Abstract
BackgroundChromosomal inversions are structural genetic variants where a chromosome segment changes its orientation. While sporadic de novo inversions are known genetic risk factors for cancer susceptibility, it is unknown if common polymorphic inversions are also associated with the prognosis of common tumors, as they have been linked to other complex diseases. We studied the association of two well-characterized human inversions at 17q21.31 and 8p23.1 with the prognosis of lung, liver, breast, colorectal, and stomach cancers.ResultsUsing data from The Cancer Genome Atlas (TCGA), we observed that inv8p23.1 was associated with overall survival in breast cancer and that inv17q21.31 was associated with overall survival in stomach cancer. In the meta-analysis of two independent studies, inv17q21.31 heterozygosity was significantly associated with colorectal disease-free survival. We found that the association was mediated by the de-methylation of cg08283464 and cg03999934, also linked to lower disease-free survival.ConclusionsOur results suggest that chromosomal inversions are important genetic factors of tumor prognosis, likely affecting changes in methylation patterns.
Highlights
Chromosomal inversions are structural genetic variants where a chromosome segment changes its orientation with respect to a reference genome
We studied the role of the inversions at 8p23.1 and 17q21.31 in cancer prognosis as these two inversions are well-characterized and can be genotyped to high accuracy using SNP array data [6, 8, 12]
Mediation analysis We evaluated whether gene expression or DNA methylation were mediators of the association between inversion inv17q21.31 and colorectal recurrence
Summary
Chromosomal inversions are structural genetic variants where a chromosome segment changes its orientation with respect to a reference genome. Ancient non-recurrent inversions define divergent haplotypes, each linked to an inversion status, as inverted and standard chromosomes do not recombine [6]. Based on this observation, different methods on nucleotide variation data have been implemented to call inversions status from haplotype differences [7, 8]. Chromosomal inversions are structural genetic variants where a chromosome segment changes its orientation. While sporadic de novo inversions are known genetic risk factors for cancer susceptibility, it is unknown if common polymorphic inversions are associated with the prognosis of common tumors, as they have been linked to other complex diseases. We studied the association of two well-characterized human inversions at 17q21.31 and 8p23.1 with the prognosis of lung, liver, breast, colorectal, and stomach cancers
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