Comparative Genomic Analysis of Early and Late Onset Colorectal Cancer
Adnan Ahmad Ansari
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The colorectal cancer (CRC) is reported as one of the most common cancer worldwide. In women, it is ranked as the second most and in men it is ranked as the third most common cancer. Additionally it is fourth most common cause of cancer related deaths worldwide results in approximately 608,000 deaths/year. CRC can be subdivided into hereditary (~ 30% cases) or sporadic (~70% cases) cancers depending on the presence or absence of familial genetic predisposition. In order to find out somatic and germline variants that are predisposing to CRC we sequenced 28 pairs of normal and tumor samples of early onset CRC using whole exome sequencing. We also reanalyzed TCGA CRC data for germline variants. Somatic mutations analysis revealed recurrent mutations in APC, TP53, KRAS, PIK3CA and SMAD4 genes. In addition, we found significant mutations in the conserved regions of BRCA2, BRAF and POLE genes. Of note, we found that the samples with somatic mutation P286R in POLE gene also showed hyper-mutation. Pathway analysis showed the aberrations of Wnt, P53, TGF-β and PI3K signaling pathways. Germline analysis of data indicated MLL3 as an important gene and two germline variants R894W and Y816* in MLL3 as a risk factor of CRC. Other important genes having germline variants include CDC27, TopBP1, BRCA1, MYH11, RB1, POLE, MYH9 and NBN genes. Comparison of somatic and germline variants of early onset CRC with late onset CRC shows that it is difficult to distinguish between them at genomic level.