Genomes and Genes
Summary: Tumor suppressor genes located in the 5q21 region on the long arm of human chromosome 5. The mutation of these genes is associated with familial adenomatous polyposis (ADENOMATOUS POLYPOSIS COLI) and GARDNER SYNDROME, as well as some sporadic colorectal cancers.
- Hung K, Maricevich M, Richard L, Chen W, Richardson M, Kunin A, et al. Development of a mouse model for sporadic and metastatic colon tumors and its use in assessing drug treatment. Proc Natl Acad Sci U S A. 2010;107:1565-70 pubmed publisher..These studies suggest that mTOR inhibitors should be further explored as potential colorectal cancer therapies in patients whose tumors do not have activating mutations in KRAS. ..
- Sussan T, Yang A, Li F, Ostrowski M, Reeves R. Trisomy represses Apc(Min)-mediated tumours in mouse models of Down's syndrome. Nature. 2008;451:73-5 pubmed publisher..Upregulation of Ets2 and, potentially, other genes involved in this kind of protective effect may provide a prophylactic effect in all individuals, regardless of ploidy...
- Brock M, Hooker C, Ota Machida E, Han Y, Guo M, Ames S, et al. DNA methylation markers and early recurrence in stage I lung cancer. N Engl J Med. 2008;358:1118-28 pubmed publisher..Methylation of the promoter region of the four genes in patients with stage I NSCLC treated with curative intent by means of surgery is associated with early recurrence. ..
- Segditsas S, Sieber O, Deheragoda M, East P, Rowan A, Jeffery R, et al. Putative direct and indirect Wnt targets identified through consistent gene expression changes in APC-mutant intestinal adenomas from humans and mice. Hum Mol Genet. 2008;17:3864-75 pubmed publisher..Several of the newly identified, differentially expressed genes represent potential diagnostic or therapeutic targets for intestinal tumours. ..
- Amos Landgraf J, Kwong L, Kendziorski C, Reichelderfer M, Torrealba J, Weichert J, et al. A target-selected Apc-mutant rat kindred enhances the modeling of familial human colon cancer. Proc Natl Acad Sci U S A. 2007;104:4036-41 pubmed..We believe that the Pirc rat kindred can address many of the current gaps in the modeling of human colon cancer. ..
- Polakis P. The many ways of Wnt in cancer. Curr Opin Genet Dev. 2007;17:45-51 pubmed..This review summarizes the reported genetic defects in the Wnt pathway, with an emphasis on their functional contribution to human tumor progression. ..
- Ramocki N, Wilkins H, Magness S, Simmons J, Scull B, Lee G, et al. Insulin receptor substrate-1 deficiency promotes apoptosis in the putative intestinal crypt stem cell region, limits Apcmin/+ tumors, and regulates Sox9. Endocrinology. 2008;149:261-7 pubmed
- Korsisaari N, Kasman I, Forrest W, Pal N, Bai W, Fuh G, et al. Inhibition of VEGF-A prevents the angiogenic switch and results in increased survival of Apc+/min mice. Proc Natl Acad Sci U S A. 2007;104:10625-30 pubmed..Therefore, VEGF-A inhibition may be a previously uncharacterized strategy for the prevention of the angiogenic switch and growth in intestinal adenomas. ..
- Kanter Smoler G, Fritzell K, Rohlin A, Engwall Y, Hallberg B, Bergman A, et al. Clinical characterization and the mutation spectrum in Swedish adenomatous polyposis families. BMC Med. 2008;6:10 pubmed publisher..Finding the causative mutations has great implications for the families. Correlating the genotypes to the phenotypes could help to improve the diagnosis and follow-up of patients...
- Yamada Y, Mori H. Multistep carcinogenesis of the colon in Apc(Min/+) mouse. Cancer Sci. 2007;98:6-10 pubmed
- Jass J. Colorectal cancer: a multipathway disease. Crit Rev Oncog. 2006;12:273-87 pubmed..CRC comprises subgroups with particular clinical, pathological, and molecular features. ..
- Hes F, Nielsen M, Bik E, Konvalinka D, Wijnen J, Bakker E, et al. Somatic APC mosaicism: an underestimated cause of polyposis coli. Gut. 2008;57:71-6 pubmed..The patient with 10 or more adenomas in the colon poses a diagnostic challenge. Beside germline mutations in the APC and MUTYH genes, only four cases of mosaic APC mutations have been reported...
- Aretz S, Stienen D, Friedrichs N, Stemmler S, Uhlhaas S, Rahner N, et al. Somatic APC mosaicism: a frequent cause of familial adenomatous polyposis (FAP). Hum Mutat. 2007;28:985-92 pubmed..Some of the deviations from the expected phenotype in FAP can be explained by the presence of somatic mosaicism. ..
