: Discussionmentioning

confidence: 99%

Association of Pathogenic Variants in Hereditary Cancer Genes With Multiple Diseases

et al. 2022

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IMPORTANCE Knowledge about the spectrum of diseases associated with hereditary cancer syndromes may improve disease diagnosis and management for patients and help to identify high-risk individuals.OBJECTIVE To identify phenotypes associated with hereditary cancer genes through a phenome-wide association study. DESIGN, SETTING, AND PARTICIPANTSThis phenome-wide association study used health data from participants in 3 cohorts. The Electronic Medical Records and Genomics Sequencing (eMERGEseq) data set recruited predominantly healthy individuals from 10 US medical centers from July 16, 2016, through February 18, 2018, with a mean follow-up through electronic health records (EHRs) of 12.7 (7.4) years. The UK Biobank (UKB) cohort recruited participants from March 15, 2006, through August 1, 2010, with a mean (SD) follow-up of 12.4 (1.0) years. The Hereditary Cancer Registry (HCR) recruited patients undergoing clinical genetic testing at Vanderbilt University Medical Center from May 1, 2012, through December 31, 2019, with a mean (SD) follow-up through EHRs of 8.8 (6.5) years.EXPOSURES Germline variants in 23 hereditary cancer genes. Pathogenic and likely pathogenic variants for each gene were aggregated for association analyses.MAIN OUTCOMES AND MEASURES Phenotypes in the eMERGEseq and HCR cohorts were derived from the linked EHRs. Phenotypes in UKB were from multiple sources of health-related data. RESULTS A total of 214 020 participants were identified, including 23 544 in eMERGEseq cohort (mean [SD] age, 47.8 [23.7] years; 12 611 women [53.6%]), 187 234 in the UKB cohort (mean [SD] age, 56.7 [8.1] years; 104 055 [55.6%] women), and 3242 in the HCR cohort (mean [SD] age, 52.5 [15.5] years; 2851 [87.9%] women). All 38 established gene-cancer associations were replicated, and 19 new associations were identified. These included the following 7 associations with neoplasms: CHEK2 with leukemia (odds ratio [OR], 3.81 [95% CI, 2.64-5.48]) and plasma cell neoplasms (OR, 3.12 [95% CI, 1.84-5.28]), ATM with gastric cancer (OR, 4.27 [95% CI,) and pancreatic cancer (OR, 4.44 [95% CI,), MUTYH (biallelic) with kidney cancer (OR, 32.28 [95% CI,), MSH6 with bladder cancer (OR, 5.63 [95% CI,), and APC with benign liver/intrahepatic bile duct tumors (OR, 52.01 [95% CI,). The remaining 12 associations with nonneoplastic diseases included BRCA1/2 with ovarian cysts (OR, 3.15 [95% CI,] and 3.12 [95% CI, 2.36-4.12], respectively), MEN1 with acute pancreatitis (OR, 33.45 [95% CI,.02]), APC with gastritis and duodenitis (OR, 4.66 [95% CI,), and PTEN with chronic gastritis (OR, 15.68 [95% CI,). CONCLUSIONS AND RELEVANCEThe findings of this genetic association study analyzing the EHRs of 3 large cohorts suggest that these new phenotypes associated with hereditary cancer genes may facilitate early detection and better management of cancers. This study highlights the potential benefits of using EHR data in genomic medicine.

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Section: Discussionmentioning

confidence: 99%

Association of Pathogenic Variants in Hereditary Cancer Genes With Multiple Diseases

et al. 2022

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“…Moreover, patient P24 had a chronic myeloid leukemia (CML), which rapidly progressed to a CD10+CD19+ lymphoid blastic crisis. Of note, Bazinet et al also described a patient with a secondary B‐ALL, after initial myelodysplastic syndrome and chronic myelomonocytic leukemia, who harbored a CHEK2 p.Tyr159His variant which impaired BRCA1 binding 35 . Taken together, p.Thr367Metfs*15 is a moderate risk variant for cancer predisposition.…”

Section: Discussionmentioning

confidence: 99%

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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Advances in molecular characterization of myeloid proliferations associated with Down syndrome

Kalev‐Zylinska

2022

Front. Genet.

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Myeloid leukemia associated with Down syndrome (ML-DS) has a unique molecular landscape that differs from other subtypes of acute myeloid leukemia. ML-DS is often preceded by a myeloproliferative neoplastic condition called transient abnormal myelopoiesis (TAM) that disrupts megakaryocytic and erythroid differentiation. Over the last two decades, many genetic and epigenetic changes in TAM and ML-DS have been elucidated. These include overexpression of molecules and micro-RNAs located on chromosome 21, GATA1 mutations, and a range of other somatic mutations and chromosomal alterations. In this review, we summarize molecular changes reported in TAM and ML-DS and provide a comprehensive discussion of these findings. Recent advances in the development of CRISPR/Cas9-modified induced pluripotent stem cell-based disease models are also highlighted. However, despite significant progress in this area, we still do not fully understand the pathogenesis of ML-DS, and there are no targeted therapies. Initial diagnosis of ML-DS has a favorable prognosis, but refractory and relapsed disease can be difficult to treat; therapeutic options are limited in Down syndrome children by their stronger sensitivity to the toxic effects of chemotherapy. Because of the rarity of TAM and ML-DS, large-scale multi-center studies would be helpful to advance molecular characterization of these diseases at different stages of development and progression.

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Common clonal origin of chronic myelomonocytic leukemia and B-cell acute lymphoblastic leukemia in a patient with a germline CHEK2 variant

Abstract: Common clonal origin of chronic myelomonocytic leukemia and B cell acute lymphoblastic leukemia in a patient with a germline CHEK2 variant

Cited by 4 publications

References 50 publications

Association of Pathogenic Variants in Hereditary Cancer Genes With Multiple Diseases

Association of Pathogenic Variants in Hereditary Cancer Genes With Multiple Diseases

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

Advances in molecular characterization of myeloid proliferations associated with Down syndrome

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