“…For example, a BRCA2 nonsense variant (p.Lys944Ter) 39 and a FANCM nonsense variant (p.Arg486Ter) 40 displayed LOH in the tumor samples of two patient with CRC, as well as LOH of a NBN missense variant (p.Ile171Val) in the tumor sample of a patient with NSCLC previously suggested to increase the risk of developing NSCLC. 41 In addition, a WRN nonsense variant (p.Arg369Ter) showed a high allele frequency (>85%) in the tumor sample of a patient with pancreatic cancer in line with previous suggestions that loss-of-function variants within WRN might be associated with an increased predisposition to pancreatic cancer. 42 Of note, the LOH in tumor tissue detected by NGS was confirmed by SNParray.Fig.…”
Genomic screening of cancer patients for predisposing variants is traditionally based on age at onset, family history and type of cancer. Whereas the clinical guidelines have proven efficient in identifying families exhibiting classical attributes of hereditary cancer, the frequency of patients with alternative presentations is unclear. We identified and characterized germline variants in 636 patients with advanced solid cancer using whole exome sequencing. Pathogenic and likely pathogenic germline variants among 168 genes associated with hereditary cancer were considered. These variants were identified in 17.8% of the patients and within a wide range of cancer types. In particular, patients with mesothelioma, ovarian cancer, cervical cancer, urothelial cancer, and cancer of unknown primary origin displayed high frequencies of pathogenic variants. Variants were predominantly found in DNA-repair pathways and about half were within genes involved in homologous recombination repair. Twenty-two
BRCA1
and
BRCA2
germline variants were identified in 12 different cancer types, of which 10 (45%) were not previously identified in these patients based on the current clinical guidelines. Loss of heterozygosity and somatic second hits were identified in several of the affected genes, supporting possible causality for cancer development. A potential treatment target based on the pathogenic germline variant could be suggested in 25 patients (4%). The study demonstrates a high frequency of pathogenic germline variants in the homologous recombination pathway in patients with advanced solid cancers. We infer that genetic screening in this group of patients may reveal high-risk families and identify patients with potential PARP inhibitor sensitive tumors.
“…For example, a BRCA2 nonsense variant (p.Lys944Ter) 39 and a FANCM nonsense variant (p.Arg486Ter) 40 displayed LOH in the tumor samples of two patient with CRC, as well as LOH of a NBN missense variant (p.Ile171Val) in the tumor sample of a patient with NSCLC previously suggested to increase the risk of developing NSCLC. 41 In addition, a WRN nonsense variant (p.Arg369Ter) showed a high allele frequency (>85%) in the tumor sample of a patient with pancreatic cancer in line with previous suggestions that loss-of-function variants within WRN might be associated with an increased predisposition to pancreatic cancer. 42 Of note, the LOH in tumor tissue detected by NGS was confirmed by SNParray.Fig.…”
Genomic screening of cancer patients for predisposing variants is traditionally based on age at onset, family history and type of cancer. Whereas the clinical guidelines have proven efficient in identifying families exhibiting classical attributes of hereditary cancer, the frequency of patients with alternative presentations is unclear. We identified and characterized germline variants in 636 patients with advanced solid cancer using whole exome sequencing. Pathogenic and likely pathogenic germline variants among 168 genes associated with hereditary cancer were considered. These variants were identified in 17.8% of the patients and within a wide range of cancer types. In particular, patients with mesothelioma, ovarian cancer, cervical cancer, urothelial cancer, and cancer of unknown primary origin displayed high frequencies of pathogenic variants. Variants were predominantly found in DNA-repair pathways and about half were within genes involved in homologous recombination repair. Twenty-two
BRCA1
and
BRCA2
germline variants were identified in 12 different cancer types, of which 10 (45%) were not previously identified in these patients based on the current clinical guidelines. Loss of heterozygosity and somatic second hits were identified in several of the affected genes, supporting possible causality for cancer development. A potential treatment target based on the pathogenic germline variant could be suggested in 25 patients (4%). The study demonstrates a high frequency of pathogenic germline variants in the homologous recombination pathway in patients with advanced solid cancers. We infer that genetic screening in this group of patients may reveal high-risk families and identify patients with potential PARP inhibitor sensitive tumors.
“…NBS1 has emerged as a prostate cancer-susceptibility gene, with its variant being more prevalent in patients with familial history rather than sporadic prostate cancer [85]. The relation between NBS1 variant and increased cancer susceptibility is also observed in lung cancer [86], liver cancer and intrahepatic cholangiocarcinoma (IHC) [87].…”
Genome instability is a hallmark of cancer cells and can be accelerated by defects in cellular responses to DNA damage. This feature of malignant cells opens new avenues for tumor targeted therapy. MRE11-RAD50-NBS1 complex plays a crucial role in sensing and repair of DNA damage. Through interacting with other important players of DNA damage response, MRE11-RAD50-NBS1 complex is engaged in various DNA damage repair pathways. Mutations in any member of this complex may lead to hypersensitivity to genotoxic agents and predisposition to malignancy. It is assumed that the defects in the complex may contribute to tumorigenesis and that treatments targeting the defect may be beneficial to cancer patients. Here, we summarized the recent research findings of the role of MRE11-RAD50-NBS1 complex in tumorigenesis, cancer treatment and discussed the potential approaches of targeting this complex to treat cancer.
“…suggested that the rs1801320 variant (substitution of G to C at position 135 in 5ʹ untranslated region) of the RAD51 gene may be associated with smoking- and drinking-related larynx cancer in Poland [ 17 ]. We found that a mutation in a gene involved in DSB repair, p.I171V of the NBN gene, is associated with laryngeal cancer (OR = 11.70) and multiple primary tumors (OR = 28.35) and we also observed a significantly increased risk of lung cancer for the p.I171V variant (OR = 7.76) [ 7 , 8 ].…”
Section: Discussionmentioning
confidence: 99%
“…In our previous study it was shown that the heterozygous p.I171V mutation of the NBN gene, involved in DSB repair, may contribute to laryngeal cancer (OR = 11.70) and multiple primary tumors (OR = 28.35) [ 7 ]. We observed a significantly increased risk of lung cancer for carriers of the p.I171V variant (OR = 7.76) [ 8 ].…”
IntroductionThe inactivation of both alleles of the ATM gene leads to ataxiatelangiectasia syndrome, whereas carriers of monoallelic mutations in the ATM gene are associated with increased risk of different types of cancer. Three substitutions in the ATM gene (c.6095G>A, c.7630-2A>C, c.5932G>T) are the most common mutations causing ataxia-telangiectasia among Polish patients. The aim of this study was to determine whether these ATM mutations are associated with increased risk of tobacco-related cancers.Material and methods783 Polish patients with tobacco-related cancers were included in the study (468 with lung cancer, 153 with a single laryngeal cancer, 86 with multiple primary tumors localized in the larynx and 76 multiple primary tumors localized in the head or neck). The control group consisted of 464 healthy subjects from the Polish population. Three ATM mutations – c.5932G>T, c.6095G>A, c.7630-2A>C – were tested among selected patients. Molecular analyses were performed using high resolution melting analysis (HRMA) and restriction fragment length polymorphism (RFLP).ResultsIn the present study, we detected only one mutation, c.7630-2A>C, and no carriers of c.5932G>T, c.6095G>A mutations in the ATM gene among Polish patients with tobacco-related cancers. A patient with c.7630-2A>C mutation was diagnosed with lung adenocarcinoma, the most common type of lung cancer. One carrier of c.6095G>A mutation was found in the control group.ConclusionsThe results indicate that the studied ATM variants do not seem to be associated with tobacco-related cancers in Poland.
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