We studied a large kindred with a history of colorectal cancer of early onset. Proctosigmoidoscopic examination of 51 family members identified only 2 with familial polyposis coli, which strongly predisposes those who have it to colorectal cancer and which is defined as the presence of more than 100 polyps in the colon. However, eight family members had 2 to 40 colonic polyps. We suspected that in this family, colorectal cancer was the result of a mutation in the gene on chromosome 5 that is responsible for familial polyposis coli. To test our hypothesis, we obtained genotypic information on 81 family members with respect to seven polymorphic DNA markers previously shown to be linked to the locus for familial polyposis coli. Multilocus analysis of the data demonstrated genetic linkage (lod score, 5.58) between these markers and the locus responsible for the defined syndrome of colonic polyps or colorectal cancer in this kindred. These findings constitute evidence that the genetic defect in this family is a mutation in the gene that causes familial polyposis coli. We conclude that mutations at the genetic locus for familial polyposis coli may be the cause of other, more subtle syndromes involving an inherited susceptibility to colonic adenomatous polyps and colorectal cancer.

Familial adenomatous polyposis (FAP), a Mendelian disorder that includes familial polyposis coli (FPC) and Gardner syndrome (GS), has an autosomal dominant mode of inheritance. It is characterized by hundreds to thousands of adenomatous polyps that can progress to carcinoma of the colon, suggesting that the gene that harbors the FAP germ-line mutation may play an important role in the somatic genetic pathway to colon cancer. The defect responsible for FAP was recently mapped to the long arm of chromosome 5 by linkage between the FPC phenotype and a locus defined by DNA probe pC11p11 (D5S71), located at 5q21-22. Because an important next step in the paradigm for identification of a disease gene is to obtain a more precise localization, we isolated and mapped by linkage six additional polymorphic DNA markers in the FAP region. Subsequent linkage analysis in six pedigrees, three having the FPC phenotype and three segregating GS, placed the FAP locus very close to a new marker, YN5.48 (D5S81), that is approximately 17 centimorgans distal to C11p11 on the genetic map. The analysis revealed no evidence of genetic heterogeneity between the two phenotypes, a question that had not been clearly resolved by the earlier studies. The new set of markers in the near vicinity of the FAP locus represents a further step toward isolation of the genetic defect and provides the opportunity for preclinical diagnosis of risk status for colon cancer among individuals in families that are segregating adenomatous polyposis.

The inherited genetic defect in adenomatous polyposis has been localized to a small region on the long arm of chromosome 5. Sixteen DNA marker loci were used to construct a linkage map of the chromosome. When five kindreds segregating a gene for adenomatous polyposis coli were characterized with a number of the markers, significant linkage was found between one marker and the disease gene. Linkage analysis determined the location of the defective gene within a primary genetic map of chromosome 5.

A group of researchers recently reported a specific chromosome abnormality consisting of a deletion in the long arm (q) of chromosome 2 in patients with adenomatous colorectal polyposis. Using a high resolution chromosome banding technique and a blind study design, the authors karyotyped two patients with Gardner syndrome, two patients with familial polyposis, and four normal controls. No deletion was found in chromosome 2.

Inheritance of mutationally altered oncogenes could predispose individuals to the development of specific tumors and account for familial tumor phenotypes. Using adjacent DNA sequence polymorphisms as genetic markers, we have examined two oncogenes, the Kirsten ras2, isolated from a human colon cancer cell line, and the Harvey ras1, isolated from a human bladder cancer cell line, for their role in the genetic etiology of inherited colon cancer in Gardner syndrome. Both oncogene loci have been shown to be unlinked to the Gardner syndrome locus and are, therefore, eliminated as candidates for the Gardner syndrome gene.

Mesenteric fibromatosis has been reported in frequent association with familial polyposis and with Gardner's syndrome. This vague “benign” process has been characterized as a postsurgical phenomenon with low morbidity. Two cases of spontaneous mesenteric fibromatosis, noted at the time of original laparotomy for colectomy in Gardner's syndrome patients, are reported. No history of abdominal trauma was present, and both have well-documented Gardner's findings. A 32% incidence of desmoid reaction is reported among affected members of the original Gardner's syndrome Kindred 109; five or 55% of these patients had the mesenteric form of the process. The potential fatal course of the mesenteric disease is emphasized.

