Colonic adenoma risk in familial colorectal cancer--a study of six extended kindreds.

OBJECTIVES: Most colorectal cancers (CRCs) arise from adenomatous polyps, but the effects of CRC family history on adenoma risk are not well known. This issue is clinically relevant since several medical societies currently recommend earlier and more rigorous colorectal screening for individuals with a strong family history of CRC. METHODS: Colonoscopies were performed in 236 first-, second-, and third-degree relatives of 40 index CRC cases from six large kindreds selected from a large population database. The kindreds were selected for significantly greater risk of CRCs compared with the overall population. Known hereditary colon cancer syndromes were clinically and genetically excluded. RESULTS: Thirty-seven percent of relatives were found to have adenomas on colonoscopy. The average age of diagnosis for colon cancer was 63 yr and advanced adenomas 56 yr. Independent predictors of adenomatous polyps in the relatives were advancing age (P < 0.0001), male gender (P < 0.001), and greater degree of relation to CRC cases (P < 0.01). There was no significant predilection of colorectal tumors for the right or left colon. A higher degree of relationship to CRC cases was a significant predictor of having simple and advanced adenomas, but not hyperplastic polyps after adjustment for age and gender. CONCLUSIONS: These data support the current recommendations for colonoscopy starting before the age of 50 yr in individuals with a strong family history of CRC.

An evidence-based, multidisciplinary approach to the clinical considerations, management, and surveillance of adrenal lesions in familial adenomatous polyposis: report of three cases.

Adrenal masses are commonly discovered incidentally in patients with familial adenomatous polyposis, and adrenal malignancies have been rarely reported. Individuals with familial adenomatous polyposis frequently undergo abdominal CT-scan examinations for surveillance or symptoms. Adrenal lesions often are detected unexpectedly and are thus becoming a common clinical problem in this population. Adrenal lesions encompass a heterogeneous spectrum of pathologic entities, including primary adrenocortical and medullary tumors, benign or malignant lesions, hormonally active or inactive lesions, metastases, and infections. When an adrenal mass is detected, the clinician needs to address two crucial questions: 1) is the mass malignant? and 2) is it hormonally active? This article presents three new cases of incidental adrenal lesions in familial adenomatous polyposis, reviews the medical literature for this setting, and provides an overview of the diagnostic clinical approach and management of the adrenal findings in familial adenomatous polyposis patients.

Intron 4 mutation in APC gene results in splice defect and attenuated FAP phenotype.

The adenomatous polyposis coli (APC) protein is a tumor suppressor frequently involved in the development of inherited and sporadic colon cancers. Somatic mutations of the APC gene are found in 80% of all colon cancers. Inherited mutations result in familial adenomatous polyposis (FAP) as well as an attenuated form of this syndrome. FAP is characterized by the early age onset of hundreds to thousands of colonic adenomatous polyps and a virtual certainty of colon cancer unless the colon is removed. The attenuated form of FAP (AFAP) is characterized by fewer adenomas, later onset of adenomas and cancer, and a decreased lifetime cancer risk. We report a 37-year-old man with a history of more than 50 colonic adenomatous polyps, located predominately in the right colon. An insertion of a single thymidine between the second and third base pairs of intron 4 of the APC gene was identified (c.531+2_531+3insT). Monoallelic hybrid cells harboring a single copy of human chromosome 5 were generated from patient lymphoblasts. Sequencing of the APC cDNA product from these cells revealed a single RNA transcript with aberrant splicing in the mutant mRNA whereby exon 4 is deleted. The translational reading frame is shifted after codon 140 and a translational stop is generated predicting a truncated protein of 147 amino acids, thus indicating that the intronic mutation is disease causing. The lack of a secondary transcript from the mutant allele suggests that incomplete exon skipping is not the molecular mechanism behind the attenuated phenotype.

Current status of genetic testing for colorectal cancer susceptibility.

Over 130,000 new cases of colon cancer are diagnosed annually. Approximately 20% to 30% of these are attributable to familial risk, and 3% to 5% belong to a hereditary colorectal cancer predisposition syndrome. Recent discoveries of the genes responsiblefor the inherited colorectal cancer conditions have expanded the field of commercial genetic testing. Health-care providers who use genetic testing in clinical practice are aware of the benefits that genetic testing can confer on screening, prevention, and treatment options for patients with a personal and/or family history of colon cancer. When genetic test results are correctly interpreted, the information they provide can offer medical guidance for the entire family. The psychological impact, however, of presymptomatic testing can be multifaceted. There are unprecedented benefits but also complex issues surrounding genetic testing. For these reasons, the practice of offering genetic testing to individuals at high risk for colon cancer is heavily fortified with guidelines and recommendations. This review covers the current availability and limitations of genetic testing for inherited colorectal cancer syndromes and focuses on guidelines that address the psychological, ethical, and social concerns stemming from genetic testing.