Identifying a Region of Interest in Site- and Stage-Specific Colon Cancer on Chromosome 13

Sivarajasingham, Nala S.; Baker, Richard P.; Tilsed, Jonathan; Greenman, John; Monson, J. R. T.; Cawkwell, Lynn

doi:10.1245/aso.2003.03.004

Cited by 8 publications

(8 citation statements)

References 21 publications

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“…The loss of function nature of the mutations is in agreement with the mutations being homozygous in three tumors and the partial LOH at the FGF9 region in four other heterozygous mutations. In the published literature, LOH in this region was clearly observed when the analysis was restricted to right-sided Dukes' stage C colon tumors [Sivarajasingham et al, 2003] and we noted that three out of four primary colon tumors with FGF9 mutations were right-sided.…”

Section: Discussionmentioning

confidence: 56%

“…Fibroblast growth factor 9 (FGF9; MIM] 600921) was an attractive target for the following reasons: First, FGF9 has been identified as a target for b-catenin/T-cell factor [Hendrix et al, 2006;Imai et al, 2002]. Second, FGF9 maps to chromosome 13q11-12, which is a common area of loss of heterozygosity (LOH) in colorectal carcinomas [Sivarajasingham et al, 2003] and gain of 13q is common in these tumors [Abdel-Rahman et al, 2001]. Finally, FGFR2 and FGFR3 encoding putative receptors for FGF9 show occasional somatic mutations in human cancers Dai et al, 2001;Jang et al, 2001;Karoui et al, 2001;Pollock et al, 2007] and the FGFR2 locus was recently implicated in susceptibility to breast cancer [Easton et al, 2007].…”

Section: Introductionmentioning

confidence: 99%

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SomaticFGF9mutations in colorectal and endometrial carcinomas associated with membranousβ-catenin

et al. 2008

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We previously described striking molecular features including high frequency of membranous beta-catenin in subsets of familial colon cancers with as yet unknown predisposition. We hypothesized that such tumors might carry mutations in Wnt/beta-catenin target genes. Fibroblast growth factor 9 (FGF9) was an attractive target, as it maps to a common area of loss of heterozygosity (LOH) in colorectal carcinomas on 13q12.11. Here, we report, for the first time, the occurrence of FGF9 mutations in human cancers. We found a total of six distinct FGF9 mutations including one frameshift, four missense, and one nonsense, in 10 (six colorectal and four endometrial) out of 203 tumors and cell lines. The frameshift mutation was detected in five different tumors. Mapping of these mutations onto the crystal structure of FGF9 predicted that they should all lead to loss of function albeit through variable mechanisms. The p.R173K mutation should diminish ligand affinity for heparin/heparan sulfate, the p.V192M, p.D203G, and p.L188YfsX18 (FGF9(Delta205-208)) mutations should negatively impact ligand's interaction with receptor, while p.G84E and p.E142X (FGF9(Delta142-208)) mutations should interfere with ligand folding. Consistent with these structural predictions, the p.V192M, p.D203G, and p.L188YfsX18 (FGF9(Delta205-208)) mutations impaired the ability of ligand to activate mitogen-activated protein kinase (MAPK) cascade in cultured cells expressing FGF receptors. LOH was observed in seven out of nine FGF9 mutant tumors, supporting the predicted loss of function. Interestingly, eight out of 10 (80%) of the FGF9 mutant tumors showed normal membranous beta-catenin expression and the absence of mutation in the beta-catenin gene (CTNNB1). These data suggest that FGF9 plays a role in colorectal and endometrial carcinogenesis.

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Section: Discussionmentioning

confidence: 56%

Section: Introductionmentioning

confidence: 99%

SomaticFGF9mutations in colorectal and endometrial carcinomas associated with membranousβ-catenin

et al. 2008

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“…In other studies, colon tumors have shown the highest area of allelic imbalance corresponding to chromosome 13q11.2-11. This region includes the large tumor suppressor two gene (LATS2) and FGF9, suggesting that FGF9 may be involved in carcinogenesis [20].…”

Section: Discussionmentioning

confidence: 99%

Genes Regulated by Nkx2-3 in Sporadic and Inflammatory Bowel Disease-Associated Colorectal Cancer Cell Lines

Lin

Pastor

et al. 2010

Dig Dis Sci

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“…HD is a very rare double‐mutation event that has been a key indicator for successful localization and positional cloning of many TSGs. Second, although the 13q12.11 region is very close to the centromeric region of chromosome 13, frequent LOH was still observed in many tumors including colon cancer, esophageal squamous‐cell carcinoma, HCC, and non‐small‐cell lung cancer (Tamura et al, 1997; Li et al, 2001a, b; Sivarajasingham et al, 2003). In all of these studies, D13S175 was the marker closest to the centromere of chromosome 13 for LOH analysis.…”

Section: Discussionmentioning

confidence: 99%

Molecular genetic evidence supporting a novel human hepatocellular carcinoma tumor suppressor locus at 13q12.11

Chen

Yeh

Chen

et al. 2005

Genes Chromosomes & Cancer

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A novel 1-cM (1.8 Mb) homozygous deletion (HD) on 13q12.11 was identified in a human hepatocellular carcinoma (HCC) cell line, SK-Hep-1, after high-density genetic marker scan and Southern blotting analysis. A loss of heterozygosity (LOH) analysis indicated that LOH frequency of the HD region in 48 pairs of HCC tissues was 52%. Interestingly, the occurrence of LOH in the 13q12.11 HD region is significantly associated with early-onset HCC, inferred from Fisher's exact test (P = 0.0047) and Mann-Whitney test (P = 0.023). Since the novel 1-cM (1.8 Mb) HD region is gene-rich with more than 37 predicted transcripts, we used a candidate gene approach by examining down-regulation of known tumor suppressor genes (TSGs), including LATS2, TG737, CRYL1, and GJB2, in HCC tissues. We detected only 14% down-regulation of the LAST2 gene that flanks the outside of the HD, in HCC tissues, by quantitative RT-PCR assays. However, we observed significant down-regulation of the TG737, CRYL1, and GJB2 genes located within the HD in 59, 64, and 71% of HCC tissues, respectively. Together, our results indicated that the identified 13q12.11 HD region contained at least three significant down-regulated TSGs, and preferential LOH in early-onset HCC patients is a putative tumor suppressor locus in HCC.

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Identifying a Region of Interest in Site- and Stage-Specific Colon Cancer on Chromosome 13

Cited by 8 publications

References 21 publications

SomaticFGF9mutations in colorectal and endometrial carcinomas associated with membranousβ-catenin

SomaticFGF9mutations in colorectal and endometrial carcinomas associated with membranousβ-catenin

Genes Regulated by Nkx2-3 in Sporadic and Inflammatory Bowel Disease-Associated Colorectal Cancer Cell Lines

Molecular genetic evidence supporting a novel human hepatocellular carcinoma tumor suppressor locus at 13q12.11

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