lunes, 4 de agosto de 2014

Whole-exome sequencing identifies rare pathogenic variants in new predisposition genes for familial colorectal cancer : Genetics in Medicine : Nature Publishing Group

Whole-exome sequencing identifies rare pathogenic variants in new predisposition genes for familial colorectal cancer : Genetics in Medicine : Nature Publishing Group



Whole-exome sequencing identifies rare pathogenic variants in new predisposition genes for familial colorectal cancer

Genetics in Medicine
 
(2014)
 
doi:10.1038/gim.2014.89
Received
 
Accepted
 
Published online 

Abstract

Purpose:

Colorectal cancer is an important cause of mortality in the developed world. Hereditary forms are due to germ-line mutations in APCMUTYH, and the mismatch repair genes, but many cases present familial aggregation but an unknown inherited cause. The hypothesis of rare high-penetrance mutations in new genes is a likely explanation for the underlying predisposition in some of these familial cases.

Methods:

Exome sequencing was performed in 43 patients with colorectal cancer from 29 families with strong disease aggregation without mutations in known hereditary colorectal cancer genes. Data analysis selected only very rare variants (0–0.1%), producing a putative loss of function and located in genes with a role compatible with cancer. Variants in genes previously involved in hereditary colorectal cancer or nearby previous colorectal cancer genome-wide association study hits were also chosen.

Results:

Twenty-eight final candidate variants were selected and validated by Sanger sequencing. Correct family segregation and somatic studies were used to categorize the most interesting variants inCDKN1BXRCC4EPHX1NFKBIZSMARCA4, and BARD1.

Conclusion:

We identified new potential colorectal cancer predisposition variants in genes that have a role in cancer predisposition and are involved in DNA repair and the cell cycle, which supports their putative involvement in germ-line predisposition to this neoplasm.
Genet Med advance online publication 24 July 2014

Keywords:

 
colorectal neoplasm; genetic variant; genetic predisposition to disease; hereditary disease; next-generation sequencing

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