The past decade has witnessed the elucidation of the specific genetic bases of nearly twenty inherited predispositions to cancer. This information not only is yielding immediate practical benefits in the form of genetic testing but also is providing important insights into mechanisms regulating cancer susceptibility.
The inheritance of a predisposition to a sporadic event such as tumor formation has always presented an interesting problem. The complexity of this problem is compounded by studies of the age dependence of cancer incidence and other studies that suggest that multiple genetic changes are required for cancer formation. This prompted Knudson to postulate that individuals with an autosomal dominant cancer susceptibility inherited one genetic alteration that was rate-limiting for tumor formation but that subsequent steps also were required for a tumor to form. Over the years, Knudson's hypothesis has been refined to include the idea that one of the key subsequent steps is a somatic, inactivating mutation of the wild-type allele inherited from the unaffected parent. Knudson's hypotheses have been confirmed abundantly within the last 20 years (e.g., Rb in retinoblastoma, Chap. 36; APC in colorectal cancer, Chap. 48), and concrete demonstrations of the multiple genetic events required for tumorigenesis have emerged (e.g., colorectal cancer, Chap. 48). The characterization of the genes underlying inherited predispositions to neoplasia also has provided important insights into the nature of tumor suppressor genes.
It appears that most tumor suppressor genes can be broadly divided into two groups, called gatekeepers and caretakers. Gatekeepers are genes that directly regulate the growth of tumors by inhibiting their growth or by promoting their death. The functions of these genes are rate-limiting for tumor growth, and as a result, both the maternal and paternal copies of these genes must be inactivated for a tumor to develop (Fig. 27-1). In accord with Knudson's hypothesis, predisposed individuals inherit one damaged copy of such a gene and as a result require only one additional mutation for tumor initiation. The identity of gatekeepers varies with each tissue such that inactivation of a given gene leads to specific forms of cancer predisposition. For example, inherited mutations of APC lead to colon tumors but not kidney cancers (see Chap. 48), whereas inherited mutations of VHL predispose to kidney cancers but not colon cancers (see Chap. 41). Because these gatekeeping genes are rate-limiting for tumor initiation, they must be mutated in sporadic cancers through somatic mutations as well as mutated in the germ line of predisposed individuals.
Pathways to neoplasia. Inherited mutation of either a gatekeeper or caretaker can predispose an individual to neoplasia. However, additional genetic changes are required to convert a predisposed cell to a neoplastic cell. In the case of the caretaker pathway, three additional mutations generally are required. However, the genetic instability that follows inactivation of the second caretaker allele accelerates the accumulation of the latter mutations. In the case of the gatekeeper pathway, only one additional mutation (inactivation of the second gatekeeper allele) is required to initiate neoplasia. (Although the concepts depicted in this figure apply to all inherited cancer susceptibilities, variations do occur. For example, inherited mutations of both alleles of a caretaker gene occur in recessively inherited diseases such as xeroderma pigmentosum, and a single dominant negative mutation can substitute for two inactivating mutations of a caretaker gene).
In contrast, inactivation of caretakers does not directly promote growth of tumors. Rather, inactivation of caretakers leads to a genetic instability that only indirectly promotes growth by causing an increased mutation rate. Because numerous mutations are required for the full development of a cancer, inactivation of caretakers, with the consequent increase in genetic instability, can greatly accelerate the development of cancers. Caretaker mutations in the germ line occur in two different forms. In dominantly inherited diseases (e.g., hereditary nonpolypsosis colorectal cancer; see Chap. 32), only one mutant allele of the caretaker is inherited; as with gatekeepers, the remaining allele of the caretaker gene must be mutated for a phenotypic defect (i.e., increased mutation rate) to be realized (see Fig. 27-1). In other cases, both alleles of the gene must be inherited in mutant form to cause susceptibility (e.g., XP; see Chap. 28). The targets of the accelerated mutagenesis that occurs in cells with defective caretakers are the gatekeeping tumor suppressor genes, other tumor suppressor genes (whose inactivation can lead to tumor progression), and oncogenes (genes whose activation leads to cancer). Somatic mutations of caretaker genes are only rarely found as initiating events in tumors arising in the general population, presumably because such mutations would still need to be followed by several other mutations in order for a tumor to initiate (see Fig. 27-1).
For the purposes of this book, we have divided cancer susceptibility syndromes into two forms, gatekeepers and caretakers, based on the predominant mechanism underlying the susceptibility. In some cases, the mechanism underlying the susceptibility is not completely characterized, and the assignments were made based on the best current evidence. For example, the BRCA1 and BRCA2 genes (see Chap. 47) have been hypothesized to function as caretakers in some studies and as gatekeepers in others; further research will be required to discriminate the true role of these genes in tumor suppression.