Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:Q86TM3 (cage)
 29,987 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Biallelic germline mutations in the base excision repair enzyme gene MUTYH lead to multiple colorectal adenomas and carcinomas referred to as MUTYH-associated polyposis. MUTYH removes adenine misincorporated opposite the DNA oxidation product, 8-oxoguanine (OG), thereby preventing accumulation of G:C to T:A transversion mutations. The most common cancer-associated MUTYH variant proteins when expressed in bacteria exhibit reduced OG:A mismatch affinity and adenine removal activity. However, direct evaluation of OG:A mismatch repair efficiency in mammalian cells has not been assessed due to the lack of an appropriate assay. To address this, we developed a novel fluorescence-based assay of OG:A repair and measured the repair capacity of MUTYH-associated polyposis variants expressed in Mutyh-/- mouse embryonic fibroblasts (MEFs). The repair of a single site-specific synthetic lesion in a green fluorescent protein reporter leads to green fluorescent protein expression with co-expression of a red fluorescent protein serving as the transfection control. Cell lines that stably express the MUTYH-associated polyposis variants G382D and Y165C have significantly lower OG:A repair versus wild-type MEFs and MEFs expressing human wild-type MUTYH. The MUTYH allele that encodes the Q324H variant is found at a frequency above 40% in samples from different ethnic groups and has long been considered phenotypically silent but has recently been associated with increased cancer risk in several clinical studies. In vitro analysis of Q324H MUTYH expressed in insect cells showed that it has reduced enzyme activity similar to that of the known cancer variant G382D. Moreover, we find that OG:A repair in MEFs expressing Q324H was significantly lower than wild-type controls, establishing that Q324H is functionally impaired and providing further evidence that this common variant may lead to increased cancer risk.
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PMID:Cancer-associated variants and a common polymorphism of MUTYH exhibit reduced repair of oxidative DNA damage using a GFP-based assay in mammalian cells. 2292 31

Distribution of cancer-predisposing mutations demonstrates significant interethnic variations. This study aimed to evaluate patterns of APC and MUTYH germ-line mutations in Russian patients with colorectal malignancies. APC gene defects were identified in 26/38 (68%) subjects with colon polyposis; 8/26 (31%) APC mutations were associated with 2 known mutational hotspots (p.E1309Dfs*4 [n = 5] and p.Q1062fs* [n = 3]), while 6/26 (23%) mutations were novel (p.K73Nfs*6, p.S254Hfs*12, p.S1072Kfs*9, p.E1547Kfs*11, p.L1564X and p.C1263Wfs*22). Biallelic mutations in MUTYH gene were detected in 3/12 (25%) remaining subjects with polyposis and in 6/90 (6.7%) patients with colorectal cancer (CRC) carrying KRAS p.G12C substitution, but not in 231 early-onset CRC cases negative for KRAS p.G12C allele. In addition to known European founder alleles p.Y179C and p.G396D, this study revealed a recurrent character of MUTYH p.R245H germ-line mutation. Besides that, 3 novel pathogenic MUTYH alleles (p.L111P, p.R245S and p.Q293X) were found. Targeted next-generation sequencing of 7 APC/MUTYH mutation-negative DNA samples identified novel potentially pathogenic POLD1 variant (p.L460R) in 1 patient and known low-penetrant cancer-associated allele CHEK2 p.I157T in 3 patients. The analysis of 1120 healthy subjects revealed 15 heterozygous carriers of recurrent MUTYH mutations, thus the expected incidence of MUTYH-associated polyposis in Russia is likely to be 1:23 000.
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PMID:Spectrum of APC and MUTYH germ-line mutations in Russian patients with colorectal malignancies. 2940 63

Patients with heritable cancer syndromes characterized by germline PTEN mutations (termed PTEN hamartoma tumor syndrome, PHTS) benefit from PTEN-enabled cancer risk assessment and clinical management. PTEN-wildtype patients (~50%) remain at increased risk of developing certain cancers. Existence of germline mutations in other known cancer susceptibility genes has not been explored in these patients, with implications for different medical management. We conducted a 4-year multicenter prospective study of incident patients with features of Cowden/Cowden-like (CS/CS-like) and Bannayan-Riley-Ruvalcaba syndromes (BRRS) without PTEN mutations. Exome sequencing and targeted analysis were performed including 59 clinically actionable genes from the American College of Medical Genetics and Genomics (ACMG) and 24 additional genes associated with inherited cancer syndromes. Pathogenic or likely pathogenic cancer susceptibility gene alterations were found in 7 of the 87 (8%) CS/CS-like and BRRS patients and included MUTYH, RET, TSC2, BRCA1, BRCA2, ERCC2 and HRAS. We found classic phenotypes associated with the identified genes in 5 of the 7 (71.4%) patients. Variant positive patients were enriched for the presence of second malignant neoplasms compared to patients without identified variants (OR = 6.101, 95% CI 1.143-35.98, p = 0.035). Germline variant spectrum and frequencies were compared to The Cancer Genome Atlas (TCGA), including 6 apparently sporadic cancers associated with PHTS. With comparable overall prevalence of germline variants, the spectrum of mutated genes was different in our patients compared to TCGA. Intriguingly, we also found notable enrichment of variants of uncertain significance (VUS) in our patients (OR = 2.3, 95% CI 1.5-3.5, p = 0.0002). Our data suggest that only a small subset of PTEN-wildtype CS/CS-like and BRRS patients could be accounted for by germline variants in some of the known cancer-related genes. Thus, the existence of alterations in other and more likely non-classic cancer-associated genes is plausible, reflecting the complexity of these heterogeneous hereditary cancer syndromes.
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PMID:Unexpected cancer-predisposition gene variants in Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome patients without underlying germline PTEN mutations. 2968 80