- Nielsen M, Hes F, Nagengast F, Weiss M, Mathus Vliegen E, Morreau H, et al. Germline mutations in APC and MUTYH are responsible for the majority of families with attenuated familial adenomatous polyposis. Clin Genet. 2007;71:427-33 pubmed
- Barker N, Ridgway R, van Es J, van de Wetering M, Begthel H, van den Born M, et al. Crypt stem cells as the cells-of-origin of intestinal cancer. Nature. 2009;457:608-11 pubmed publisher..Even after 30weeks, large adenomas are very rare in these mice. We conclude that stem-cell-specific loss of Apc results in progressively growing neoplasia...
- Brozek I, Plawski A, Podralska M, Kanka C, Slomski R, Limon J. Thyroid cancer in two siblings with FAP syndrome and APC mutation. Int J Colorectal Dis. 2008;23:331-2 pubmed
- Li P, Schulz S, Bombonati A, Palazzo J, Hyslop T, Xu Y, et al. Guanylyl cyclase C suppresses intestinal tumorigenesis by restricting proliferation and maintaining genomic integrity. Gastroenterology. 2007;133:599-607 pubmed
- Yekkala K, Baudino T. Inhibition of intestinal polyposis with reduced angiogenesis in ApcMin/+ mice due to decreases in c-Myc expression. Mol Cancer Res. 2007;5:1296-303 pubmed publisher..This study shows that c-Myc is critical for Apc-dependent intestinal tumorigenesis in mice and provides a potential therapeutic target in the treatment of colorectal cancer. ..
- Pollard P, Deheragoda M, Segditsas S, Lewis A, Rowan A, Howarth K, et al. The Apc 1322T mouse develops severe polyposis associated with submaximal nuclear beta-catenin expression. Gastroenterology. 2009;136:2204-2213.e1-13 pubmed publisher..We propose that the Apc(1322T) mutation produces submaximal beta-catenin levels that promote early tumor growth more effectively than the Apc(Min) mutation. ..
- Ignatenko N, Holubec H, Besselsen D, Blohm Mangone K, Padilla Torres J, Nagle R, et al. Role of c-Myc in intestinal tumorigenesis of the ApcMin/+ mouse. Cancer Biol Ther. 2006;5:1658-64 pubmed..Thus, conditional inactivation of c-Myc, mediated by Fabpl4xat-132-driven Cre-recombinase, suppresses Apc-dependent intestinal tumorigenesis in adult ApcMin/+ mice, without apparent effect on normal intestinal mucosa. ..
- Wilkins J, Sansom O. C-Myc is a critical mediator of the phenotypes of Apc loss in the intestine. Cancer Res. 2008;68:4963-6 pubmed publisher..The importance of investigating Apc and C-Myc gene function in the correct tissue context is also discussed. ..
- Zeilstra J, Joosten S, Dokter M, Verwiel E, Spaargaren M, Pals S. Deletion of the WNT target and cancer stem cell marker CD44 in Apc(Min/+) mice attenuates intestinal tumorigenesis. Cancer Res. 2008;68:3655-61 pubmed publisher..Our results show an important role for CD44 in intestinal tumorigenesis and suggest that CD44 does not affect proliferation but is involved in the control of the balance between survival and apoptosis in the intestinal crypt. ..
- Meuller J, Kanter Smoler G, Nygren A, Errami A, Gronberg H, Holmberg E, et al. Identification of genomic deletions of the APC gene in familial adenomatous polyposis by two independent quantitative techniques. Genet Test. 2004;8:248-56 pubmed..This deletion was further verified and characterized with long-range PCR. The MLPA test ensures a sensitive high-throughput screening for large deletions of the APC gene and can easily be implemented in the diagnostic testing for FAP. ..
- Cardoso J, Molenaar L, de Menezes R, van Leerdam M, Rosenberg C, Möslein G, et al. Chromosomal instability in MYH- and APC-mutant adenomatous polyps. Cancer Res. 2006;66:2514-9 pubmed..The aneuploid changes detected at early stages of MYH-driven tumorigenesis may underlie accelerated tumor progression, increased cancer risk, and poor prognosis in MAP. ..
- Erdman S, Sohn J, Rao V, Nambiar P, Ge Z, Fox J, et al. CD4+CD25+ regulatory lymphocytes induce regression of intestinal tumors in ApcMin/+ mice. Cancer Res. 2005;65:3998-4004 pubmed..Similarities with cancer of the breast, prostate, lung, and other sites raise the possibility of broader roles for regulatory lymphocytes in prevention and treatment of epithelial cancers in humans. ..
