The Etiology of Cancer: Somatic Cell Genetics

27 May

While germline genetic factors are likely to be involved as major causes in the genesis and de- velopment of 20% or more of human cancers, it is now evident that genetic alterations in so- matic cells occur in virtually all neoplasms. A somatic mutation results in a hereditary alteration in the non-germ cells of the mature or maturing organism. Although this definition does not re- quire that the heritably transmitted change necessarily be due to an alteration in the genome it- self, epigenetic alterations that result in the neoplastic transformation are not usually considered as mutations.

Early in this century Theodore Boveri (1914), after extensive studies of the mitotic appara- tus and chromosomes of both normal and neoplastic cells, proposed that cells of malignant neo- plasms possess the uniform characteristic of abnormal karyotypic morphology. Such abnormalities  might reside in the mitotic apparatus as well as in the structure and/or chromo- somes themselves. While Boveri’s thesis lay almost dormant until the revolution in molecular genetics during the last several decades, today it is apparent that his original thesis probably applies to virtually all known neoplasms. A number of studies over the years have reported nor- mal karyotypes in both human (Tseng and Jones, 1969; Joensuu et al., 1986; Mitelman, 1981) and animal neoplasms (Mitelman, 1974; Nowell et al., 1967), but more recent studies have ques- tioned the significance  of “normal”  karyotypes  in malignant  cells. While nearly one-third  of more than 300 cases of acute lymphoblastic leukemia exhibited normal karyotypes, as evidenced in a workshop in 1980 (Mitelman, 1981), more recent advances have questioned the normalcy of earlier studies (Yunis, 1984; Misawa et al., 1988). In addition, more extensive investigation of “diploid” transplantable hepatomas in rats (Wolman et al., 1973) did not confirm earlier reports of normal karyotypes in these solid tumors. Thus, it is likely that with refinement of cytogenetic methods, virtually all malignant  neoplasms  will be found to exhibit abnormal  karyotypes,  as Boveri postulated.

TYPES OF STRUCTURAL  MUTATIONS:  SOMATIC  AND GERMLINE GENETICS

We have already noted (Chapter 5) that a variety of different types of mutations including chro- mosomal deletions may result in germline inherited cancer predisposition. However, the variety of known genetic mutations that can be found in neoplastic cells is quite extensive and likely to be expanded as more detailed knowledge of structural alterations in DNA occurs. Table 6.1 lists structural mutations in genes that may result in the alteration of genetic expression, the hallmark of the “relative autonomy”  of our original definition of neoplasia (Chapter 2). While “silent” mutations occur, even some of these may lead ultimately to alterations in expression and/or reg-

ulation of genetic information (Shub and Goodrich-Blair,  1992). The events listed in Table 6.1 may potentially occur in most genes, but they are most relevant to the expression and function of genes that play a significant role in the neoplastic transformation, i.e., proto- and cellular onco- genes and tumor suppressor genes. Although we have discussed several of these genes already (Chapters 4 and 5), their characteristics are reviewed in Table 6.2. Point mutations in genes can lead to structural alterations in the gene product that change its function, as in the case of the ras proto- and cellular oncogenes that code for G proteins important in signal transduction (Chapter

7). Dominant negative mutations (Herskowitz, 1987) result in a new gene product that interferes with the function of the normal gene product, which is encoded by the remaining normal allele. Probably  the most common  somatic  mutation  in neoplasia  involves  structural  alterations  in genes that govern chromosomal alterations, insertional mutagenesis, and gene amplification (Ta- ble 6.1). In fact, the frequency of the latter type of mutations is significantly higher than that of point mutations in cells (Holliday, 1991). Dynamic mutations are the result of changes in the copy number of repeated sequences within genes. In the fragile X syndrome, there is more than a fourfold increase in the number of CGG repeats within the coding sequence of a specific X- linked gene, the FMR-1 gene (Fu et al., 1991). This syndrome is a leading cause of mental retar- dation worldwide (Nelson, 1995) and has been associated with a possible increase in neoplastic disease (Cunningham  and Dickerman, 1988). On the other hand, fragile sites—i.e., regions of chromosomes exhibiting instability toward breakage in the presence of antifolates, ionizing radi- ation—and  certain carcinogens  have been related to chromosomal  rearrangements  commonly

seen in a variety of different types of neoplasms (Yunis and Hoffman, 1989; De Braekeleer et al.,

1985). These mutations are to be distinguished from those induced by “mutator” genes, which cause microsatellite  instability  resulting from a lack or alteration  of “mismatch”  DNA repair (Chapter 3). Although mutations in such genes have been linked to the germline inheritance of nonpolyposis colon cancer, somatic mutations in these “mutator” genes occur as somatic muta- tions in colon and other neoplasms (Rüschoff et al., 1995). Recombinatorial  events are many times associated  with chromosomal  alterations  but may occur within the individual  chromo- some, as evidenced by various rates of sister chromatid exchange in both normal (Elbling and Colot, 1986) and neoplastic (Slavutsky et al., 1984) cells.

Theoretically,  somatic mutations may reflect any one or several of the mutations (Table

6.1) occurring within a single cell. Furthermore,  spontaneous  mutations occur in somatic cells quite frequently (Chapter 3; Bridges et al., 1994). In studying somatic mutations in neoplastic cells, until recently the principal evidence for the occurrence of somatic mutations in neoplasia was the presence of chromosomal abnormalities. The expansion of methods and increased knowl- edge of gene structure have now made it possible to identify point, frameshift, and small deletion mutations in individual genes involved in carcinogenesis,  i.e., oncogenes and tumor suppressor genes. However, the major dilemma in the importance of somatic mutagenesis in neoplastic dis- ease is whether such mutations are the result or the primary cause of the neoplastic process.

Random Posts

Comments are closed.