A small fraction of cancers occur in patients with a genetic predisposition. In these families, the affected individuals have a predisposing loss-of-function mutation in one allele of a tumor-suppressor gene. The tumors in these patients show a loss of the remaining normal allele as a result of somatic events (point mutations or deletions), in agreement with the two-hit hypothesis (Fig. 25-4). Thus, most cells of an individual with an inherited loss-of-function mutation in a tumor-suppressor gene are functionally normal, and only the rare cells that develop a mutation in the remaining normal allele will exhibit uncontrolled regulation.
Roughly 100 syndromes of familial cancer have been reported, although many are rare. The majority are inherited as autosomal dominant traits, although some of those associated with DNA repair abnormalities (xeroderma pigmentosum, Fanconi’s anemia, ataxia telangiectasia) are autosomal recessive. Table 25-3 shows a number of cancer predisposition syndromes and the responsible genes. The current paradigm states that the genes mutated in familial syndromes can also be targets for somatic mutations in sporadic (noninherited) tumors. The study of cancer syndromes has thus provided invaluable insights into the mechanisms of progression for many tumor types. This section examines the case of inherited colon cancer in detail, but similar lessons can be applied to many of the cancer syndromes listed in Table 25-3. In particular, the study of inherited colon cancer will clearly illustrate the difference between two types of tumor-suppressor genes: the gatekeepers, which directly regulate the growth of tumors, and the caretakers, which, when mutated, lead to genetic instability and therefore act indirectly on tumor growth.
TABLE 25-3Cancer Predisposition Syndromes and Associated Genes ||Download (.pdf) TABLE 25-3 Cancer Predisposition Syndromes and Associated Genes
|Syndrome ||Gene ||Chromosome ||Inheritance ||Tumors |
|Ataxia telangiectasia ||ATM ||11q22-q23 ||AR ||Breast |
|Autoimmune lymphoproliferative syndrome || |
|10q24 1q23 ||AD ||Lymphomas |
|Bloom syndrome ||BLM ||15q26.1 ||AR ||Several types |
|Cowden syndrome ||PTEN ||10q23 ||AD ||Breast, thyroid |
|Familial adenomatous polyposis ||APC ||5q21 ||AD ||Intestinal adenoma, colorectal |
|Familial melanoma ||p16INK4 ||9p21 ||AD ||Melanoma, pancreatic |
|Familial Wilms’ tumor ||WT1 ||11p13 ||AD ||Kidney (pediatric) |
|Hereditary breast/ovarian cancer || |
|AD ||Breast, ovarian, colon, prostate |
|Hereditary diffuse gastric cancer ||CDH1 ||16q22 ||AD ||Stomach |
|Hereditary multiple exostoses || |
|AD ||Exostoses, chondrosarcoma |
|Hereditary prostate cancer ||HPC1 ||1q24-25 ||AD ||Prostate |
|Hereditary retinoblastoma ||RB1 ||13q14.2 ||AD ||Retinoblastoma, osteosarcoma |
|Hereditary nonpolyposis colon cancer (HNPCC) || |
|AD ||Colon, endometrial, ovarian, stomach, small bowel, ureter carcinoma |
|Hereditary papillary renal carcinoma ||MET ||7q31 ||AD ||Papillary kidney |
|Juvenile polyposis ||SMAD4 ||18q21 ||AD ||Gastrointestinal, pancreatic |
|Li-Fraumeni ||TP53 ||17p13.1 ||AD ||Sarcoma, breast |
|Multiple endocrine neoplasia type 1 ||MEN1 ||11q13 ||AD ||Parathyroid, endocrine, pancreas, and pituitary |
|Multiple endocrine neoplasia type 2a ||RET ||10q11.2 ||AD ||Medullary thyroid carcinoma, pheochromocytoma |
|Neurofibromatosis type 1 ||NF1 ||17q11.2 ||AD ||Neurofibroma, neurofibrosarcoma, brain |
|Neurofibromatosis type 2 ||NF2 ||22q12.2 ||AD ||Vestibular schwannoma, meningioma, spine |
|Nevoid basal cell carcinoma syndrome (Gorlin’s syndrome) ||PTCH ||9q22.3 ||AD ||Basal cell carcinoma, medulloblastoma, jaw cysts |
|Tuberous sclerosis || |
|AD ||Angiofibroma, renal angiomyolipoma |
|von Hippel–Lindau ||VHL ||3p25-26 ||AD ||Kidney, cerebellum, pheochromocytoma |
Familial adenomatous polyposis (FAP) is a dominantly inherited colon cancer syndrome due to germline mutations in the adenomatous polyposis coli (APC) tumor-suppressor gene on chromosome 5. Patients with this syndrome develop hundreds to thousands of adenomas in the colon. Each of these adenomas has lost the normal remaining allele of APC but has not yet accumulated the required additional mutations to generate fully malignant cells (Fig. 25-2). The loss of the second functional APC allele in tumors from FAP families often occurs through loss of heterozygosity. However, out of these thousands of benign adenomas, several will invariably acquire further abnormalities and a subset will even develop into fully malignant cancers. APC is thus considered to be a gatekeeper for colon tumorigenesis: in the absence of mutation of this gatekeeper (or a gene acting within the same pathway), a colorectal tumor simply cannot form. Figure 25-5 shows germline and somatic mutations found in the APC gene. The function of the APC protein is still not completely understood, but it likely provides differentiation and apoptotic cues to colonic cells as they migrate up the crypts. Defects in this process may lead to abnormal accumulation of cells that should normally undergo apoptosis.
