Genetics of Head and Neck Cancer

Cancer of the head and neck accounts for about 5% of all deaths of cancer in the United States (26). Since approximately 1980, innovations in standard surgical treatment, radiation therapy, and chemotherapy have resulted in only modest improvements in survival from squamous cell carcinoma of the head and neck. The goal of research directed at understanding the basic genetic mechanisms of head and neck cancer is to increase the survival rate among persons with cancer of the head and neck.

Most malignant tumors among humans develop in a complex interaction between genetic and environmental factors. At the most basic level, all cancers are genetic in that development and progression occur because of accumulation of chromosomal and genetic mutations. Four basic relationships can be identified: persons with genetic predisposition for cancer but no environmental exposure, persons with environmental exposure but no genetic predisposition, spontaneous mutations among persons who have neither genetic predisposition nor environmental exposure, and persons with both genetic predisposition and environmental exposure (27). There has long been evidence that squamous cell carcinoma of the head and neck may have a genetic basis despite the existence of known and multifactorial environmental influences (27,28 and 29). In families with smoking-related malignant disease, genetic analysis supports an autosomal dominant inheritance pattern (30). This genetic susceptibility also may explain why some persons with only mild tobacco or alcohol exposure have squamous cell carcinoma of the head and neck, whereas others with many times more use never do (27).

Loss or alteration of cell-cycle control is an intrinsic factor in the development of cancer. Tumor suppressor genes are genes that have been identified as having regulatory control of the cell cycle. When such regulatory forces are altered or lost because of mutational events, cell-cycle control is changed. Poorly regulated or prolific cell growth can occur, and cancers can develop.

Oncogenes are genes that have been causally identified with the development of cancer. An example is the RET oncogene. Germline mutations in RET, located on chromosome 10q11.2, have been identified in families that manifest hereditary medullary carcinoma of the thyroid (31). Identification of RET mutations is used as screening for multiple endocrine neoplasia type 2b and familial medullary carcinoma of the thyroid. Because early identification and management of medullary carcinoma of the thyroid markedly affect outcome and survival, genetic screening of patients and their close relatives has become a critical part of the diagnosis and management of medullary carcinoma of the thyroid. In most cancer types, both loss of tumor suppressor genes and oncogene activation occur. The former is believed to be more important than the latter for squamous cell carcinoma of the head and neck (32). Many of the known oncogenes and tumor suppressor genes are common to many cancers, and identification of a genetic abnormality in one tumor type often is relevant to others.

Some persons are more susceptible to cancer because they are heterozygous for a tumor suppressor or oncogene mutation. Because a single, inherited altered gene already is present in a diploid cell (one hit), only the remaining normal gene copy has to mutate for cancer to develop (two hits). Without the original hereditary abnormality, development of cancer is less likely because two acquired mutations would have to occur. This premise has been shown to be true for some cancers. Retinoblastoma occurs in both heritable and sporadic patterns. Sporadic retinoblastoma is unilateral (30). Persons with the hereditary form have loss or mutation and inactivation of a tumor suppressor gene called Rb1. These persons have a hereditarily determined single hit. The likelihood that retinoblastoma will develop is nearly 50%, and these lesions often are bilateral. Fifty percent of offspring are susceptible to the cancer. The RB1 tumor suppressor gene helps to regulate transcription of other genes and thus is involved in regulation of the cell cycle. Insertion of a normal RB1 gene can result in a return of normal cell regulation (33).

Cytogenetics has been used in the study of squamous cell carcinoma of the head and neck (34,35). Several chromosomal abnormalities have been identified. Oncogenes and tumor suppressor genes are presumed to be located at the breakpoints of these deletions, amplifications, and translocations. Common chromosomal abnormalities identified in squamous cell carcinoma of the head and neck include 3p-, believed to be an early chromosomal change in squamous cell carcinoma of the head and neck; 11q13 rearrangements, the location of the cyclin D1 oncogene (36); and 9p21-22, the site of cell cycle gene p16 (32). Loss of 18q is likely related to advanced disease and carries a poor prognosis (36,37). Other chromosomal losses include 5q, 8p, and 13q,17p. Amplifications include 3q, 5q, and 11q. Cancer cells can be haploid (half the normal DnA content), diploid (two times the normal DNA content), or tetraploid (four times the normal DNA content). Aneuploidy (abnormal DNA content) is a feature of many cancer cells. It is believed to be caused by altered proliferation of tumor cells and to reflect aggressive clinical behavior (38). Ploidy analysis, however, has not shown any prognostic factors and has done little to help identify the nature of head and neck cancer (38).

