Abstract:CHEK2 gene is known as a tumor suppressor gene in breast cancer (BC), which plays a role in DNA repair. The germ line mutations in CEHK2 have been associated with different types of cancer. The present study was aimed at studying the association between CHEK2 mutations and BC. Peripheral blood was collected from patients into a test tube containing EDTA, and DNA was extracted from blood samples. Then, we analyzed mutations including 1100delc, IVS2+1>A, del5395bp, and I157T within CHEK2 gene in patients with BC… Show more
“…The most common gene with PVs identified in the eoRC patients was the DDRR gene CHEK2 (19/844, 2.25%, Fig. 2 A, Table S3 and S4 ), consistent with a recent report by Carlo et al 16 Of patients with CHEK2 PVs, 47.3% (n = 9/19) had a common, highly damaging variant (c.1100delC, p.Thr367Met fs ) that is known to be associated with an increased risk for breast, prostate, colorectal and thyroid cancers (Table S4 ) 34 – 37 . Figure 2 Enrichment of PVs in DDRR genes.…”
Pathogenic variants (PVs) in multiple genes are known to increase the risk of early-onset renal cancer (eoRC). However, many eoRC patients lack PVs in RC-specific genes; thus, their genetic risk remains undefined. Here, we determine if PVs in DNA damage response and repair (DDRR) genes are enriched in eoRC patients undergoing cancer risk assessment. Retrospective review of de-identified results from 844 eoRC patients, undergoing testing with a multi-gene panel, for a variety of indications, by Ambry Genetics. PVs in cancer-risk genes were identified in 12.8% of patients-with 3.7% in RC-specific, and 8.55% in DDRR genes. DDRR gene PVs were most commonly identified in CHEK2, BRCA1, BRCA2, and ATM. Among the 2.1% of patients with a BRCA1 or BRCA2 PV, < 50% reported a personal history of hereditary breast or ovarian-associated cancer. No association between age of RC diagnosis and prevalence of PVs in RC-specific or DDRR genes was observed. Additionally, 57.9% patients reported at least one additional cancer; breast cancer being the most common (40.1% of females, 2.5% of males). Multi-gene testing including DDRR genes may provide a more comprehensive risk assessment in eoRC patients. Further validation is needed to characterize the association with eoRC. Renal cancer (RC) often develops with no signs or symptoms and is referred to as the "silent disease" 1. While factors including smoking, environment, obesity, and race have been linked to increased risk of RC, inherited factors are the most well-validated source of increased risk 2-4. Hereditary RC syndromes, typically associated with early-onset disease and a clinically significant family history of cancer, result from germline pathogenic variants (PV) in high-penetrance 'RC-specific' genes including VHL, MET, FLCN, TSC1, TSC2, FH, SDH, PTEN and BAP1 5-7. A previous report of an early-onset RC (eoRC) cohort screened with an RC-specific panel found 6.1% of individuals had a PV in an RC-specific gene 7. However, for most eoRC patients a PV in an RC-specific gene is not identified, leaving many eoRC genetically undefined. Thus, there is a need to identify additional genes related to eoRC risk. Currently, there are no National Comprehensive Cancer Network (NCCN) guidelines for detection, prevention, or risk reduction in individuals who present with an eoRC but lack a PV in a defined RC-specific gene 8 .
“…The most common gene with PVs identified in the eoRC patients was the DDRR gene CHEK2 (19/844, 2.25%, Fig. 2 A, Table S3 and S4 ), consistent with a recent report by Carlo et al 16 Of patients with CHEK2 PVs, 47.3% (n = 9/19) had a common, highly damaging variant (c.1100delC, p.Thr367Met fs ) that is known to be associated with an increased risk for breast, prostate, colorectal and thyroid cancers (Table S4 ) 34 – 37 . Figure 2 Enrichment of PVs in DDRR genes.…”
Pathogenic variants (PVs) in multiple genes are known to increase the risk of early-onset renal cancer (eoRC). However, many eoRC patients lack PVs in RC-specific genes; thus, their genetic risk remains undefined. Here, we determine if PVs in DNA damage response and repair (DDRR) genes are enriched in eoRC patients undergoing cancer risk assessment. Retrospective review of de-identified results from 844 eoRC patients, undergoing testing with a multi-gene panel, for a variety of indications, by Ambry Genetics. PVs in cancer-risk genes were identified in 12.8% of patients-with 3.7% in RC-specific, and 8.55% in DDRR genes. DDRR gene PVs were most commonly identified in CHEK2, BRCA1, BRCA2, and ATM. Among the 2.1% of patients with a BRCA1 or BRCA2 PV, < 50% reported a personal history of hereditary breast or ovarian-associated cancer. No association between age of RC diagnosis and prevalence of PVs in RC-specific or DDRR genes was observed. Additionally, 57.9% patients reported at least one additional cancer; breast cancer being the most common (40.1% of females, 2.5% of males). Multi-gene testing including DDRR genes may provide a more comprehensive risk assessment in eoRC patients. Further validation is needed to characterize the association with eoRC. Renal cancer (RC) often develops with no signs or symptoms and is referred to as the "silent disease" 1. While factors including smoking, environment, obesity, and race have been linked to increased risk of RC, inherited factors are the most well-validated source of increased risk 2-4. Hereditary RC syndromes, typically associated with early-onset disease and a clinically significant family history of cancer, result from germline pathogenic variants (PV) in high-penetrance 'RC-specific' genes including VHL, MET, FLCN, TSC1, TSC2, FH, SDH, PTEN and BAP1 5-7. A previous report of an early-onset RC (eoRC) cohort screened with an RC-specific panel found 6.1% of individuals had a PV in an RC-specific gene 7. However, for most eoRC patients a PV in an RC-specific gene is not identified, leaving many eoRC genetically undefined. Thus, there is a need to identify additional genes related to eoRC risk. Currently, there are no National Comprehensive Cancer Network (NCCN) guidelines for detection, prevention, or risk reduction in individuals who present with an eoRC but lack a PV in a defined RC-specific gene 8 .