Germline and somatic mutations in the tumor-suppressor gene APC. APC encodes a 2843-amino-acid protein with six major domains: an oligomerization region (O), armadillo repeats (ARM), 15-amino-acid repeats (15 aa), 20-amino-acid repeats (20 aa), a basic region, and a domain involved in binding EB1 and the Drosophila discs large homologue (E/D). Shown are the positions within the APC gene of a total of 650 somatic and 826 germline mutations (from the APC database at http://www.umd.be/APC/). The vast majority of these mutations result in the truncation of the APC protein. Germline mutations are found to be relatively evenly distributed up to codon 1600 except for two mutation hotspots at amino acids 1061 and 1309, which together account for one-third of the mutations found in familial adenomatous polyposis (FAP) families. Somatic APC mutations in colon tumors cluster in an area of the gene known as the mutation cluster region (MCR). The location of the MCR suggests that the 20-amino-acid domain plays a crucial role in tumor suppression.
In contrast to patients with FAP, patients with hereditary nonpolyposis colon cancer (HNPCC, or Lynch’s syndrome) do not develop multiple polyposis, but instead develop only one or a small number of adenomas that rapidly progress to cancer. Most HNPCC cases are due to mutations in one of four DNA mismatch repair genes (Table 25-3), which are components of a repair system that is normally responsible for correcting errors in freshly replicated DNA. Germline mutations in MSH2 and MLH1 account for more than 90% of HNPCC cases, whereas mutations in MSH6 and PMS2 are much less frequent. When a somatic mutation inactivates the remaining wild-type allele of a mismatch repair gene, the cell develops a hypermutable phenotype characterized by profound genomic instability, especially for the short repeated sequences called microsatellites. This microsatellite instability (MSI) favors the development of cancer by increasing the rate of mutations in many genes, including oncogenes and tumor-suppressor genes (Fig. 25-2). These genes can thus be considered caretakers. Interestingly, CIN can also be found in colon cancer, but MSI and CIN appear to be mutually exclusive, suggesting that they represent alternative mechanisms for the generation of a mutator phenotype in this cancer (Fig. 25-2). Other cancer types rarely exhibit MSI, but most exhibit CIN.
Although most autosomal dominant inherited cancer syndromes are due to mutations in tumor-suppressor genes (Table 25-3), there are a few interesting exceptions. Multiple endocrine neoplasia type 2, a dominant disorder characterized by pituitary adenomas, medullary carcinoma of the thyroid, and (in some pedigrees) pheochromocytoma, is due to gain-of-function mutations in the protooncogene RET on chromosome 10. Similarly, gain-of-function mutations in the tyrosine kinase domain of the MET oncogene lead to hereditary papillary renal carcinoma. Interestingly, loss-of-function mutations in the RET gene cause a completely different disease, Hirschsprung’s disease (aganglionic megacolon [Chap. 52]).
Although the Mendelian forms of cancer have taught us much about the mechanisms of growth control, most forms of cancer do not follow simple patterns of inheritance. In many instances (e.g., lung cancer), a strong environmental contribution is at work. Even in such circumstances, however, some individuals may be more genetically susceptible to developing cancer, given the appropriate exposure, due to the presence of modifier alleles.