Germline CHEK2 and ATM Variants in Myeloid and Other Hematopoietic Malignancies

Stubbins, Ryan J.; Korotev, Sophia C.; Godley, Lucy A.

doi:10.1007/s11899-022-00663-7

Cited by 18 publications

(10 citation statements)

References 97 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Mutations in CHEK2 have been reported to have a moderate risk of BC. We have obtained three mutations in CHEK2 , i.e., CHEK2 p.W114L , p.R180C , and p.M314I, in which the first two mutations are located in the region referred to as forkhead-associated domain (FHA) located approximately from 113 to 180 residues, whereas CHEK2 p.M314I is located in the kinase domain that further activates the downstream effector proteins ( Stubbins et al, 2022 ). The FHA domain is responsible for CHEK2 dimerization in a phosphorylation-dependent manner ( Durocher and Jackson, 2002 ), which is considered important for full activation of CHEK2 by trans-phosphorylation within the kinase domain ( Kleibl et al, 2008 ).…”

Section: Discussionmentioning

confidence: 99%

Clinico-genomic findings, molecular docking, and mutational spectrum in an understudied population with breast cancer patients from KP, Pakistan

Ahmad,

Ali,

Khalil

et al. 2024

Front. Genet.

View full text Add to dashboard Cite

In this study, we report the mutational profiles, pathogenicity, and their association with different clinicopathologic and sociogenetic factors in patients with Pashtun ethnicity for the first time. A total of 19 FFPE blocks of invasive ductal carcinoma (IDC) from the Breast Cancer (BC) tissue and 6 normal FFPE blocks were analyzed by whole-exome sequencing (WES). Various somatic and germline mutations were identified in cancer-related genes, i.e., ATM, CHEK2, PALB2, and XRCC2. Among a total of 18 mutations, 14 mutations were somatic and 4 were germline. The ATM gene exhibited the maximum number of mutations (11/18), followed by CHEK2 (3/18), PALB2 (3/18), and XRCC2 (1/18). Except one frameshift deletion, all other 17 mutations were nonsynonymous single-nucleotide variants (SNVs). SIFT prediction revealed 7/18 (38.8%) mutations as deleterious. PolyPhen-2 and MutationTaster identified 5/18 (27.7%) mutations as probably damaging and 10/18 (55.5%) mutations as disease-causing, respectively. Mutations like PALB2 p.Q559R (6/19; 31.5%), XRCC2 p.R188H (5/19; 26.31%), and ATM p.D1853N (4/19; 21.05%) were recurrent mutations and proposed to have a biomarker potential. The protein network prediction was performed using GeneMANIA and STRING. ISPRED-SEQ indicated three interaction site mutations which were further used for molecular dynamic simulation. An average increase in the radius of gyration was observed in all three mutated proteins revealing their perturbed folding behavior. Obtained SNVs were further correlated with various parameters related to the clinicopathological status of the tumors. Three mutation positions (ATMp. D1853N, CHEK2 p.M314I, and PALB2 p.T1029S) were found to be highly conserved. Finally, the wild- and mutant-type proteins were screened for two drugs: elagolix (DrugBank ID: DB11979) and LTS0102038 (a triterpenoid, isolated from the anticancer medicinal plant Fagonia indica). Comparatively, a higher number of interactions were noted for normal ATM with both compounds, as compared to mutants.

show abstract

Section: Discussionmentioning

confidence: 99%

Clinico-genomic findings, molecular docking, and mutational spectrum in an understudied population with breast cancer patients from KP, Pakistan

Ahmad,

Ali,

Khalil

et al. 2024

Front. Genet.

View full text Add to dashboard Cite

show abstract

“…Not surprisingly, emerging evidence also supports the association of certain CHEK2 gene mutations with myeloid and lymphoid malignancies. LoF CHEK2 mutations are now increasingly recognized as risk factors for myeloid malignancies (myeloproliferative neoplasms, myelodysplastic syndromes, and acute myeloid leukemia) (8,9). Interestingly, pre-clinical murine models suggest a role of CHEK2 mutations (CHEK2 c.1100delC allele) in development of hematopoietic malignancies besides other solid tumors like breast and lung cancer (10).…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, in our patient with NGS negative remission, we have taken the approach of close monitoring with NGS testing without pursuing HCT. In the future, novel agents like poly (ADP-ribose) polymerase (PARP) inhibitors may be a potential therapeutic option for patients with ATM or CHEK2 mutation associated malignancies (8). The patient's fraternal twin and mother have also undergone genetic counseling and been educated regarding the need for cancer surveillance.…”

Section: Discussionmentioning

confidence: 99%

“…Heterozygous pathogenic germline mutations in CHEK2 (c.1100delC) have been associated with an increased risk of hereditary breast, prostate, kidney, thyroid, and colon cancers (5)(6)(7). Congenital CHEK2 inactivation is also associated with an increased risk of hematologic malignancies, mainly myeloid neoplasms like myelodysplastic syndrome (MDS) (8). A recent study showed a two times higher frequency of unbalanced structural chromosomal rearrangements (58%) among patients harboring germline CHEK2 mutations, in comparison to non-carriers (27%) in MDS patients (9).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Case report: Tisagenlecleucel for treatment of relapsed B- acute lymphoblastic leukemia in a patient with CHEK2 mutation

Ipe

Angiolillo²,

Jacobsohn³

et al. 2023

Front. Pediatr.

