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Evidence Supporting Exclusion of the DCC Gene and a Portion of Chromosome 18q as the Locus for Susceptibility to Hereditary Nonpolyposis Colorectal Carcinoma in Five Kindreds¹

Department of Medical Genetics, University of Helsinki, 00290 Helsinki, Finland [P. P., P. S., L. P., A. d. l. C.]; Finnish Red Cross Blood Transfusion Service, 00310 Helsinki, Finland [P. S.]; Department of Surgery, Jyväskylä Central Hospital, 40620 Jyväskylä, Finland [J-P., M.]; Second Department of Surgery, Helsinki University Central Hospital, 00290 Helsinki, Finland [H. J.]; and Johns Hopkins Oncology Center, Baltimore, Maryland 21231 [J. W. S., K. R. C., B. V.]

Hereditary non-polyposis colorectal carcinoma (HNPCC) syndrome is characterized by early onset and multiple cancers of predominantly the proximal colon and occasionally other organs. The mode of transmission is compatible with autosomal dominant inheritance but the location and characteristics of the putative susceptibility gene are unknown. We performed linkage analyses with the aim of proving or excluding the existence of a susceptibility locus on 18q. This hypothesis was based on the frequent involvement of the DCC gene in colorectal carcinoma and on the previously reported linkage between HNPCC and the Kidd blood group locus (JK) also on 18q. Seven HNPCC families were tested with eight polymorphisms, including three from within DCC. The DCC locus could be excluded as the HNPCC susceptibility locus in five families in which the two point logarithm-of-odds scores were -3.66, -3.63, -4.12, -7.90, and -3.74 at the recombination fraction of 0.00. In the remaining two families linkage could be neither excluded nor confirmed. The added pairwise logarithm-of-odds score for all seven families was -22.65 at the recombination fraction of 0.00. Multipoint analyses of linkage in the seven families suggested exclusion of some 60 cM in the region DCC-D18S18-D18S22-D18S7 as the site for HNPCC susceptibility locus. In addition to DCC, the excluded portion comprises JK.

¹ Aided by grants from the Academy of Finland, the Finnish Cancer Society, the Sigrid Juselius Foundation, the Clayton Fund, and the McAshan Fund and NIH Grants CA 47527 and CA 35494. Part of this study was done at the Folkhälsan Institute of Genetics.

² To whom requests for reprints should be addressed.

Received 3/ 7/91. Accepted 6/10/91.

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