Discovery of Colorectal Cancer Susceptibility Genes in High-Risk Families

Colorectal cancer remains one of the most common cancers in the US with 146,970 new diagnoses and 49,920 deaths estimated for 2009. Colon cancer is also one of the most familial of cancers. Individuals with a first-degree relative with colon cancer have a 2- to 3-fold increased risk, and those with more than one first-degree relative with colon cancer, or a single first-degree relative affected at age 50 years, have a 3- to 6-fold greater risk than those with no family history. The most prominent high-risk colorectal cancer susceptibility genes, APC, MLH1, MSH2, MSH6, and PTEN, were all discovered more than a decade ago. Currently, mutation screening of these genes, plus a short list of additional genes that are responsible for a very small fraction of colorectal cancer, plays an important role in the clinical management of individuals with a strong family history of the disease or syndromic evidence for the presence of a gene mutation.

At the other end of the risk spectrum, genome-wide association studies have identified a number of common alleles with very modest effects on colorectal cancer risk; their clinical utility has yet to be established. However, taken together, the known spectrum of genetic effects only explain about one quarter of the overall familial excess of colorectal cancer. It should be emphasized that, at present, the vast majority of individuals seen at familial cancer clinics are counseled on the basis of their family history alone because they do not have mutations in the known susceptibility genes. Accordingly, the long-term objective of this project is to identify the majority of genes responsible for the unexplained component of inherited colorectal cancer risk. Nextgen DNA sequencing is well suited for application to research questions in genetic susceptibility for which linkage analysis is confounded by extensive genetic heterogeneity. Taking advantage of unparalleled familial cancer genetics resources available through the Utah Population Database, candidate genes have been identified by sequencing all of the gene exons in the human genome from a series of colorectal cancer cases with a very strong family history of colorectal cancer not explained by one of the currently known high-risk susceptibility genes.

• Study Design:
  • Case Set
• Study Type:
  • Case Set
• Total number of consented subjects: 51
• Subject Sample Telemetry Report (SSTR)

• BioProject
• PubMed
• Sequence Read Archive
• BioSample
• MeSH
• PMC

Subjects originate from among 35 multi-case high-risk colon cancer pedigrees ascertained through the Utah Population Database (UPDB). Cases consisted of pairs of affected first cousins or affected first cousins-once-removed where each subject of the pair also had a first-degree relative diagnosed with colon cancer. Cases were removed when genotypes failed to confirm when genotyped on an Illumina Infinium OmniExpressExome SNP array. Cases were those free from pathogenic variants in any of a panel of 28 known or suspected susceptibility genes.

• Primary Phenotype: Colorectal Neoplasms, Hereditary Nonpolyposis

• Principal Investigator
  • Sean Vahram Tavtigian, PhD. University of Utah, Salt Lake City, UT, USA.
• Funding Source
  • R01CA164138. National Institutes of Health, Bethesda, MD, USA.