View full text Add to dashboard Cite

BackgroundGermline Checkpoint Kinase 2 gene (CHEK2) mutations can increase the risk of solid tumors. Recently, they have been identified as risk factors for hematologic malignancies. However, to the best of our knowledge, B-acute lymphoblastic leukemia (B-ALL) has never been described as a presenting manifestation of germline CHEK2 mutation. Chimeric antigen receptor-T (CAR-T) cell therapy directed against CD19 antigen (tisagenlecleucel) is a novel cellular therapy for treatment of relapsed/refractory (R/R) B-ALL. The use of tisagenlecleucel has not been described in patients with CHEK2 mutation.Case PresentationWe describe a case of a pediatric patient with a heterozygous pathogenic germline CHEK2 mutation (c.1100delC; p.Thr367Metfs*15) successfully treated with tisagenlecleucel for relapsed B-ALL to avoid hematopoietic cell transplant (HCT). The twelve-year-old boy was diagnosed with National Cancer Institute (NCI) high-risk B-ALL (white blood cell count >50,000/mcL), with no extramedullary disease. Cytogenetic analysis revealed normal karyotype but fluorescent in situ hybridization (FISH) showed 93% positivity for CRLF2::P2RY8 rearrangement. He was treated as per Children's Oncology Group (COG) AALL1131 therapy and achieved a complete remission. Seven months after diagnosis, he was found to have papillary thyroid carcinoma with no evidence of metastatic disease. The patient underwent a total thyroidectomy with central lymph node biopsy and radioactive iodine therapy. The patient's biological mother and fraternal twin brother carry the same germline CHEK2 mutation with no history of malignancy. The biological father tested negative for the familial mutation. The patient's genetic panel also identified three variants of unclear significance: CDKN2A (c.37 °C > T; p.Arg124Cys), FLCN (c.62G > A; p.Cys21Tyr) and SDHAF2 (c.139A > G; p.Met47Val). Extended family history also revealed a diagnosis of anaplastic thyroid cancer in maternal uncle at the age of 44 years. Fifteen months after diagnosis the patient had a relapse of B-ALL (both medullary and extramedullary with blasts in CSF), which was successfully treated with tisagenlecleucel. The patient remains in remission 3 years after receiving tisagenlecleucel.ConclusionAs conventional chemotherapy and radiation can potentially increase the risk of DNA damage and development of secondary malignancies, CD19 CAR-T therapy (tisagenlecleucel) can be used as a substitute for intensive re-induction chemotherapy and HCT in patients with a germline CHEK2 mutation.

show abstract

“…The p.Arg95Ter CHEK2 variant, resulting in a missense alteration, reported in Individual 5, was previously reported in endometrial carcinoma and choriocarcinoma [ 48 ], but never previously in MDS. Additionally, Stubbins et al recently reported a potential association with myeloid malignancies and MDS and CHEK2 germline variants [ 49 ].…”

Section: Discussionmentioning

confidence: 99%

CHEK2 Alterations in Pediatric Malignancy: A Single-Institution Experience

Abdelghani

Schieffer

Cottrell

et al. 2023

Cancers

View full text Add to dashboard Cite

Background: Approximately 10% of pediatric malignancies are secondary to germline alterations in cancer-predisposing genes. Checkpoint kinase 2 (CHEK2) germline loss-of-function variants have been reported in pediatric cancer patients, but clinical phenotypes and outcomes are poorly described. We present our single-institution experience of pediatric oncology patients with CHEK2 germline alterations, including clinical presentations and outcomes. Methods: Pediatric oncology patients with CHEK2 germline alterations were identified among those assessed by clinical or translational research at the Institute for Genomic Medicine at Nationwide Children’s Hospital. A chart review of disease course was conducted on identified patients. Results: We identified 6 patients with germline CHEK2 variants from a cohort of 300 individuals, including 1 patient with concurrent presentation of Burkitt lymphoma and neuroblastoma, 3 patients with brain tumors, 1 patient with Ewing sarcoma, and 1 patient with myelodysplastic syndrome. Three patients had a family history of malignancies. Four patients were in remission; one was undergoing treatment; one patient had developed treatment-related meningiomas. We review prior data regarding CHEK2 variants in this population, challenges associated with variant interpretation, and genetic counseling for individuals with CHEK2 variants. Conclusions: CHEK2 germline loss-of-function alterations occur in patients with a variety of pediatric tumors. Larger multicenter studies will improve our understanding of the incidence, phenotype, and molecular biology of CHEK2 germline variants in pediatric cancers.

show abstract

Germline CHEK2 and ATM Variants in Myeloid and Other Hematopoietic Malignancies

Cited by 18 publications

References 97 publications

Clinico-genomic findings, molecular docking, and mutational spectrum in an understudied population with breast cancer patients from KP, Pakistan

Clinico-genomic findings, molecular docking, and mutational spectrum in an understudied population with breast cancer patients from KP, Pakistan

Case report: Tisagenlecleucel for treatment of relapsed B- acute lymphoblastic leukemia in a patient with CHEK2 mutation

CHEK2 Alterations in Pediatric Malignancy: A Single-Institution Experience

Contact Info

Product

Resources

About