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Clinical Cancer Research 13, 4331, August 1, 2007. doi: 10.1158/1078-0432.CCR-06-2613
© 2007 American Association for Cancer Research
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Human Cancer Biology

Mitochondrial Mutations Are a Late Event in the Progression of Head and Neck Squamous Cell Cancer

Suhail K. Mithani1, Janis M. Taube2, Shaoyu Zhou3, Ian M. Smith3, Wayne M. Koch3, William H. Westra2 and Joseph A. Califano3

Authors' Affiliations: 1 Division of Plastic and Reconstructive Surgery, Department of Surgery, 2 Department of Pathology, and 3 Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins Medical Institutions, Baltimore, Maryland

Requests for reprints: Joseph A. Califano, Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins Medical Institutions, 601 North Caroline Street, 6th Floor, Baltimore, MD 21287-0910. Phone: 410-502-5153; E-mail: jcalifa{at}jhmi.edu.


   Abstract
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Materials and Methods
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Purpose: To determine the timing of mitochondrial mutations in the progression of head and neck squamous cell carcinoma.

Experimental Design: Twenty-three mitochondrial mutations were identified in 12 tumors using a high-throughput mitochondrial sequencing array. Areas of adjacent dysplastic and normal epithelium adjacent to tumors were sequenced using conventional methods for the presence of mutations that occurred in the corresponding tumor.

Results: Two of 23 (8.7%) tumor mitochondrial mutations (2 of 12 tumors) were present in both the areas of adjacent dysplasia and normal epithelium. Five of 23 (21.7%) tumor mitochondrial mutations (4 of 12 tumors) were present in areas of adjacent dysplasia. Eleven of 12 tumors contained nonsynonymous mutations that resulted in protein coding alterations. A significant difference (P < 0.01, {chi}2) was found in the incidence of mitochondrial mutation that occurred after development of cancer compared with adjacent areas dysplasia and normal epithelium.

Conclusions: The majority of mitochondrial mutations occur during or after the transition of preneoplastic epithelium to cancer in head and neck squamous cell carcinoma, indicating that these are a late event in head and neck carcinogenesis.

The mitochondrial genome is a 16.6-kb double-stranded circular DNA containing no introns, including 13 genes that encode proteins that are involved in aerobic respiration, 22 tRNAs, and 2 rRNAs. The mitochondrial genome contains limited DNA repair mechanisms and is susceptible to DNA damage acquired both from reactive oxygen species generated by cellular metabolism and from extrinsic carcinogens, including tobacco and other substances. This susceptibility to mutation can potentially cause generation of additional reactive oxygen species due to impairment of oxidative phosphorylation, facilitating DNA damage to the nuclear or mitochondrial genome as well as dysregulation of apoptosis and other cellular processes (1).

Mitochondrial mutations have been identified in a variety of human cancers (2–13) in frequencies ranging from 30% to 70%. Germ-line mitochondrial mutations have been associated with increased risk for breast and ovarian cancer (5). Defects in protein function in genes bearing mitochondrial mutations have been shown in several cancer types and may contribute to carcinogenesis. Subunits of cytochrome oxidase are mutated in close to 40% of colorectal cancers (14), and cytochrome c activity is diminished in a subset of tumors of this variety (15). Cytochrome c activity has also been shown to be diminished in hepatocellular carcinoma (16), which has also been shown to harbor mitochondrial mutations. A specific mutation of the mitochondrial ATPase6 gene in a murine prostate cancer model has been shown to impair function of this gene and cause significant increase in tumor growth, presumably through increased reactive oxygen species generation (17).

Small studies of head and neck squamous cell carcinoma (HNSCC) have shown a frequency of mitochondrial mutation ranging from 21% to 51% and have focused on the displacement loop (D-loop) region. The timing of other mitochondrial mutations in the progression from normal mucosa to invasive tumor has not been well established (18, 19). The D-loop, which has propensity for mutation, was found to carry mutations in 21% to 53% of HNSCC (20, 21). Sequencing of 80% of the mitochondrial genome using conventional methods has revealed mutation in 46% in a limited cohort of HNSCC (2). Recently, a study by our group, using a high-throughput mitochondrial sequencing array for the entire mitochondrial genome, has shown a 49% of incidence of mitochondrial mutation in HNSCC in another limited cohort (22).

