Autosomal Dominant
Principles
• Tumor-suppressor gene
• Multistep carcinogenesis
• Somatic mutation
• Cytogenetic and genomic instability
• Variable expressivity
Major Phenotypic Features
• Age at onset: Adolescence through mid-adulthood
• Colorectal adenomatous polyps
• Colorectal cancer
• Multiple primary cancers
History and Physical Findings
R.P., a 35-year-old man, was referred to the cancer genetics clinic by his oncologist. He had just undergone a total colectomy; the colonic mucosa had more than 2000 polyps and pathological changes consistent with adenomatous polyposis coli. In addition to his abdominal scars and colostomy, he had retinal pigment abnormalities consistent with congenital hypertrophy of the retinal pigment epithelium. Several of his relatives had died of cancer. He did not have a medical or family history of other health problems. On the basis of the medical history and suggestive family history, the geneticist counseled R.P. that he most likely had familial adenomatous polyposis. The geneticist explained the surveillance protocol for R.P.'s children and the possibility of using molecular testing to identify those children at risk for familial adenomatous polyposis. Because R.P. did not have contact with his family and family studies were therefore not possible, R.P. elected to proceed with direct screening of the adenomatous polyposis coli gene (APC); he had a nonsense mutation in exon 15 of one APC allele.
Background
Disease Etiology and Incidence
At least 50% of individuals in Western populations develop a colorectal tumor, including benign polyps, by the age of 70 years, and approximately 10% of these individuals eventually develop colorectal carcinoma. Approximately 15% of colorectal cancer is familial, including familial adenomatous polyposis (FAP, MIM 175100) and hereditary nonpolyposis colorectal cancer. FAP is an autosomal dominant cancer predisposition syndrome caused by inherited mutations in the APC gene. It has a prevalence of 2 to 3 per 100,000 and accounts for less than 1% of colon cancers. Somatic APC mutations also occur in more than 80% of sporadic colorectal tumors (see Chapter 15).
Pathogenesis
The APC protein directly or indirectly regulates transcription, cell adhesion, the microtubular cytoskeleton, cell migration, crypt fission, apoptosis, and cell proliferation. It forms complexes with several different proteins, including β-catenin.
Both alleles of APC must be inactivated for adenoma formation. The high frequency of somatic loss of function in the second APC allele defines FAP as an autosomal dominant condition. As described in Chapter 15, this somatic loss of function can occur by a variety of mechanisms, including loss of heterozygosity, intragenic mutation, transcriptional inactivation, and, rarely, dominant negative effects of the inherited mutant allele. More than 95% of intragenic APC mutations cause truncation of the APC protein. Loss of functional APC usually results in high levels of free cytosolic β-catenin; free β-catenin migrates to the nucleus, binds to T-cell factor 4, and inappropriately activates gene expression. Consistent with this mechanism, mutations of the β-catenin gene have been identified in some colorectal carcinomas without APCmutations.
Although loss of functional APC causes affected cells to form dysplastic foci within intestinal crypts, these cells are not cancerous and must acquire other somatic mutations to progress to cancer (see Chapter 15). This progression is characterized by cytogenetic instability resulting in the loss of large chromosomal segments and, consequently, loss of heterozygosity. Specific genetic alterations implicated in this progression include activation of the KRAS or NRAS oncogenes, inactivation of a tumor-suppressor gene on 18q, inactivation of the TP53 gene, and alterations in methylation leading to transcriptional silencing of tumor-suppressor genes. As cells accumulate mutations, they become increasingly neoplastic and eventually form invasive and metastatic carcinomas.
Phenotype and Natural History
FAP is characterized by hundreds to thousands of colonic adenomatous polyps (Fig. C-15). It is diagnosed clinically by the presence of either more than 100 colorectal adenomatous polyps or between 10 and 100 polyps in an individual with a relative with FAP. Adenomatous polyps usually appear between 7 and 40 years of age and rapidly increase in number. If untreated, 7% of patients develop colorectal cancer by 21 years of age, 87% by 45 years, and 93% by 50 years.
FIGURE C-15 The mucosa of an ascending colon resected from a patient with familial adenomatous polyposis. Note the enormous number of polyps. See Sources & Acknowledgments.
