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The APC I1307K allele and cancer risk in a community-based study of Ashkenazi Jews

Abstract

Mutations in APC are classically associated with familial adenomatous polyposis (FAP), a highly penetrant autosomal dominant disorder characterized by multiple intestinal polyps and, without surgical intervention, the development of colorectal cancer1 (CRC). APC is a tumour-suppressor gene, and somatic loss occurs in tumours. The germline T-to-A transversion responsible for the APC I1307K allele converts the wild-type sequence to a homopolymer tract (A8) that is genetically unstable and prone to somatic mutation. The I1307K allele was found in 6.1% of unselected Ashkenazi Jews and higher proportions of Ashkenazim with family or personal histories of CRC (ref. 2). To evaluate the role of I1307K in cancer, we genotyped 5,081 Ashkenazi volunteers in a community survey. Risk of developing colorectal, breast and other cancers were compared between genotyped I1307K carriers and non-carriers and their first-degree relatives.

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Figure 1: Graphs showing: (a) cumulative risks of CRC in first-degree relatives of carriers (red) and non-carriers (blue), (b) estimated risks of CRC in I1307K carriers (red) and non-carriers (blue), (c) cumulative risks of breast cancer in first-degree relatives of carriers (red) and non-carriers (blue) and (d) estimated risks of breast cancer in I1307K carriers (red) and non-carriers (blue).

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Acknowledgements

We are grateful to B. Vogelstein, K. Kinzler and M. Redston for communication of unpublished results. F. Collins, M. Gail, R. Hoover, K. Offit, W. Foulkes, B. Vogelstein and G. Petersen all made helpful suggestions regarding the manuscript.

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Correspondence to Lawrence C. Brody.

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Woodage, T., King, S., Wacholder, S. et al. The APC I1307K allele and cancer risk in a community-based study of Ashkenazi Jews. Nat Genet 20, 62–65 (1998). https://doi.org/10.1038/1722

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