There have been several studies that have characterized a molecular progression model for HNSCC to determine where along the continuum of malignant transformation mutations and cytogenetic changes occur. Studies have shown that allelic loss at the 3p (23, 24) and 9p (23–25) loci occurs as an early event in carcinogenesis, before histopathologic development of dysplasia, and that the majority of genetic alterations occur before the development of an invasive phenotype (23). HNSCCs often exhibit widespread mucosal alteration adjacent to invasive cancer. These changes represent the lateral clonal expansion of premalignant clones that contain genetic alterations that are often identical to those found in associated invasive tumors (23, 26, 27). The timing of mitochondrial mutation as it relates to histopathologic progression in HNSCC has not yet been definitively determined, and previous studies that have surveyed premalignant lesions have been limited by looking at the D-loop rather than the entire mitochondrial genome (28, 29). In this study, we use data from a whole mitochondria sequencing array (22) to characterize the mutations that are present throughout the mitochondrial genome in 12 HNSCC tumors in a prior study. Areas of dysplasia and normal epithelium adjacent to the tumor were identified, microdissected, and sequenced to determine at what point in the histopathologic progression HNSCC mitochondrial mutations can be found.


   Materials and Methods
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Results
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 References
 
Sample procurement. An initial cohort of 83 patients was sequenced for mutations in the mitochondrial genome. Mitochondrial mutation status in these tumors was identified by sequencing of tumors and matched leukocyte DNA samples using the MitoChip version 2.0 mitochondrial resequencing array (Affymetrix) as described previously (22). Tumors with missense mutations or mutations located in a functional portion of the mitochondrial genome were identified by comparison of tumor sequence with matched leukocyte sequence. For those tumors with mitochondrial mutations (n = 41), surgical resection specimens were reviewed to identify cases with premalignant changes present in adjacent surface epithelium (n = 12). From each case, at least one representative tissue block was selected for lesional microdissection and DNA extraction.

H&E-stained slides were reviewed by a head and neck pathologist with extensive experience in grading dysplasias of the upper aerodigestive tract (W.H.W.). The presence and degree of dysplasia was graded according to the guidelines established by the WHO (30). Areas of histologically normal epithelium were identified as well.

Microdissection and DNA extraction. Sections (10 µm) were cut from paraffin blocks and microdissected using H&E-stained slides as a guide. The samples were placed in xylene for 12 h with subsequent centrifugation at 13,500 rpm. The tissue pellets were then digested in 1% SDS/proteinase K over 48 h at 48°C. Subsequent phenol-chloroform extraction and ethanol precipitation were done, and samples were stored at –20°C.

Sequencing. To assess DNA microdissected from area of normal and dysplasia, multiple pairs of primers were designed to amplify mitochondrial segments. The forward and reverse primers are listed in Table 1 . PCR amplification was done using 100 ng of sample DNA as template. The PCRs were carried out in a 96-well thermocycler. Cycling conditions were as follows: a denaturation step at 95°C for 5 min was followed by 30 cycles of denaturation at 95°C for 1 min, annealing at 60°C for 1 min, primer extension at 72°C for 1 min, and one final extension at 72°C for 5 min. Amplified fragments were separated on an agarose gel and visualized by ethidium bromide staining. PCR products were purified using a Qiagen gel extraction kit (Qiagen). The purified DNA products were then sequenced with dye terminator platform using the ABI BigDye cycle sequencing kit (Applied Biosystems) using the same primers as for initial amplification to sequence.