Although nonpenetrance is very rare, patients with germline mutations of APC do not necessarily develop adenomas or colorectal cancer; they are only predisposed. The rate-limiting step in adenoma formation is somatic mutation of the wild-type APC allele. Progression of an adenoma to carcinoma requires the accumulation of other genetic alterations. Patients with FAP are at much greater risk than the general population for development of colorectal carcinoma for two reasons. First, although the average time to progress from adenoma to carcinoma is approximately 23 years, these patients develop adenomas earlier in life and are less likely to die of other causes before the development of carcinoma. Second, although less than 1% of adenomas progress to carcinoma, patients have tens to thousands of adenomas, each with the potential to transform to carcinoma. Thus the likelihood that at least one adenoma will progress to become an adenocarcinoma is a near certainty.
The penetrance and expressivity of APC mutations depend on the particular APC mutation, genetic background, and environment. Mutations in different regions of the gene are variously associated with Gardner syndrome (an association of colonic adenomatous polyposis, osteomas, and soft tissue tumors), congenital hypertrophy of the retinal pigment epithelium, attenuated adenomatous polyposis coli, or Turcot syndrome (colon cancer and central nervous system tumors, usually medulloblastoma). Modifier genes in the human genome may cause patients with identical germline mutations to have dissimilar clinical features. Many studies of sporadic colorectal tumorigenesis identify an enhanced risk for individuals consuming diets high in animal fat; therefore, given the common mechanism of tumorigenesis, diet is likely to play a role in FAP as well.
Management
Early recognition of FAP is necessary for effective intervention, that is, prevention of colorectal cancer. After the development of polyps, definitive treatment is total colectomy with ileoanal pull-through. Recommended surveillance for patients at risk for FAP is colonoscopy every 1 to 2 years beginning at 10 to 12 years of age. To focus this surveillance, molecular testing is recommended to identify at-risk family members.
Inheritance Risk
The empirical lifetime risk for colorectal cancer among Western populations is 5% to 6%. This risk is markedly modified by family history. Patients who have a sibling with adenomatous polyps but no family history of colorectal cancer have a 1.78 relative risk; the relative risk increases to 2.59 if a sibling developed adenomas before the age of 60 years. Patients with a first-degree relative with colorectal cancer have a 1.72 relative risk; this relative risk increases to 2.75 if two or more first-degree relatives had colorectal cancer. If an affected first-degree relative developed colorectal cancer before 44 years of age, the relative risk increases to more than 5.
In contrast to these figures for all colorectal cancer, a patient with FAP or an APC germline mutation has a 50% risk for having a child affected with FAP in each pregnancy. The absence of a family history of FAP does not preclude the diagnosis of FAP in a parent because approximately 20% to 30% of patients have a new germline APC mutation. Prenatal diagnosis is available by linkage analysis or by testing for the mutation if the mutation in the parent has been defined. Because of intrafamilial variation in expressivity, the severity, time at onset, and associated features cannot be predicted.
Germline APC mutations are not detected in between 10% and 30% of individuals with a clinical phenotype of typical FAP and in 90% of individuals with “attenuated” FAP (FAP phenotype, except there are fewer than 100 adenomas). Among these patients, 10% are germline homozygotes or compound heterozygotes for a mutation in the DNA repair gene MYH; another 10% carry one mutant MYH allele in their germline. Heterozygosity for a mutant MYH allele increases the risk for colon cancer threefold; having both alleles mutant increases risk 50-fold. A patient with FAP and no APC mutation should be investigated for MYHmutations, particularly if there is a family history suggestive of autosomal recessive inheritance (see FAP2, MIM 608456).
Questions for Small Group Discussion
1. Name additional disorders that demonstrate autosomal dominant inheritance but are recessive at the cellular level. Why do these diseases exhibit autosomal dominant inheritance if two mutations are required for expression of the disease?
2. Discuss some other mendelian disorders that have modeled or provided insights into more common diseases, including at least one for cancer and one for dementia.
3. What does the association of attenuated adenomatous polyposis coli with early truncations of APC suggest about the biochemical basis of attenuated adenomatous polyposis coli compared with classic FAP?
References
Jasperson KW, Burt RW. APC-associated polyposis conditions. [Available from] http://www.ncbi.nlm.nih.gov/books/NBK1345/.
Jenkins MA, Croitoru ME, Monga N, et al. Risk of colorectal cancer in monoallelic and biallelic carriers of MYH mutations: a population-based case-family study. Cancer Epidemiol Biomarkers Prev. 2006;15:312–314.
Kerr SE, Thomas CB, Thibodeau SN, et al. APC germline mutations in individuals being evaluated for familial adenomatous polyposis: a review of the Mayo Clinic experience with 1591 consecutive tests. J Mol Diagn. 2013;15:31–43.