Section 3

#### Familial Cancer Syndromes: The Role of Caretakers and Gatekeepers

Abstract  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.

### Introduction

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.

###### Fig. 27-1

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 ...

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