CancerVolume 11, Issue 5 p. 967-972 ArticleFree Access A recheck of kindred 107, which has shown a high frequency of breast cancer F. E. Stephens Ph.D., F. E. Stephens Ph.D. Laboratory of Human Genetics, University of Utah, Salt Lake City, UtahSearch for more papers by this authorEldon J. Gardner Ph.D., Eldon J. Gardner Ph.D. Laboratory of Human Genetics, University of Utah, Salt Lake City, UtahSearch for more papers by this authorCharles M. Woolf Ph.D., Charles M. Woolf Ph.D. Laboratory of Human Genetics, University of Utah, Salt Lake City, UtahSearch for more papers by this author F. E. Stephens Ph.D., F. E. Stephens Ph.D. Laboratory of Human Genetics, University of Utah, Salt Lake City, UtahSearch for more papers by this authorEldon J. Gardner Ph.D., Eldon J. Gardner Ph.D. Laboratory of Human Genetics, University of Utah, Salt Lake City, UtahSearch for more papers by this authorCharles M. Woolf Ph.D., Charles M. Woolf Ph.D. Laboratory of Human Genetics, University of Utah, Salt Lake City, UtahSearch for more papers by this author First published: September/October 1958 https://doi.org/10.1002/1097-0142(195809/10)11:5<967::AID-CNCR2820110516>3.0.CO;2-OCitations: 11AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat References 1 Gardner, E. J., and Stephens, F. E.: Breast cancer in 1 family pup. Am. J. Human Genet. 2: 30–40. 1950. 2 Gardner, E. J., and Woolf, C. M.: Intestinal poly-posis and carcinoma originating from mutation in mily group. Cancer 5: 695–699. 1952. 3 Jacobsen, O.: Heredity in Breast Cancer; a Genetic and Clinical Study of Two Hundred Pmbands. Copen hagen, Denmark. Nyt Nordisk Forlag, Arnold Busck. 1946; p. 306. 4 Penrose, L. S.; MackenWe, H. J., and Karn, M. N.: Genetical study of human mammary cancer. Brit. J. Cancer 2: 168–176. 1948. 5 Woolf, C. M.: Investigations on genetic as of carcinoma of stomach and breast. Univ. Calfornia Publ., Pub. Health 2(4): 265–349. 1955. 6 Woolf, C. M., and Gardner, E. J.: Familial dis tribution of breast cancer in a Utah kindred. Cancer 4: 515–520. 1951. Citing Literature Volume11, Issue5September/October 1958Pages 967-972 ReferencesRelatedInformation

HE RECENT medical literature has emphaT sized the importance of the relationship existing between cancer and polyps of the colon and rectum.2, 3, 1 ~ 1 2 I t is now generally agreed that a high percentage of malignant lesions in the colon and rectum originate in polyps. The literature further distinguishes the rare disease intestinal polyposis, characterized by the presence of a large number of polyps scattered throughout the large intestine, from the relatively common condition in which only a single polyp or a few in number are present.21 9, l2 Routine sigmoidoscopic examinations carried out in various clinics in the United States have shown that approximately 5 per cent of all individuals more than 35 years of age have one or more polyps of the rectum or sigmoid.l0,11 The disease intestinal polyposis is only rarely seen in routine clinical examinations.9 Intestinal polyposis is hrther noted for its familial nature and its dominant mode of inheritance.3~ 4 ? 9 No evidence in the literature indicates that heredity plays any type of etiological role for the occurrence of a single polyp or a few polyps, even though pathologically the only difference between this condition and intestinal polyposis appears to be the number of polyps present. For the past five years the Laboratory of Human Genetics at the University 01 Utah has been conducting studies designed to show whether specific types of human neoplasms have an inherited tendency. One phase of these studies has been the collection and analysis of kindreds showing a high incidence of specific types of cancer.4.596, 13914 Several kindreds have been collected in which cancer of the large intestine has occurred among several members. Sigmoidoscopic examinations carried out on the living members more than G years of age of one of these kindreds showed

CancerVolume 4, Issue 3 p. 515-520 ArticleFree Access The familial distribution of breast cancer in a Utah Kindred Charles M. Woolf M.S., Charles M. Woolf M.S. Laboratory of Human Genetics, University of Utah, Salt Lake City, UtahSearch for more papers by this authorEldon J. Gardner Ph.D., Eldon J. Gardner Ph.D. Laboratory of Human Genetics, University of Utah, Salt Lake City, UtahSearch for more papers by this author Charles M. Woolf M.S., Charles M. Woolf M.S. Laboratory of Human Genetics, University of Utah, Salt Lake City, UtahSearch for more papers by this authorEldon J. Gardner Ph.D., Eldon J. Gardner Ph.D. Laboratory of Human Genetics, University of Utah, Salt Lake City, UtahSearch for more papers by this author First published: May 1951 https://doi.org/10.1002/1097-0142(195105)4:3<515::AID-CNCR2820040305>3.0.CO;2-6Citations: 8AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Citing Literature Volume4, Issue3May 1951Pages 515-520 ReferencesRelatedInformation