1,721,037 research outputs found
Mitochondrial DNA variations in tumours: Drivers or passengers?
No full textMitochondrial DNA alterations, including point mutations, deletions, inversions and
copy number variations, have been widely reported in many age-related degenerative
diseases and tumors. However, numerous studies investigating their pathogenic role in
cancer have provided inconsistent evidence. Furthermore, biological impacts of mitochondrial DNA variants vary tremendously, depending on the proportion of mutant
DNA molecules carried by the neoplastic cells (the so-called heteroplasmy). The recent
discovery of inter-genomic crosstalk between nucleus and mitochondria has reinforced
the role of mitochondrial DNA variants in perturbing this essential signaling pathway
and thus indirectly targeting nuclear genes involved in tumorigenic and invasive phenotype. Therefore, mitochondrial dysfunction is currently considered a crucial hallmark of
carcinogenesis as well as a promising target for anticancer therapy. This chapter describes
the role of different types of mitochondrial DNA alterations by mainly considering the
paradigmatic model of colorectal carcinogenesis and, in particular, it revisits the issue of
whether mitochondrial mutations are causative cancer drivers or simply genuine passenger events. The advent of high-throughput next-generation sequencing techniques, as
well as the development of genetic and pharmaceutical interventions for the treatment of
mitochondrial dysfunction in cancer, are also discusse
Mitochondrial DNA variants in colorectal carcinogenesis: Drivers or passengers?
No full textINTRODUCTION:
Mitochondrial DNA alterations have widely been reported in many age-related degenerative diseases and tumors, including colorectal cancer. In the past few years, the discovery of inter-genomic crosstalk between nucleus and mitochondria has reinforced the role of mitochondrial DNA variants in perturbing this essential signaling pathway and thus indirectly targeting nuclear genes involved in tumorigenic and invasive phenotype.
FINDINGS:
Mitochondrial dysfunction is currently considered a crucial hallmark of carcinogenesis as well as a promising target for anticancer therapy. Mitochondrial DNA alterations include point mutations, deletions, inversions, and copy number variations, but numerous studies investigating their pathogenic role in cancer have provided inconsistent evidence. Furthermore, the biological impact of mitochondrial DNA variants may vary tremendously, depending on the proportion of mutant DNA molecules carried by the neoplastic cells (heteroplasmy).
CONCLUSIONS:
In this review, we discuss the role of different type of mitochondrial DNA alterations in colorectal carcinogenesis and, in particular, we revisit the issue of whether they may be considered as causative driver or simply genuine passenger events. The advent of high-throughput techniques as well as the development of genetic and pharmaceutical interventions for the treatment of mitochondrial dysfunction in colorectal cancer are also explored
Oxidative DNA damage drives carcinogenesis in MUTYH-associated-polyposis by specific mutations of mitochondrial and MAPK genes.