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  		Table 1. Primers used to amplify and sequence mitochondrial mutations

 

   Results
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Microdissected samples and mitochondrial mutations. Twelve areas of dysplasia and normal epithelium adjacent to tumors containing mitochondrial mutations were identified and microdissected. Primary HNSCC associated with the dissected dysplasias contained a total of 23 mitochondrial mutations. Mitochondrial position, nature of mutation, and resultant amino acid changes are indicated in Table 2 . The mutations identified in tumors were those that are likely to have an effect on mitochondrial function either as nonsynonymous missense or nonsense mutation of functional genes (17 of 23, 73.9%) or affected mitochondrial rRNA (2 of 23, 8.7%). The remaining mutations were in the D-loop (2 of 23, 8.7%) or represented synonymous mutations, which do not result in amino changes (2 of 23, 8.7%).


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  		Table 2. Summary of mitochondrial mutations present in tumors, dysplasia, and normal epithelium

 
Mitochondrial mutation is found infrequently in dysplastic lesions and normal mucosa surrounding HNSCC. DNA microdissected from areas of dysplasia and normal epithelium surrounding HNSCC tumors with known mitochondrial mutations was sequenced using conventional methods (results summarized in Table 2). Four of 12 (33.3%) samples showed presence of at least one identified mutation from the tumor in an area of dysplasia, with a total of five mutations found in these areas of dysplasia. Two of 12 (16.7%) samples had identified mitochondrial mutations in areas of adjacent normal epithelium, with one single mutation found in each of these two areas of normal epithelium. Mutations that were present in normal epithelium were also present in areas of dysplasia (Fig. 1A ). Two of 12 (12.5%) patients had mitochondrial mutations, which were present in dysplastic areas but not in normal epithelium. Eighteen of 23 (78.3%) mutations were not seen in either the dysplastic epithelium or the adjacent normal epithelium (Fig. 1B). There was no evidence of mutations other that those that were originally identified in primary tumors.


Figure 1
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  		Fig. 1. Representative samples of adjacent dysplasia and normal epithelium with sequencing data. A, sample 2. G-A substitution at position 3700 in the ND1 gene resulting in amino acid substitution A-T present in both normal and dysplastic epithelium. B, sample 12. A-G substitution at position 5390 in the ND2 gene resulting in noncoding mutation of ND2 gene. Not present in either dysplasia or normal epithelium. Sequencing data corresponding to identified areas of normal and dysplastic epithelium are shown below each image.

 
The identified mutations can be grouped into three different categories based on the presence of tumor mutations in dysplasia and normal epithelium to reflect the timing of their occurrence on the continuum toward carcinogenesis. Mutations are designated as an early event if they are present in normal epithelium, dysplastic epithelium, and tumors; designated intermediate events if they are present in dysplasia and tumors but not in normal epithelium; and designated late events if they are present in tumors but not in associated dysplasia and normal epithelium (Table 3 ). Using this classification, 2 of 23 (8.7%) mutations are classified as early, 3 of 23 (13.0%) mutations are classified as intermediate, and 18 of 23 (78.2%) mutations are classified as late (Fig. 2 ). The incidence of mitochondrial mutations as late events in HNSCC carcinogenesis is statistically significantly different than the incidence as early or intermediate events independently or combined (P < 0.01, {chi}2).


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  		Table 3. Most mitochondrial mutations are late events in HNSCC

 

Figure 2
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  		Fig. 2. Occurrence of mitochondrial mutations in tumors and matched adjacent dysplastic and normal epithelium. Mutations (8.7%) are early events, 13.0% of mutations are intermediate, and 78.3% of mutations are late events. {chi}2 analysis shows a statistically significant difference between incidences of mitochondrial mutations as a late event and early and/or intermediate event (P < 0.01).

 

   Discussion
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 Abstract
 Materials and Methods
 Results
 Discussion
References
 
We have used a high-throughput mitochondrial resequencing array to identify mutations throughout the entire mitochondrial genome of a series of HNSCC. Adjacent areas of dysplasia and normal epithelium were identified, microdissected, and sequenced to determine whether mutations that were present in the tumors were also present in these areas. Mitochondrial mutations were found to generally occur late in HNSCC carcinogenesis and associated with progression from dysplasia to cancer. Based on this study, it is unclear whether these mutations are etiologically involved or are only markers for progression. Ongoing studies have shown some mitochondrial mutations are associated with characteristic tumor phenotypes (31). Given the compact nature of the mitochondrial genome and its primary role in aerobic metabolism, nonsense and missense mutation of mitochondrial genes, tRNAs, and transcriptional control elements may function independently or synergistically in dysregulation of oxidative phosphorylation, resulting in free radical damage and tumor progression (32).

