title: 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.
abstract: 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.
authors.affiliation: Department of Colorectal Surgery, Singapore General Hospital, Singapore.
authors.forename: Lai Fun
authors.initials: LF
authors.lastname: Thean
authors.affiliation: Department of Colorectal Surgery, Singapore General Hospital, Singapore.
authors.forename: Yu Hui
authors.initials: YH
authors.lastname: Wong
authors.affiliation: Department of Colorectal Surgery, Singapore General Hospital, Singapore.
authors.forename: Michelle
authors.initials: M
authors.lastname: Lo
authors.affiliation: Department of Colorectal Surgery, Singapore General Hospital, Singapore.
authors.forename: Carol
authors.initials: C
authors.lastname: Loi
authors.affiliation: Department of Colorectal Surgery, Singapore General Hospital, Singapore.
authors.forename: Min Hoe
authors.initials: MH
authors.lastname: Chew
authors.affiliation: Department of Colorectal Surgery, Singapore General Hospital, Singapore.
authors.forename: Choong Leong
authors.initials: CL
authors.lastname: Tang
authors.affiliation: Department of Colorectal Surgery, Singapore General Hospital, Singapore.|Saw Swee Hock School of Public Health, National University of Singapore, Singapore.|Duke-NUS Medical School, National University of Singapore, Singapore.
authors.forename: Peh Yean
authors.initials: PY
authors.lastname: Cheah
mesh_terms: D011125:Adenomatous Polyposis Coli / Q000235:genetics*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D002888:Chromosomes, Human, Pair 19; D015179:Colorectal Neoplasms / Q000235:genetics*; D000072467:Cytochrome P450 Family 2 / Q000235:genetics*; D016326:Extracellular Matrix Proteins / Q000235:genetics*; D005260:Female; D017491:Genes, APC; D006801:Humans; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases / Q000235:genetics; D008297:Male; D009363:Neoplasm Proteins / Q000235:genetics*; D010375:Pedigree; D062085:RNA, Long Noncoding / Q000235:genetics*
chemical_list: D016326:Extracellular Matrix Proteins; C090059:MIA protein, human; D009363:Neoplasm Proteins; D062085:RNA, Long Noncoding; C447780:EGLN2 protein, human; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C423964:CYP2A7 protein, human; D000072467:Cytochrome P450 Family 2