Breast cancer (BC) in men is rare and genetic predisposition is likely to play a relevant role in its etiology. Inherited mutations in BRCA1/2 account for about 13% of all cases and additional genes that may contribute to the missing heritability need to be investigated. In our study, a well-characterized series of 523 male BC (MBC) patients from the Italian multicenter study on MBC, enriched for non-BRCA1/2 MBC cases, was screened by a multigene custom panel of 50 cancer-associated genes. The main clinical-pathologic characteristics of MBC in pathogenic variant carriers and non-carriers were also compared. BRCA1/2 pathogenic variants were detected in twenty patients, thus, a total of 503 non-BRCA1/2 MBC patients were examined in our study. Twenty-seven of the non-BRCA1/2 MBC patients were carriers of germline pathogenic variants in other genes, including two APC p.Ile1307Lys variant carriers and one MUTYH biallelic variant carrier. PALB2 was the most frequently altered gene (1.2%) and PALB2 pathogenic variants were significantly associated with high risk of MBC. Non-BRCA1/2 pathogenic variant carriers were more likely to have personal (p = 0.0005) and family (p = 0.007) history of cancer. Results of our study support a central role of PALB2 in MBC susceptibility and show a low impact of CHEK2 on MBC predisposition in the Italian population. Overall, our data indicate that a multigene testing approach may benefit from appropriately selected patients with implications for clinical management and counseling of MBC patients and their family members.
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PMID:Insight into genetic susceptibility to male breast cancer by multigene panel testing: Results from a multicenter study in Italy. 3244 46

Although somatic mutations are the main cause of cancer, underlying germline alterations may affect cancer outcome. There is little information on comprehensive analysis of germline genome sequencing for cancer healthcare strategy. Here we studied the implication of germline cancer-associated variants on cancer counselling and therapeutic strategies by germline whole genome and tumor targeted sequencing. Fifty-five gynecological and 104 colorectal cancer (CRC) patients were enrolled. We identified 22 germline pathogenic variants in 16 cancer-associated genes. Most of them are involved in DNA repair signaling, including MLH1, BRCA1/2, MUTYH, ATM, PMS2, MSH6, BAP1, and FANCA. About 6% of cancer patients presented the secondary findings of germline variants with non-oncogenic impact, mainly on the cardiovascular system which should be carefully monitored during chemotherapy. CRC patients carrying germline susceptibility variants had better disease-free survival than those without variants. Importantly, in the CRC model, the underlying germline alterations mold the tumor somatic alteration landscape. NOTCH1 mutation was the most common somatic mutation in recurrent CRC, implying a potential therapeutic target in adjuvant setting. In conclusion, both tumor genome and germline sequence data have to be analyzed to have a more complete picture of the overall genetic foundation of cancer.
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PMID:Germline susceptibility variants impact clinical outcome and therapeutic strategies for stage III colorectal cancer. 3267 59

Endometrial intraepithelial neoplasia (EIN), also known as endometrial atypical hyperplasia (EAH) is believed to be the precursor lesion of endometrioid endometrial carcinoma (EEC). Many genetic factors play important roles in the process of carcinogenesis, however, the key genetic alterations from dysplasia to endometrial cancer remains poorly understood. Germline mutations in Lynch syndrome genes are associated with hereditary endometrial carcinoma. The role of other cancer susceptibility genes is unclear. The aim of this study was to investigate the genomic alterations of premalignant endometrial lesion and EEC, and to determine the prevalence of cancer predisposition gene mutations in an unselected endometrial carcinoma patient cohort. Here, we applied a comprehensive cancer gene panel (363 cancer-related genes) to capture the exomes of cancer-related genes. Samples were collected from 79 patients with EEC and 36 patients with EIN. Our results demonstrate that EIN harbors most of the driver events reported in EEC and for the first time we reported a high frequency of the amplification of VEGFB gene in endometrial cancer. Moreover, we identified four novel candidate cancer-associated genes (CTCF, ARHGAP35, NF1, and KDR) which may be crucial in the carcinogenesis of EEC. In addition, we identified 2 patients who had a deleterious germline mutation in Lynch syndrome genes (MLH1 and MLH2), and another 8 patients harbored germline mutations of 6 non-Lynch syndrome genes (MUTYH, GALNT12, POLE, MPL, ATM, and ERCC4) which may be associated with endometrial cancer. Larger series will have to be investigated to assess the risks and the proportion of endometrial cancers attributable to other genes.
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PMID:Genomic Comparison of Endometrioid Endometrial Carcinoma and Its Precancerous Lesions in Chinese Patients by High-Depth Next Generation Sequencing. 3088 32