No full textMUTYH is a DNA-base-excision-repair gene implicated in the activation of nuclear and mitochondrial cell-death pathways. MUTYH germline mutations cause an inherited polyposis, MUTYH-associated-polyposis, characterized by multiple adenomas and increased susceptibility to colorectal cancer. Since this carcinogenesis remains partially unknown, we searched for nuclear and mitochondrial gene alterations that may drive the tumorigenic process. Ninety-six adenomas and 7 carcinomas from 12 MUTYH-associated-polyposis and 13 classical/attenuated adenomatous polyposis patients were investigated by sequencing and pyrosequencing for the presence of mutations in KRAS, BRAF, MT-CO1/MT-CO2 and MT-TD genes. KRAS mutations were identified in 24% MUTYH-associated-polyposis vs 15% classical/attenuated familial polyposis adenomas; mutated MUTYH-associated-polyposis adenomas exhibited only c.34G>T transversions in codon 12, an alteration typically associated with oxidative DNA damage, or mutations in codon 13; neither of these mutations was found in classical/attenuated familial polyposis adenomas (PT transversions, prevalently occurring with BRAFV600E; none of the classical/attenuated familial polyposis carcinomas displayed these alterations. Comparing mitochondrial DNA from lymphocytes and adenomas of the same individuals, we detected variants in 82% MUTYH-associated-polyposis vs 38% classical/attenuated familial polyposis patients (P=0.040). MT-CO1/MT-CO2 missense mutations, which cause aminoacid changes, were only found in MUTYH-associated-polyposis lesions and were significantly associated with KRAS mutations (P=0.0085). We provide evidence that MUTYH-associated-polyposis carcinogenesis is characterized by the occurrence of specific mutations in both KRAS and phylogenetically conserved genes of mitochondrial DNA which are involved in controlling oxidative phosphorylation; this implies the existence of a colorectal tumorigenesis in which changes in mitochondrial functions cooperate with RAS-induced malignant transformation
Mitochondrial variants in MT-CO2 and D-loop instability are involved in MUTYH-associated polyposis
No full textMitochondrial DNA alterations have been widely reported in different human tumours, including colorectal carcinoma, but their mutational spectrum and pathogenic role in specific subsets of patients with polyposis syndromes have been poorly investigated. We compared the breadth of somatic variants across the mitochondrial genome of MUTYH-associated polyposis (MAP) patients with homogeneous groups of classical/attenuated familial adenomatous polyposis (FAP/AFAP) and sporadic cases. Overall, we screened 121 adenomas and seven adenocarcinomas and their corresponding germinal controls, for mitochondrial genes with a crucial role in oxidative phosphorylation and translation (MT-CO1, MT-CO2, MT-CO3, MT-TD, MT-TS1, MT-ATP6) as well as a hypervariable sequence (HV-II) within the control region displacement loop (D-loop), a marker of hypermutability and clonal expansion. The sequencing analysis revealed the presence of 17 variants, mostly causing non-synonymous changes in conserved amino acid residues, typically distributed in the MT-CO2 gene of MAP patients (P A variant. Accordingly, D-loop instability was also significantly associated with variants grouped inside the MT-CO2 gene (P = 0.0061). This is the first report showing a locus-specific distribution of mitochondrial DNA alterations in a subtype of colorectal tumourigenesis. In addition, our findings suggest that MT-CO2 variants, representing early molecular events in MAP tumorigenesis, might be a potential prognostic biomarker for the cancer-risk assessment of patients affected by this syndrome
Analisi mediante MLPA del gene APC in pazienti italiani e greci con diagnosi di poliposi attenuata.
No full textAPC haploinsufficiency, but not CTNNB1 or CDH1 gene mutations, accounts for a fraction of familial adenomatous polyposis patients without APC truncating mutations
No full textFamilial adenomatous polyposis (FAP) is an autosomal dominant condition characterized by the development of hundreds to thousands of colorectal adenomatous polyps. In addition to the classic form, there is also attenuated polyposis (attenuated adenomatous polyposis coli; AAPC), which is characterized by a milder phenotype. FAP/AAPC is caused by germline mutations in the adenomatous polyposis coli (APC) gene. Very recently, germline mutations in the base-excision repair gene MYH have been associated with recessive inheritance of multiple colorectal adenomas in a subset of patients. APC pathogenic alterations are mostly (>95%) represented by frameshift or nonsense mutations leading to the synthesis of a truncated protein. We identified 20 APC truncating mutation carriers out of 30 FAP/AAPC patients from different Italian kindreds. In the remaining 10 patients, we searched for alterations other than truncating mutations by enzymatic mutation detection, real-time quantitative RT-PCR, and genotyping of polymorphic markers encompassing the APC locus. Moreover, to assess whether mutations of genes interacting with APC can substitute or act in association with APC alterations, we sequenced both CTNNB1 (beta-catenin) and CDH1 (E-cadherin) genes. No CTNNB1 or CDH1 mutations were found. On the contrary, four patients showed a reduced APC gene expression compared with healthy subjects. In three of the four cases, genotyping results were compatible with a constitutive allelic deletion. In one case this conclusion was confirmed by haplotype segregation analysis. Our results support the notion that FAP/AAPC can result from APC constitutive haploinsufficiency, with gene deletion being a possible cause of reduced gene expression