The cell-cycle gene most widely studied in relation to cancer among humans is the tumor suppressor gene p53, found on chromosome 17p. The p53 protein helps to control the cell cycle by binding with cyclin-dependent kinins to arrest cell replication in G1 (39). This allows the cell to repair any DNA damage or mutations that have occurred. If DNA repair fails, p53 can induce apoptosis or programmed cell death (36). Loss of activity of p53 results in an increase in the number of chromosomal abnormalities (40). This loss of p53 occurs in more than half of instances of squamous cell carcinoma of the head and neck. For patients with a p53 abnormality in the index tumor, p53 can be evaluated at the margins of the tumor at the time of resection. The presence of mutant p53 at the margins is predictive of recurrence, even if the margins appear normal at light microscopic examination (41). It is likely that the presence of p53 is related to early genetic changes in squamous cell carcinoma, such as the conversion of normal mucosa to dysplastic mucosa. Although p53 overexpression has been found to be predictive of a favorable response to chemotherapy and organ preservation protocols, p53 expression has not been found to be predictive of survival from squamous cell carcinoma of the head and neck (36).

Cyclin D1, located at chromosome 11q13, is the most frequently amplified protooncogene in squamous cell carcinoma of the head and neck. This oncogene product accelerates cell cycle progression. Overexpression correlates with advanced disease and reduced overall and disease-free survival rates (32). The p16 gene product is an inhibitor of cyclin pathways and cyclin D1 and therefore is involved in cell cycle regulation. Inactivation of p16 is one of the earliest genetic events in squamous cell carcinoma of the head and neck (32).

The bcl family gene products are involved in cell cycle regulation and apoptosis. The bcl-2 gene product inhibits apoptosis by blocking p53 dependent pathways. Overexpression of bcl-2 has been linked to resistance to chemotherapy. The bax gene encodes an inhibitor of bcl-2. Bcl-xL prevents apoptosis; bcl-xs promotes apoptosis (36).

Epidermal growth factor, epidermal growth factor receptor, and transforming growth factor a are growth factor gene products frequently overexpressed in squamous cell carcinoma of the head and neck. None has been shown to be a reliable prognostic indicator or tumor marker for recurrence (32).

Squamous cell carcinoma of the head and neck arises from a clonal population of cells that have acquired many genetic alterations in a several-step process (34). Unlike the colon cancer model, in which an orderly sequence of genetic events leads from adenoma to metastatic carcinoma (42), it is likely that the genetic mutations in squamous cell carcinoma of the head and neck do not necessarily follow one rigid sequence. Nonetheless, certain genetic changes are believed to occur early and can be found in dysplastic tissue. Others occur late and reflect invasive squamous cell carcinoma. A possible progression of genetic changes for squamous cell carcinoma of the head and neck is depicted in Fig. 2.10.

FIGURE 2.10. A sequence of genetic changes in squamous cell carcinoma of the head and neck. This scheme does not imply that abnormalities arise in the sequence shown; each may be independent of the appearance of the others. It is becoming more evident, however, that some changes are associated with more advanced stages of the disease and likely also with important clinical factors, such as patient survival. Some chromosomal changes, such as loss of the short arm of chromosome 3 (3p-) and p53 mutations appear to occur early in the development of squamous cell carcinoma of the head and neck. They may have little effect on the progression to more advanced stages. Other changes, such as loss of the long arms of chromosomes 5 and 18 (5q-and 18q-) appear to occur later and may be related to greater invasiveness or increased risk of recurrence and metastasis.

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