Mitochondrial C-tract alteration in premalignant lesions of the head and neck: a marker for progression and clonal proliferation.
OBJECTIVE
Although mitochondrial DNA mutations have been described recently in many different tumor types, the nature and timing of such alterations remain unclear. In an effort to further examine the role of mitochondrial DNA mutations in carcinogenesis, we examined 137 premalignant lesions of the head and neck from 93 patients for DNA alterations in the poly-cytosine tract (C-tract) of the displacement loop, discovered recently to be a hot spot of mitochondrial DNA alteration. EXPERIMENTAL DESING: All premalignant lesions were tested using a length-based PCR assay, which amplified the C-tract region of mitochondrial DNA. Somatic microsatellites at six loci were also tested on a subset of patients with metachronous or synchronous lesions found to possess a mitochondrial C-tract alteration.


RESULTS
Thirty-four of 93 (37%) patients harbored lesions that displayed a C-tract alteration. There was a clear increase in incidence from histologically benign hyperplasia (22%) to squamous carcinoma in situ (62%: P < 0.01). We also tested synchronous dysplastic lesions, metachronous dysplastic lesions, and normal epithelium adjacent to dysplastic epithelium with this assay. In most cases, the mitochondrial C-tract status identified a clonal relationship between these lesions. Genomic microsatellites also confirmed that a clonal relationship was present in many of these cases.


CONCLUSIONS
Mitochondrial DNA alterations in the head and neck occur in the earliest premalignant lesions and demonstrate a rising incidence that parallels histological severity. These alterations are valuable as additional markers of histopathological progression.
Departments of Otolaryngology, Head and Neck Cancer Research Division, Johns Hopkins Medical Institution, Baltimore, Maryland 21205, USA.
Patrick K
PK
Ha
Betty C
BC
Tong
William H
WH
Westra
Montserrat
M
Sanchez-Cespedes
Paola
P
Parrella
Marianna
M
Zahurak
David
D
Sidransky
Joseph A
JA
Califano
D014408:Biomarkers, Tumor / Q000235:genetics*; D001706:Biopsy; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000473:pathology; D016022:Case-Control Studies; D017931:DNA Primers / Q000737:chemistry; D004272:DNA, Mitochondrial / Q000235:genetics*; D004273:DNA, Neoplasm / Q000032:analysis; D006258:Head and Neck Neoplasms / Q000235:genetics* / Q000473:pathology; D006801:Humans; D018895:Microsatellite Repeats; D009154:Mutation; D011066:Poly C / Q000235:genetics*; D016133:Polymerase Chain Reaction; D011230:Precancerous Conditions / Q000235:genetics*
D014408:Biomarkers, Tumor; D017931:DNA Primers; D004272:DNA, Mitochondrial; D004273:DNA, Neoplasm; D011066:Poly C