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Novel recurrently mutated genes in African American colon cancers.

ABSTRACT: We used whole-exome and targeted sequencing to characterize somatic mutations in 103 colorectal cancers (CRC) from African Americans, identifying 20 new genes as significantly mutated in CRC. Resequencing 129 Caucasian derived CRCs confirmed a 15-gene set as a preferential target for mutations in African American CRCs. Two predominant genes, ephrin type A receptor 6 (EPHA6) and folliculin (FLCN), with mutations exclusive to African American CRCs, are by genetic and biological criteria highly likely African American CRC driver genes. These previously unsuspected differences in the mutational landscapes of CRCs arising among individuals of different ethnicities have potential to impact on broader disparities in cancer behaviors.

SUBMITTER: Guda K

PROVIDER: S-EPMC4313860 | biostudies-other | 2015 Jan

REPOSITORIES: biostudies-other

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Novel recurrently mutated genes in African American colon cancers.

Guda Kishore K Veigl Martina L ML Varadan Vinay V Nosrati Arman A Ravi Lakshmeswari L Lutterbaugh James J Beard Lydia L Willson James K V JK Sedwick W David WD Wang Zhenghe John ZJ Molyneaux Neil N Miron Alexander A Adams Mark D MD Elston Robert C RC Markowitz Sanford D SD Willis Joseph E JE

Proceedings of the National Academy of Sciences of the United States of America 20150112 4

We used whole-exome and targeted sequencing to characterize somatic mutations in 103 colorectal cancers (CRC) from African Americans, identifying 20 new genes as significantly mutated in CRC. Resequencing 129 Caucasian derived CRCs confirmed a 15-gene set as a preferential target for mutations in African American CRCs. Two predominant genes, ephrin type A receptor 6 (EPHA6) and folliculin (FLCN), with mutations exclusive to African American CRCs, are by genetic and biological criteria highly lik ...[more]

PMID: 25583493

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Project description:The identification of genes that are differentially methylated in colorectal cancer (CRC) has potential value for both diagnostic and therapeutic interventions specifically in high-risk populations such as African Americans (AAs). However, DNA methylation patterns in CRC, especially in AAs, have not been systematically explored and remain poorly understood. Here, we performed DNA methylome profiling to identify the methylation status of CpG islands within candidate genes involved in critical pathways important in the initiation and development of CRC. We used reduced representation bisulfite sequencing (RRBS) in colorectal cancer and adenoma tissues that were compared with DNA methylome from a healthy AA subject's colon tissue and peripheral blood DNA. The identified methylation markers were validated in fresh frozen CRC tissues and corresponding normal tissues from AA patients diagnosed with CRC at Howard University Hospital. We identified and validated the methylation status of 355 CpG sites located within 16 gene promoter regions associated with CpG islands. Fifty CpG sites located within CpG islands-in genes ATXN7L1 (2), BMP3 (7), EID3 (15), GAS7 (1), GPR75 (24), and TNFAIP2 (1)-were significantly hypermethylated in tumor vs. normal tissues (P<0.05). The methylation status of BMP3, EID3, GAS7, and GPR75 was confirmed in an independent, validation cohort. Ingenuity pathway analysis mapped three of these markers (GAS7, BMP3 and GPR) in the insulin and TGF-β1 network-the two key pathways in CRC. In addition to hypermethylated genes, our analysis also revealed that LINE-1 repeat elements were progressively hypomethylated in the normal-adenoma-cancer sequence. We conclude that DNA methylome profiling based on RRBS is an effective method for screening aberrantly methylated genes in CRC. While previous studies focused on the limited identification of hypermethylated genes, ours is the first study to systematically and comprehensively identify novel hypermethylated genes, as well as hypomethylated LINE-1 sequences, which may serve as potential biomarkers for CRC in African Americans. Our discovered biomarkers were intimately linked to the insulin/TGF-B1 pathway, further strengthening the association of diabetic disorders with colon oncogenic transformation.

Project description:BACKGROUND:Cancer genes tend to be highly mutated under positive selection. Better understanding the recurrently mutated genes (RMGs) in cancer is critical for explicating the mechanisms of tumorigenesis and providing vital clues for therapy. Although some studies have investigated functional impacts of RMGs in specific cancer types, a comprehensive analysis of RMGs and their mutational impacts across cancers is still needed. METHODS:We obtained data from The Cancer Genome Atlas (TCGA) and calculated mutation rate of each gene in 31 cancer types. Functional analysis was performed to identify the important signaling pathways and enriched protein types of RMGs. In order to evaluate functional impacts of RMGs, differential expression, survival, and pairwise mutation patterns analyses were performed. RESULTS:Totally, we identified 897 RMGs and 624 of them were specifically mutant in only a single cancer type. Functional analysis demonstrated that these RMGs were enriched in hydrolases, cytoskeletal protein, and pathways like MAPK, cell cycle, PI3K-Akt, ECM receptor interaction, and energy metabolism. The differentially expressed genes potentially affected by the same common RMG showed a relatively low overlap across different cancer types. For the 19 Mucin (MUC) family genes, nine of them were RMGs and four of them (MUC17, MUC5B, MUC4, and MUC16) were common RMGs shared in 8 to 17 cancer types. The results showed that recurrent mutations in MUC genes were significantly associated with better survival prognosis. Only a small part of RMGs was differentially expressed due to their own mutations and most of them were downregulated. In addition, pairwise mutation pattern analysis revealed the high frequency of co-occurred mutations among RMGs in STAD. CONCLUSION:Through the functional analysis of RMGs, we found that six signaling pathways were disrupted in most cancer types and that energy metabolism was abnormal in tumors. The results also revealed a strong correlation between recurrently mutated genes from MUC family and human survival. In addition, gene expression and survival prognosis were associated with different mutation types of RMGs.

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Novel recurrently mutated genes in African American colon cancers.

Publications

Novel recurrently mutated genes in African American colon cancers.

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