Gastroenterology

Gastroenterology

Volume 127, Issue 2, August 2004, Pages 444-451
Gastroenterology

Clinical-alimentary tract
Genetic testing and phenotype in a large kindred with attenuated familial adenomatous polyposis

https://doi.org/10.1053/j.gastro.2004.05.003Get rights and content

Abstract

Background & Aims: An attenuated form of familial adenomatous polyposis has been described, but the phenotype remains poorly understood.Methods:We performed genetic testing on 810 individuals from 2 attenuated familial adenomatous polyposis kindreds harboring an identical germline adenomatous polyposis coli gene mutation. Colonoscopy was performed on mutation-positive persons.Results: The disease-causing mutation was present in 184 individuals. Adenomatous polyps were present in 111 of 120 gene carriers who had colonoscopy at an average age of 41 years. The median number of adenomas was 25 (range, 0–470), with striking variability of polyp numbers and a proximal colonic predominance of polyps. Colorectal cancer occurred in 27 mutation carriers (average age, 58 years; range, 29–81 years), with 75% in the proximal colon. The cumulative risk of colorectal cancer by age 80 was estimated to be 69%. An average of 3.4 recurrent polyps (range, 0–29) were found in the postcolectomy rectal remnant over a mean of 7.8 years (range, 1–34 years), with 1 rectal cancer.Conclusions: This investigation shows that attenuated familial adenomatous polyposis in the kindreds examined shows a much smaller median number of polyps than typical familial adenomatous polyposis, a wide variability in polyp number even at older ages, and a more proximal colonic location of polyps and cancer, yet it is associated with an extremely high risk of colon cancer. The phenotype of attenuated familial adenomatous polyposis mimics typical familial adenomatous polyposis in some cases but in others is difficult to distinguish from sporadic adenomas and colorectal cancer, thus making genetic testing particularly important.

Section snippets

Materials and methods

All aspects of this study were reviewed and approved by the Institutional Review Board of the University of Utah.

Mutation testing in kindreds

The entire kindred 353 included more than 4000 members spanning 7 generations. Our research efforts focused on 2 of 5 branches in which the APC mutation was transmitted. These branches were designated “B” and “E” and contained 1707 individuals. Kindred 439 contained 550 individuals. The specific AFAP mutation was present in 43 of 299 tested individuals from K353(B) and was absent in the remaining 256. One hundred four of 416 tested individuals from K353(E) carried the mutation, and 312 did not.

Discussion

The clinical characteristics of these 2 kindreds, in view of their size and genetic diagnosis, allow a highly precise definition of the colonic polyp and cancer risk of the syndrome of AFAP in the kindreds studied. The phenotype first seemed related to FAP when we found linkage in kindred 353 to the APC gene.1 Identification of the disease-causing mutation in the APC gene2 has subsequently allowed us to make precise genetic diagnoses of kindred members, accurate clarification of the phenotype,

Acknowledgements

The authors thank Stacey Maxwell and Mark Mayle for their efforts in recruiting and working with research participants, Jamie McDonald for providing genetic counseling, Melanie Nichols for coordinating and completing the mutation analysis, and Shannon Spilker for data abstraction.

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    Supported by National Cancer Institute grants R01-CA40641 and PO1-CA73992; additional support was provided by Cancer Center Support grants P30-CA42014, M01-RR00064, and N01-PC-67000 and by the Huntsman Cancer Foundation.

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