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. 2010 Oct;47(10):692-9.
doi: 10.1136/jmg.2009.076091. Epub 2010 Jun 3.

Colorectal adenomas and cancer link to chromosome 13q22.1-13q31.3 in a large family with excess colorectal cancer

Deborah W Neklason  1 , Thérèse M Tuohy, Jeffery Stevens, Brith Otterud, Lisa Baird, Richard A Kerber, Wade S Samowitz, Scott K Kuwada, Mark F Leppert, Randall W Burt
Affiliations

Colorectal adenomas and cancer link to chromosome 13q22.1-13q31.3 in a large family with excess colorectal cancer

Deborah W Neklason et al. J Med Genet. 2010 Oct.

Abstract

Background: Colorectal cancer is the fourth most common type of cancer and the second most common cause of cancer death. Fewer than 5% of colon cancers arise in the presence of a clear hereditary cancer condition; however, current estimates suggest that an additional 15-25% of colorectal cancers arise on the basis of unknown inherited factors.

Aim: To identify additional genetic factors responsible for colon cancer.

Methods: A large kindred with excess colorectal cancer was identified through the Utah Population Database and evaluated clinically and genetically for inherited susceptibility.

Results: A major genetic locus segregating with colonic polyps and cancer in this kindred was identified on chromosome 13q with a non-parametric linkage score of 24 (LOD score of 2.99 and p=0.001). The genetic region spans 21 Mbp and contains 27 RefSeq genes. Sequencing of all candidate genes in this region failed to identify a clearly deleterious mutation; however, polymorphisms segregating with the phenotype were identified. Chromosome 13q is commonly gained and overexpressed in colon cancers and correlates with metastasis, suggesting the presence of an important cancer progression gene. Evaluation of tumours from the kindred revealed a gain of 13q as well.

Conclusions: This identified region may contain a novel gene responsible for colon cancer progression in a significant proportion of sporadic cancers. Identification of the precise gene and causative genetic change in the kindred will be an important next step to understanding cancer progression and metastasis.

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Conflict of interest statement

Disclosures: No potential conflicts of interest are disclosed.

Figures

Figure 1
Figure 1. K5275 Pedigree
Trimmed pedigree representing the branches recruited for study. An asterisk indicates individuals with colonic phenotype information. Individuals with colorectal cancer are indicated as a dark filled circle/square with the age of diagnosis listed. Other cancers are listed with the age of diagnosis and cancer type. Individuals with tubular adenomas (TA) are marked with a half filled circle/square with the age at colonoscopy and size and histology of adenoma indicated. One or more siblings participated and no adenomas were identified, they are indicated as a diamond with the number of individuals noted in the diamond, and the age range of colonoscopy listed.
Figure 2
Figure 2. Genome-wide scan of K5275 using microsatellite (STR) markers and parametric linkage analysis
A set of 330 polymorphic STR markers (325 genome-wide + 5 fine map) were used for genotyping and linkage analysis. The resulting LOD scores are indicated along the Y-axis and the chromosomal boundaries according to the Marshfield genetic map are indicated along the X-axis.
Figure 3
Figure 3. Genome-wide scan of K5275 using SNP markers and nonparametric linkage analysis
A set of 10,204 SNP markers were used for genotyping and 8,214 for linkage analysis. The resulting LOD scores are indicated along the Y-axis and the chromosomal boundaries according to the Marshfield genetic map are indicated along the X-axis.
Figure 4
Figure 4. Chromosome 13q31 linkage analysis in K5275
The left axis and black line report (multipoint) NPL score for the region with a maximum of 24.12. The right axis and grey line report the corresponding (multipoint) LOD score of 2.99 for the region. Nonparametric linkage analysis was performed with genotyped microsatellite markers and SNPs in the region of interest as indicated along the x-axis using the GENEHUNTER program.
Figure 5
Figure 5. Linkage pedigree with haplotypes
Individuals' numbers correspond to pedigree positions in Figure 1. Individuals with dark filled squares/circles were coded as affected. Individuals with grey filled squares/circles were coded as unknown. Individuals noted with (#) are the boarder line-affected cases that were run in duplicate as unknown or affected. The genetic marker and corresponding allele are listed in map order and represent the most informative markers within the region with the highest heterozygosity. The precise nonrecombinant boundaries sit between rs1854204 and rs1870836 (rs2077779), individual IV-14, and between D13S265 and rs745040 (rs2351871), individual III-18).
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