title: Mitochondrial variants in MT-CO2 and D-loop instability are involved in MUTYH-associated polyposis.
abstract: Mitochondrial 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 < 0.0001), who frequently carried the hot spot m.7763G>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.
  
  
  CONCLUSIONS
  We compared the frequencies of mtDNA variants in MAP vs. FAP/AFAP/sporadic patients. We found a gene-specific (MT-CO2) distribution of mtDNA variants in MAP cases. Most mtDNA variants caused non-synonymous changes in conserved amino acid residues. D-loop instability was significantly associated with variants grouped inside MT-CO2. MT-CO2 variants might be a potential prognostic biomarker in MAP patients.
authors.affiliation: Molecular Pathology Laboratory, Unit of Pathology, Institute for Cancer Research and Treatment, FPO-IRCCS, Strada Provinciale 142, 10060, Candiolo, Torino, Italy.
authors.forename: Edoardo
authors.initials: E
authors.lastname: Errichiello
authors.affiliation: Molecular Pathology Laboratory, Unit of Pathology, Institute for Cancer Research and Treatment, FPO-IRCCS, Strada Provinciale 142, 10060, Candiolo, Torino, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Balsamo
authors.affiliation: Molecular Pathology Laboratory, Unit of Pathology, Institute for Cancer Research and Treatment, FPO-IRCCS, Strada Provinciale 142, 10060, Candiolo, Torino, Italy.
authors.forename: Marianna
authors.initials: M
authors.lastname: Cerni
authors.affiliation: Molecular Pathology Laboratory, Unit of Pathology, Institute for Cancer Research and Treatment, FPO-IRCCS, Strada Provinciale 142, 10060, Candiolo, Torino, Italy. tiziana.venesio@ircc.it.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Venesio
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics*; D000236:Adenoma / Q000235:genetics*; D011125:Adenomatous Polyposis Coli / Q000235:genetics* / Q000378:metabolism; D014408:Biomarkers, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics*; D045647:DNA Glycosylases / Q000235:genetics; D004252:DNA Mutational Analysis; D003576:Electron Transport Complex IV / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008928:Mitochondria / Q000235:genetics*; D009154:Mutation; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; C117307:KRAS protein, human; C117108:cytochrome C oxidase subunit II; D003576:Electron Transport Complex IV; D045647:DNA Glycosylases; C061738:mutY adenine glycosylase; D016283:Proto-Oncogene Proteins p21(ras)
keywords: Cytochrome c oxidase complex (COX); Displacement loop (D-loop); MUTYH-associated polyposis (MAP); Mitochondrial DNA variants