Constitutional high expression of an APC mRNA isoform in a subset of attenuated familial adenomatous polyposis patients
No full textFamilial adenomatous polyposis is an inherited condition associated with hundreds to thousands of colorectal adenomas conferring a very high risk of cancer at a young age. In addition to “classical” form, there is also an attenuated polyposis, with fewer than 100 polyps and a delayed age of cancer onset. Both classical and attenuated polyposis are characterized by a relevant phenotypic heterogeneity. The disease has been linked to constitutive mutations of either APC tumor suppressor gene, or less frequently, MYH base-excision repair gene. However, the genetic cause remains undetected in up to 70–80% of patients with the attenuated form. This analysis was performed on 26 polyposis patients with the attenuated phenotype. All patients had formerly proven to be negative for APC truncating mutations that typically represent the majority of APC gene alterations. We evaluated the APC mRNA constitutional level by real-time quantitative reverse transcription polymerase chain reaction (PCR). Eleven patients (42%) showed an anomalous APC transcription level. One patient with reduced mRNA was a carrier of a whole APC gene deletion. In seven out of the ten remaining cases, we found the increased expression of an APC mRNA isoform resulting from exon 10/15 connection and giving rise to a stable truncated peptide. Mutations neither in the invariant splice sites nor in the known transcription regulatory signals were found. Our results support the notion that in attenuated polyposis patients, a detailed investigation of APC transcription can allow detection of rare alterations. Although functional data are required, the isoform we observed might have some pathogenic role, accounting for the heterogeneous phenotype that characterizes the polyposis syndrome
High frequency of MYH gene mutations in a subset of patients with familial adenomatous polyposis
No full textBackground & Aims: Inherited colorectal polyposis has been linked to constitutive mutations of the APC tumor suppressor gene. Recently, germline mutations in the base excision repair gene MYH have been associated with a recessively inherited form of the disease.The aim of this study was to evaluate germline mutation frequencies of both MYH and APC susceptibility genes in Italian patients with attenuated familial adenomatous polyposis. Methods: The analysis was performed in 14 unrelated patients by using the protein truncation test for APC and genomic DNA sequencing for MYH. Results: Overall, we identified 7 of 14 (50%) mutation carriers. Two patients were heterozygotes for an APC truncating mutation (2 of 14 [14%]), whereas 5 proved to be homozygotes or compound heterozygotes for MYH gene alterations (5 of 14 [36%]). Two MYH missense mutations, Y165C and G382D, already found to be frequent among patients from northern Europe, were also preponderant in our survey. Individuals with APC-associated syndrome showed a dominant family history of polyposis, whereas patients with MYH-associated disease were either apparently sporadic cases or had a family history consistent with recessive inheritance. MYH biallelic mutation carriers were up to 60% (5 of 8) among patients showing at least 30 adenomas and a family history with no vertical transmission of polyposis. Conclusions: On the basis of our data, patients with attenuated familial adenomatous polyposis with >30 adenomas and no obvious vertical transmission of the disease should be considered for MYH gene testing
MUTYH-associated polyposis (MAP), the syndrome implicating Base Excision Repair in inherited predisposition to colorectal tumors
No full textIn 2002, Al-Tassan and co-workers described for the first time a recessive form of inherited polyposis associated with germline mutations of MUTYH, a gene encoding a base excision repair (BER) protein that counteracts the DNA damage induced by the oxidative stress. MUTYH-associated polyposis (MAP) is now a well-defined cancer susceptibility syndrome, showing peculiar molecular features that characterize disease progression. However, some aspects of MAP, including diagnostic criteria, genotype-phenotype correlations, pathogenicity of variants, as well as relationships between BER and other DNA repair pathways, are still poorly understood. A deeper knowledge of the MUTYH expression pattern is likely to refine our understanding of the protein role and, finally, to improve guidances for identifying and handling MAP patients
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