Assuntos
Neoplasias Colorretais/genética , Genes Supressores de Tumor , Hidroliases/genética , Proteínas/genética , Neoplasias Gástricas/genética , Proteínas Supressoras de Tumor/genética , Neoplasias Colorretais/patologia , Mutação da Fase de Leitura , Estudos de Associação Genética , Heterogeneidade Genética , Humanos , Instabilidade de Microssatélites , Repetições de Microssatélites/genética , Neoplasias Gástricas/patologiaAssuntos
Neoplasias Colorretais/genética , Citocromo-B(5) Redutase/genética , Heterogeneidade Genética , Neoplasias Colorretais/patologia , Mutação da Fase de Leitura , Genes Supressores de Tumor , Estudos de Associação Genética , Humanos , Instabilidade de Microssatélites , Repetições de Microssatélites/genéticaRESUMO
BACKGROUND: Both QKI and TMEFF2 genes are considered putative tumor suppressor genes (TSGs). In gastric (GC) and colorectal (CRC) cancers, downregulation of their expressions is known to be frequent. However, QKI and TMEFF2 mutations that could potentially inactivate their functions are not reported in cancers. METHODS: In a genome database, we observed that both QKI and TMEFF2 harbor mononucleotide repeats, which could be mutated in cancers with high microsatellite instability (MSI-H). For this, we studied 79 GCs and 124 CRCs for the mutations and their intratumoral heterogeneity (ITH). RESULTS: Six of 34 GCs (17.6%) and 10 of 79 CRCs (12.7%) with MSI-H exhibited QKI frameshift mutations while five of 79 CRCs (6.3%) with high MSI (MSI-H) exhibited TMEFF2 frameshift mutations. However, we found no such mutation in microsatellite stable/low MSI (MSS/MSI-L) cancers within the mononucleotide repeats. We also studied ITH for the detected frameshift mutations in 16 cases of CRCs and detected that QKI and TMEFF2 frameshift mutations showed regional ITH in 2 (12.5%) and 1 (6.3%) cases, respectively. CONCLUSIONS: Our data show that candidate TSG genes QKI and TMEFF2 harbor mutational ITH as well as the frameshift mutations in GC and CRC with MSI-H. From this observation, frameshift mutations of QKI and TMEFF2 may play a role in tumorigenesis through their TSG inactivation in GC and CRC.
Assuntos
Neoplasias Colorretais/genética , Mutação da Fase de Leitura , Genes Supressores de Tumor , Proteínas de Membrana/genética , Proteínas de Neoplasias/genética , Proteínas de Ligação a RNA/genética , Neoplasias Gástricas/genética , Neoplasias Colorretais/patologia , Análise Mutacional de DNA , Heterogeneidade Genética , Humanos , Gradação de Tumores , Estadiamento de Neoplasias , Neoplasias Gástricas/patologiaRESUMO
ß2-microglobulin (B2M), a component of major histocompatibility complex class I, plays an important role in host immune reaction to tumor, and inactivation of B2M is known to contribute to resistance to immune checkpoint blockade (ICB) treatment. To further characterize the B2M alterations in tumors, we analyzed B2M hotspot mutations in 2765 benign and malignant tumor tissues by Sanger sequencing and found B2M mutations in 9 (7.5%) microsatellite-unstable (MSU) colorectal cancers (CRCs) and 3 leukemias (0.6-1.3%), but not in other tumors. Targeted sequencing panel analysis for MSU CRCs showed that B2M-mutated MSU CRCs harbored more driver mutations including TP53 than B2M-wild-type MSU CRCs. Of note, bi-allelic B2M alterations, which had been known to be accumulated during ICB treatment, were frequently found (3/9) in ICB treatment-naive CRCs. Clinicopathologic parameters including CD8 + T cell numbers, cancer stages and patients' survival, however, were not significantly different between B2M-mutated and B2M-wild-type MSU CRCs. Our results indicate that B2M mutation abundance is tissue type-specific (e.g., MSU CRCs) and that genetic makeup of B2M mutation might possibly shape the MSU CRC genomes even before the ICB therapies. Our results show that B2M mutation is common in MSU CRCs, which is one of the main targets for ICB treatment, suggesting that frequent B2M mutation status should be reminded for MSU CRCs in patient selection of ICB.
