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Common Familial Colorectal Cancer Linked to Chromosome 7q31: A Genome-Wide Analysis

¹ Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah; ² University of California Irvine, Irvine, California; ³ Karmanos Cancer Institute, Wayne State University, Detroit, Michigan; ⁴ Departments of Pathology and Oncology, Johns Hopkins University, Baltimore, Maryland; ⁵ Colorado School of Public Health, Denver, Colorado; ⁶ Duke University, Durham, North Carolina; ⁷ University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; ⁸ University of Texas Southwestern Medical Center, Dallas, Texas; ⁹ University of Texas M. D. Anderson Medical Cancer Center, Houston, Texas; ¹⁰ Cancer Therapy and Research Center and University of Texas San Antonio, San Antonio, Texas; ¹¹ University of Pennsylvania, Philadelphia, Pennsylvania; ¹² Massachusetts General Hospital Statistical Coordinating Center, Boston, Massachusetts; ¹³ Yale Center for Informatics, New Haven, Connecticut; and ¹⁴ National Cancer Institute, Rockville, Maryland

Requests for reprints: Deborah W. Neklason, Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope, Salt Lake City, UT 84112-5550. Phone: 801-587-9882; Fax: 801-585-5763; E-mail: Deb.neklason{at}hci.utah.edu.

Key Words: sibpair • genetic linkage • colorectal cancer • 7q31

Present investigations suggest that 30% of colorectal cancer cases arise on the basis of inherited factors. We hypothesize that the majority of inherited factors are moderately penetrant genes, common in the population. We use an affected sibling pair approach to identify genetic regions that are coinherited by siblings with colorectal cancer. Individuals from families with at least two siblings diagnosed with colorectal adenocarcinoma or high-grade dysplasia were enrolled. Known familial colorectal cancer syndromes were excluded. A genome-wide scan on 151 DNA samples from 70 kindreds was completed using deCODE 1100 short tandem repeat marker set at an average 4-cM density. Fine mapping on a total of 184 DNAs from 83 kindreds was done in regions suggesting linkage. Linkage analysis was accomplished with Merlin analysis package. Nonparametric linkage analysis revealed three genetic regions with logarithm of the odds (LOD) scores 2.0: Ch. 3q29, LOD 2.61 (P = 0.0003); Ch. 4q31.3, LOD 2.13 (P = 0.0009); and Ch. 7q31.31, LOD 3.08 (P = 0.00008). Affected siblings with increased sharing at the 7q31 locus have a 3.8-year (± 3.5) earlier age of colorectal cancer onset although this is not statistically significant (P = 0.11). No significant linkage was found near genes causing known syndromes or regions previously reported (8q24, 9q22, and 11q23). The chromosome 3q21–q24 region reported to be linked in colorectal cancer relative pairs is supported by our study, albeit a minor peak (LOD 0.9; P = 0.02). No known familial cancer genes reside in the 7q31 locus, and thus the identified region may contain a novel susceptibility gene responsible for common familial colorectal cancer. [Cancer Res 2008;68(21):8993–7]