Chromosome 19q13 disruption alters expressions of CYP2A7, MIA and MIA-RAB4B lncRNA and contributes to FAP-like phenotype in APC mutation-negative familial colorectal cancer patients

• Published in: PloS one Vol. 12; no. 3; p. e0173772
• Main Authors: Thean, Lai Fun, Wong, Yu Hui, Lo, Michelle, Loi, Carol, Chew, Min Hoe, Tang, Choong Leong, Cheah, Peh Yean
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 17.03.2017; Public Library of Science (PLoS)
• Subjects: Adenomatous polyposis coli; Adenomatous Polyposis Coli - genetics; Adenomatous polyposis coli protein; Algorithms; Aryl Hydrocarbon Hydroxylases - genetics; Binding sites; Biology and Life Sciences; Cancer; Cancer patients; Chromatin; Chromosome 19; Chromosome deletion; Chromosomes; Chromosomes, Human, Pair 19; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - genetics; Colorectal surgery; Cooperation; Copy number; CYP2A7 gene; Cytochrome P450 Family 2 - genetics; Deoxyribonucleic acid; DNA; Epigenetics; Ethnicity; Extracellular Matrix Proteins - genetics; Familial adenomatous polyposis; Female; Gastric cancer; Gene expression; Gene mutation; Genes; Genes, APC; Genetic aspects; Genetic disorders; Genomes; Genomics; Health aspects; Heterozygosity; Humans; Hypoxia-Inducible Factor-Proline Dioxygenases - genetics; Kinases; Loss of heterozygosity; Male; Medicine and Health Sciences; Melanoma; Minority & ethnic groups; miRNA; Mucosa; Mutation; Neoplasm Proteins - genetics; Non-coding RNA; Patients; Pedigree; Polymerase chain reaction; Polyposis coli; Polyps; Prostate; Research and Analysis Methods; Ribonucleic acid; RNA; RNA, Long Noncoding - genetics; Siblings; Stomach cancer; Studies; Tumorigenesis
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0173772

Familial adenomatous polyposis (FAP) is an autosomal-dominantly inherited form of colorectal cancer (CRC) caused by mutation in the adenomatous polyposis coli (APC) gene. Our ability to exhaustively screen for APC mutations identify microsatellite-stable and APC-mutation negative familial CRC patients, enabling us to search for novel genes. We performed genome-wide scan on two affected siblings of one family and 88 ethnicity- and gender-matched healthy controls to identify deletions shared by the siblings. Combined loss of heterozygosity, copy number and allelic-specific copy number analysis uncovered 5 shared deletions. Long-range polymerase chain reaction (PCR) confirmed chromosome 19q13 deletion, which was subsequently found in one other family. The 32 kb deleted region harbors the CYP2A7 gene and was enriched with enhancer, repressor and insulator sites. The wildtype allele was lost in the polyps of the proband. Further, real-time RT-PCR assays showed that expressions of MIA and MIA-RAB4B located 35 kb upstream of the deletion, were up-regulated in the polyps compared to the matched mucosa of the proband. MIA-RAB4B, the read-through long non-coding RNA (lncRNA), RAB4B, PIM2 and TAOK1 share common binding site of a microRNA, miR-24, in their 3'UTRs. PIM2 and TAOK1, two target oncogenes of miR-24, were co-ordinately up-regulated with MIA-RAB4B in the polyps, suggesting that MIA-RAB4B could function as competitive endogenous RNA to titrate miR-24 away from its other targets. The data suggest that the 19.13 deletion disrupted chromatin boundary, leading to altered expression of several genes and lncRNA, could contribute to colorectal cancer via novel genetic and epigenetic mechanisms.