Assuntos
Neoplasias Colorretais/genética , Predisposição Genética para Doença , Instabilidade de Microssatélites , Repetições de Microssatélites/genética , Mutação/genética , Alelos , Neoplasias Colorretais/patologia , Neoplasias Colorretais/terapia , Humanos , Imunoterapia/métodosRESUMO
A scaffold protein DAB2 and its interaction partner DAB2IP have putative tumor suppressor gene (TSG) functions. Previous studies identified that both DAB2 and DAB2IP genes were inactivated by promoter hypermethylation in human cancers, but their mutational alterations in cancers remain largely unknown. The aim of our study was to find whether DAB2 and DAB2IP were mutated in gastric (GCs) and colorectal cancers (CRCs) by DNA sequencing. Both DAB2 and DAB2IP have mononucleotide repeats in their coding sequence that could be mutation targets in high microsatellite instability (MSI-H) cancers. We analyzed GC and CRC tissues and found that 8 of 34 GCs (23.5%) and 15 of 79 CRCs (20.0%) with MSI-H harbored DAB2IP frameshift mutations. DAB2 frameshift mutations were found in 2 of 79 CRCs (2.5%) with MSI-H. These mutations were not detected in microsatellite stable (MSS) cancers. We also found intratumoral heterogeneity (ITH) of DAB2IP frameshift mutations in 7 of 16 CRCs (43.8%). Loss of DAB2IP protein expression was found in approximately 20% of GCs and CRCs irrespective of MSI and DAB2IP frameshift mutation status. Our study shows that the TSG DAB2IP harbored frameshift mutations and ITH as well as expression loss. Together these tumor alterations might play a role in tumorigenesis of GC and CRC with MSI-H by down-regulating the tumor-inhibiting activities of DAB2IP.
Assuntos
Adenocarcinoma/genética , Neoplasias Gastrointestinais/genética , Proteínas Ativadoras de ras GTPase/genética , Análise Mutacional de DNA , Mutação da Fase de Leitura , Genes Supressores de Tumor , Humanos , Instabilidade de MicrossatélitesRESUMO
MYH11 functions as a contractile protein, converting chemical energy into mechanical energy through adenosine triphosphate hydrolysis. In cancers, an oncogenic fusion CBFB/MYH11 and frameshift mutations have been reported. Truncating mutants of MYH11 exhibited increased ATPase and motor activity, suggesting their roles in energy balance and movement of cancer cells. MYH11 gene has a mononucleotide repeat (C8) in the coding sequences that could be a mutational target in the cancers exhibiting microsatellite instability (MSI). We analyzed the C8 repeat in 79 gastric cancers (GCs) and 124 colorectal cancers (CRCs) including 113 high MSI (MSI-H) and 90 microsatellite stable/low MSI cases. We detected MYH11 frameshift mutations in 4 (11.8%) GCs and 17 (21.5%) CRCs with MSI-H (21/113, 18.6%), but not in microsatellite stable/low MSI cancers (0/90) (P<0.001). We also analyzed intratumoral heterogeneity (ITH) of the MYH11 frameshift mutations and found that 10 of 16 CRCs (62.5%) harbored the regional ITH. Our results show that MYH11 gene harbors somatic frameshift mutations mostly associated with mutational ITH, which together may be features of MSI-H GCs and CRCs. Practically, the data suggest that multiregional analysis is needed for a better evaluation of mutation status in MSI-H tumors to overcome ITH.
Assuntos
Neoplasias Colorretais/genética , Éxons , Mutação da Fase de Leitura , Instabilidade de Microssatélites , Cadeias Pesadas de Miosina/genética , Proteínas de Neoplasias/genética , Neoplasias Gástricas/genética , Neoplasias Colorretais/patologia , Humanos , Neoplasias Gástricas/patologiaRESUMO
Diminished ANK3 contributes to cell survival by inhibiting detachment-induced apoptosis. TP53BP1 that interacts with p53 and MFN1 that encodes a mitochondrial membrane protein are considered to have tumor suppressor gene (TSG) functions. HACD4 involving fatty acid synthesis and TCPL10 with transcription regulation functions are considered TSGs. Many genes involved in DNA methylations such as LCMT2, RNMT, TRMT6, METTL8 and METTL16 are often perturbed in cancer. The aim of our study was to find whether these genes were mutated in colorectal cancer (CRC). In a genome database, we observed that each of these genes harbored mononucleotide repeats in the coding sequences, which could be mutated in cancers with high microsatellite instability (MSI-H). For this, we studied 124 CRCs for the frameshift mutations of these genes and their intratumoral heterogeneity (ITH). ANK3, HACD4, TCP10L, TP53BP1, MFN1, LCMT2, RNMT, TRMT6, METTL8 and METTL16 harbored 11 (13.9%), 3 (3.8%), 0 (0%), 5 (6.3%), 1 (1.3%), 2 (2.5%), 4 (5.1%), 3 (3.8%), 2 (2.5%) and 2 (2.5%) of 79 CRCs with MSI-H, respectively. However, we found no such mutations in microsatellite stable (MSS) cancers in the nucleotide repeats. There were ITH of the frameshift mutations of ANK3, MFN1 and TP53BP1 in 1 (6.3%), 1 (6.3%) and 1 (6.3%) cases, respectively. Our data exhibit that cancer-related genes ANK3, HACD4, TP53BP1, MFN1, LCMT2, RNMT, TRMT6, METTL8 and METTL16 harbor mutational ITH as well as the frameshift mutations in CRC with MSI-H. Also, the results suggest that frameshift mutations of these genes might play a role in tumorigenesis through their inactivation in CRC.
