The lifetime risk of colorectal cancer in the U.S. is 6% and this tumor is the second leading cause of cancer death after lung cancer. Colorectal cancer (CRC) screening programs that include the removal of precancerous adenomatous polyps are the key to prevention, early diagnosis, and survival. Understanding the genetic and environmental risk factors that impact colon cancer initiation and progression constitute a complementary piece of these prevention efforts.
Sequentially ascertained pedigree and twin studies indicate that 20-30% of colon cancer cases appear to arise in the setting of inherited susceptibility 1-3
. Three to five percent of colon cancer cases arise in the setting of well characterized inherited syndromes 4
. These include syndromes in which colonic adenomatous polyps occur as a part of 1) familial adenomatous polyposis, 2) MUTYH associated polyposis or MAP, 2) hereditary nonpolyposis colon cancer (HNPCC or Lynch syndrome); and those where colonic hamartomatous polyps are found, 3) Peutz-Jeghers syndrome, 4) juvenile polyposis and, 5) Cowden syndrome. Each has now been associated with a gene or genes, that when mutated, gives rise to the condition. Although the inherited mutations are rare in the population, the genes involved have been found to be very important for initiation and progression of all colon cancers. The genetic basis of the remaining 15 to 25% inherited colon cancer susceptibility is poorly understood.
Individuals with more than one first-degree relative with colon cancer or a single first-degree relative with colon cancer diagnosed at age ≤ 50 years have a 3- to 6-fold greater risk than those with no family history 5-6
. Multiple recent studies have characterized “high-risk colon cancer families” that fulfilled clinical criteria for HNPCC, but were not one of the inherited syndromes based on phenotype as well as tumor and germline genetic testing 7-10
. This nonsyndromic type of susceptibility is less penetrant than observed in the known inherited syndromes. The average age of colorectal cancer diagnosis in these nonsyndromic cases is in the mid 50's to early 60's, a decade earlier than the general population (70 years) whereas the average age in Lynch Syndrome is 44 years. Defining the colon cancer etiology of this population may again reveal genes that are generally important in colon cancer development.
Association studies report several low-penetrance genetic variants associated with colon cancer risk that could account for a yet to be defined proportion of the familial colon cancer cases 11-12
. A genome-wide association study of approximately 7000 colon cancer cases and controls identified a region on 8q24 with an odds ratio for colon cancer of approximately 1.2 13
. The odds ratio climbed to 2.6 with coinheritance of single nucleotide polymorphisms (SNPs) on 8q24, 11q23 and 18q21 in a follow up study of 14000 cases and controls 14
. Affected-relative-pair studies have also reported genetic regions that are co-inherited more often in first-degree relatives with CRC than those without. These include 7q31, 9q22.33, 3q21-24, and 11q23 with some minor peaks in agreement across studies 15-18
. These reports support the paradigm that common inherited colon cancer arises from a number of susceptibility genes of lower penetrance than the well described syndromes of colon cancer.
Large families whereby precise inheritance can be correlated with phenotype offer another approach to identify isolated specific loci with well defined recombinant boundaries. Large families identified through Utah Population Database (UPDB), a genealogic resource linked to vital records and Utah and Idaho statewide cancer registries, are the foundation of what we have come to understand about both sporadic and inherited colon cancers 2 19-23
. We report one such large family ascertained through UPDB and identified as having a statistical excess of colorectal cancer. Phenotypic and genetic analysis revealed a significant genetic locus on chromosome 13q that is linked to the colonic adenomatous polyp and cancer phenotype.