Mitochondrial mutations occurred only in invasive tumors and not in dysplasia in the majority of samples (8 of 12, 66.7%), and most mutations (18 of 23, 78.3%) were found in invasive disease and not in the dysplasia and normal epithelium associated with tumors. This timing of occurrence is similar to other genetic alterations that have been previously described in HNSCC, such as cyclin D1 amplification and pTEN deletion, which have been shown to occur after histopathologic progression to dysplasia (33).

The concordance of tumor-specific mutations with mutations in adjacent normal epithelium and dysplasia (2 of 23 mutations in 2 of 12 samples) indicates that a minority of mitochondrial mutations occur as an early event HNSCC carcinogenesis before occurrence of invasion or dysplastic histologic changes. However, in these cases, a characteristic clonal relationship is identified by identical mitochondrial mutations in normal dysplastic and invasive tumor. This is consistent with the lateral spread of altered clonal progenitors of invasive disease and is indirect evidence for an etiologic role for mitochondrial mutation in carcinogenesis. The late occurrence of mitochondrial mutation may also indicate that this provides a clonal advantage during the later stages of invasion and acquisition of metastatic potential.

Previous studies by our group on a different cohort of HNSCC investigated the frequency of mitochondrial deletions and insertions of the polycytosine tract (C-tract) of the D-loop of premalignant lesions of the head and neck in the absence of HNSCC and found that 37% of lesions had alterations of the C-tract and incidence of alteration correlated with grade of lesion (28). Another study that surveyed the D-loop for somatic mutations in HNSCC and an at-risk population revealed low frequency of mutation of the hypervariable regions of the D-loop in the at-risk population (29). These studies focus on the D-loop, which has a high incidence of polymorphism and poorly understood mechanism of functional effect. Our current study represents an expansion of this previous work and shows a propensity for development of more potentially functional mutations that may disrupt oxidative phosphorylation later in carcinogenesis. Our analysis of dysplasia in direct relation to tumor with mitochondrial mutations provides a more direct view of the mitochondrial genetic progression of the disease because tumor growth presumably represents expansion of a clonal population with a selective growth advantage, possibly derived from mitochondrial mutation. Further studies about the functional effect and oncogenic potential of mitochondrial mutations are ongoing.

Information about the role, patterns, and timing of mitochondrial mutations in HNSCC may serve to potentially facilitate clinical applications related to detection of these mutations. With the advent of high-throughput approaches, rapid, accurate genotyping of the complete mitochondrial genome in a particular tumor has become feasible. Knowledge of the role of mitochondrial mutation in tumor biology and knowledge of particular mutations present in a particular tumor or type of tumor may be helpful in assessing cancer risk, distinguishing between new primary cancers versus recurrence, or identifying the site of origin of an unknown primary tumor.


   Footnotes
 
Grant support: J.A. Califano is a Damon Runyon-Lilly Clinical Investigator supported by the Damon Runyon Cancer Research Foundation grant CI-#9, a Clinical Innovator Award from the Flight Attendant Medical Research Institute, the National Institute of Dental and Craniofacial Research grant 1R01DE015939-01, and the National Cancer Institute Head and Neck Specialized Program of Research Excellence grant P50 CA96784. W.M. Koch is supported by the National Institute of Dental and Craniofacial Research grant R01 DE013152.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 10/29/06; revised 2/28/07; accepted 3/16/07.


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Commentary

A Disturbance in the Force—Mitochondrial Mutations in Squamous Cell Carcinoma of the Head and Neck
Ezra E.W. Cohen
Clin. Cancer Res. 2007 13: 4317-4319. [Full Text] [PDF]



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