Assuntos
Biomarcadores Tumorais/genética , Neoplasias do Colo/genética , Mutação da Fase de Leitura , Instabilidade de Microssatélites , Sequências Repetitivas de Ácido Nucleico , Anquirinas/genética , Carcinogênese , Neoplasias do Colo/patologia , DNA de Neoplasias/genética , GTP Fosfo-Hidrolases/genética , Humanos , Hidroliases , Proteínas de Membrana/genética , Metiltransferases/genética , Proteínas de Transporte da Membrana Mitocondrial/genética , Prognóstico , Proteína O-Metiltransferase/genética , Proteínas/genética , Proteínas Supressoras de Tumor/genética , Proteína 1 de Ligação à Proteína Supressora de Tumor p53/genéticaAssuntos
Neoplasias Colorretais/genética , Mutação da Fase de Leitura/genética , Genes Supressores de Tumor , Proteínas Serina-Treonina Quinases/genética , Receptores da Fosfolipase A2/genética , Neoplasias Gástricas/genética , Humanos , Repetições de Microssatélites/genética , Polimorfismo Conformacional de Fita SimplesRESUMO
Both CUX1 and SIRT1 are considered tumor suppressor genes (TSGs), but it is not known whether CUX1 and SIRT1 alterations are different between high microsatellite instability (MSI-H) and microsatellite stable MSI (MSS) cancers. We identified frameshift mutations of CUX1 in 4 cases of colorectal cancer (CRC) and of SIRT1 in 1 case of gastric cancer (GC) and 3 cases of CRC. All of them were found in GC or CRC with MSI-H (3.5% of MSI-H for each gene), but neither in GC nor CRC with MSS. In addition, we analyzed intratumoral heterogeneity (ITH) of the CUX1 frameshift mutation and found that two CRCs (12.5%) harbored regional ITH of the frameshift mutation. Our data indicate that there exist frameshift mutations of CUX1 and SIRT1 genes as well as ITH of CUX1 frameshift mutation in MSI-H cancers, which together might play a role in tumorigenesis of GC and CRC with MSI-H.
Assuntos
Transformação Celular Neoplásica/genética , Neoplasias Colorretais/genética , Proteínas de Homeodomínio/genética , Proteínas Nucleares/genética , Proteínas Repressoras/genética , Sirtuína 1/genética , Neoplasias Gástricas/genética , Mutação da Fase de Leitura , Humanos , Instabilidade de Microssatélites , Fatores de TranscriçãoAssuntos
Neoplasias Colorretais/genética , Genes Supressores de Tumor , Mutação/genética , Proteínas do Tecido Nervoso/genética , Neoplasias Gástricas/genética , Proteínas de Ciclo Celular , Neoplasias Colorretais/patologia , Proteínas do Citoesqueleto , Progressão da Doença , Humanos , Neoplasias Gástricas/patologiaRESUMO
Frameshift mutation of genes containing mononucleotide repeats is a feature of gastric (GC) and colorectal cancers (CRC) with microsatellite instability (MSI). In the public genome database, we found that human HSPA4 gene encoding a heats hock protein 70 protein (HSP70-4) and MED13 gene had mononucleotide repeats in the coding sequences that could be targets for frameshift mutation in cancers with MSI. HSP70-4 is a member of HSP70 that is known to play a role in cell survival. MED13 is a member of MED genome-wide transcription regulators that function as a regulator for diverse biological processes. In this study, we analyzed the mutations in 79 GCs and 124 CRCs including high MSI (MSI-H) and microsatellite stable/low MSI (MSS/MSI-L) cases by single-strand conformation polymorphism analysis and DNA sequencing. We found frameshift mutations of HSPA4 gene in two cancers (one GC and one CRC) and MED13 gene in the other two cancers (one GC and one CRC). The frameshift mutations were deletions of one base (c.2396delA (p.Asn799MetfsX50)) in HSPA4 and (c.2175delA (p.Lys725AsnfsX4)) in MED13. Each of HSPA4 and MED13 mutations were detected in GC with MSI-H (1/34: 2.9 %) and CRC with MSI-H (1/79: 1.3 %), but not in those with MSS. Our data show that unconventional HSPA4 and MED13 genes harbored frameshift mutations in GC and CRC with MSI. These mutations might possibly inactivate their functions and could be a feature of GC and CRC with MSI-H.