“…As a tumor suppressor gene, CHEK2 plays a critical role in DNA repair and maintenance of chromosome stability, and it is prone to mutate and cause cancer [ 15 – 17 ]. Studies have shown that CHEK2 mutations are involved in cancer occurrence and chemotherapeutic drug resistance [ 18 – 21 ]. Our previous study [ 7 ] have shown that CHEK2 Y390C mutation could inhibit the efficacy of CHEK2 in response to DNA damage agents, thus indicating Y390C mutation significantly impaired CHEK2 function during DNA damage response.…”
BackgroundThis study aimed to investigate the mechanism of CHEK2 gene dysfunction in drug resistance of triple negative breast cancer (TNBC) cells.Material/MethodsTo perform our study, a stable CHEK2 wild type (CHEK2 WT) or CHEK2 Y390C mutation (CHEK2 Y390C) expressed MDA-MB-231 cell line was established. MTT assay, cell apoptosis assay and cell cycle assay were carried out to analyze the cell viability, apoptosis, and cell cycle respectively. Western blotting and qRT-PCR were applied for related protein and gene expression detection.ResultsWe found that the IC50 value of DDP (Cisplatin) to CHEK2 Y390C expressed MDA-MB-231 cells was significantly higher than that of the CHEK2 WT expressed cells and the control cells. After treatment with DDP for 48 h, cells expressing CHEK2 WT showed lower cell viability than that of the CHEK2 Y390C expressed cells and the control cells; compared with the CHEK2 Y390C expressed cells and the control cells, cells expressing CHEK2 WT showed significant G1/S arrest. Meanwhile, we found that compared with the CHEK2 Y390C expressed cells and the control cells, cell apoptosis was significantly increased in CHEK2 WT expressed cells. Moreover, our results suggested that cells expressing CHEK2 WT showed higher level of p-CDC25A, p-p53, p21, Bax, PUMA, and Noxa than that of the CHEK2 Y390C expressed cells and the control cells.ConclusionsOur findings indicated that CHEK2 Y390C mutation induced the drug resistance of TNBC cells to chemotherapeutic drugs through administrating cell apoptosis and cell cycle arrest via regulating p53 activation and CHEK2-p53 apoptosis pathway.
Purpose: Pathogenic variants (PVs) in a number of genes are known to increase the risk of hereditary renal cancer (hRC). However, many early-onset RC (eoRC) patients undergoing genetic testing lack PVs in hRC genes; thus, their genetic risk remains undefined. To determine if PVs in DNA damage response (DDR) genes are enriched in a convenience sample of eoRC patients undergoing genetic testing.
Materials and Methods: Retrospective review of results for 844 unselected eoRC patients, undergoing genetic testing with a multi-gene cancer panel by Ambry Genetics [between July 2012 and December 2016]. The patients were tested with CancerNext and/or CancerNext Expanded panels for a variety of indications. Identified PVs were compared with patient characteristics.Results: Mean age of RC diagnosis was 48 years [range 24-60]. In addition to eoRC, 57.9% patients tested reported at least one additional cancer; breast cancer being the most common (40.1% of females, 2.5% of males). PVs in cancer risk genes were identified in 12.8% of patients-3.7% in RC-specific genes, and 8.55% in DDR genes. DDR gene PVs were most commonly identified in CHEK2, BRCA1/2, and ATM. Among the 2.1% of patients with a BRCA1/2 PV, <50% reported a personal history of hereditary breast/ovarian-associated cancer.No association between age of RC diagnosis, and prevalence of PVs in RC-specific or DDR genes was observed.
Conclusions:Multi-gene panel testing including DDR genes may provide a more comprehensive risk assessment in unselected eoRC patients, and their families. Validation in larger datasets is needed to characterize the association with eoRC.
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