- Gonzalez S, Blanco I, Campos O, Julià M, Reyes J, Llompart A, et al. Founder mutation in familial adenomatous polyposis (FAP) in the Balearic Islands. Cancer Genet Cytogenet. 2005;158:70-4 pubmed..Although this codon is a hot-spot, the haplotype analysis of these families is consistent for the presence of a founder effect of the 5-bp deletion at codon 1061 in FAP families in the Spanish Balearic Islands. ..
- Tranah G, Giovannucci E, Ma J, Fuchs C, Hunter D. APC Asp1822Val and Gly2502Ser polymorphisms and risk of colorectal cancer and adenoma. Cancer Epidemiol Biomarkers Prev. 2005;14:863-70 pubmed..No gene-environment interactions were observed with these risk factors or with other dietary risk factors previously hypothesized to interact with the APC Asp1822Val polymorphism. ..
- Renkonen E, Nieminen P, Abdel Rahman W, Moisio A, Jarvela I, Arte S, et al. Adenomatous polyposis families that screen APC mutation-negative by conventional methods are genetically heterogeneous. J Clin Oncol. 2005;23:5651-9 pubmed..Significant differences were observed in clinical manifestations between subgroups, emphasizing the importance of accurate genetic and clinical characterization for the proper management of such families. ..
- Ju J, Hong J, Zhou J, Pan Z, Bose M, Liao J, et al. Inhibition of intestinal tumorigenesis in Apcmin/+ mice by (-)-epigallocatechin-3-gallate, the major catechin in green tea. Cancer Res. 2005;65:10623-31 pubmed
- Clement G, Braunschweig R, Pasquier N, Bosman F, Benhattar J. Alterations of the Wnt signaling pathway during the neoplastic progression of Barrett's esophagus. Oncogene. 2006;25:3084-92 pubmed
- Galiatsatos P, Foulkes W. Familial adenomatous polyposis. Am J Gastroenterol. 2006;101:385-98 pubmed
- Colbert L, Mai V, Tooze J, Perkins S, Berrigan D, Hursting S. Negative energy balance induced by voluntary wheel running inhibits polyp development in APCMin mice. Carcinogenesis. 2006;27:2103-7 pubmed..Although EX affected IGF-1 and corticosterone, neither marker was related to total polyp number. ..
- Ionescu D, Papachristou G, Schoen R, Hedge M, Richards C, Monzon F. Attenuated familial adenomatous polyposis: a case report with mixed features and review of genotype-phenotype correlation. Arch Pathol Lab Med. 2005;129:1401-4 pubmed..Differences in the APC mutation sites alone cannot completely account for intrafamilial and interfamilial variation in the polyposis phenotypes. ..
- Aceto G, Curia M, Veschi S, De Lellis L, Mammarella S, Catalano T, et al. Mutations of APC and MYH in unrelated Italian patients with adenomatous polyposis coli. Hum Mutat. 2005;26:394 pubmed..Moreover, the proportion of cases with an attenuated polyposis phenotype was higher (p = 0.0008) among patients negative for APC and MYH mutations than among carriers of APC or biallelic MYH mutations. ..
- Tanaka T, Kohno H, Suzuki R, Hata K, Sugie S, Niho N, et al. Dextran sodium sulfate strongly promotes colorectal carcinogenesis in Apc(Min/+) mice: inflammatory stimuli by dextran sodium sulfate results in development of multiple colonic neoplasms. Int J Cancer. 2006;118:25-34 pubmed..The findings also suggest that strong oxidative/nitrosative stress caused by DSS-induced inflammation may contribute to the colonic neoplasms development. ..
- Batlle E, Bacani J, Begthel H, Jonkheer S, Jonkeer S, Gregorieff A, et al. EphB receptor activity suppresses colorectal cancer progression. Nature. 2005;435:1126-30 pubmed..Our data demonstrate that loss of EphB expression represents a critical step in colorectal cancer progression. ..
- Chen W, Khazaie K, Zhang G, Weissleder R, Tung C. Detection of dysplastic intestinal adenomas using a fluorescent folate imaging probe. Mol Imaging. 2005;4:67-74 pubmed..2.2%), and confirmed the source of FFP-positive cells to be primarily an F4/80-positive macrophage subpopulation. Taken together, these results indicate that probe potentially can be used to image dysplastic intestinal adenomas in vivo. ..
- Rao C, Yang Y, Swamy M, Liu T, Fang Y, Mahmood R, et al. Colonic tumorigenesis in BubR1+/-ApcMin/+ compound mutant mice is linked to premature separation of sister chromatids and enhanced genomic instability. Proc Natl Acad Sci U S A. 2005;102:4365-70 pubmed..Together, our studies suggest that BubR1 and Apc functionally interact in regulating metaphase-anaphase transition, deregulation of which may play a key role in genomic instability and development and progression of colorectal cancer. ..
- García Lozano J, Cordero C, Fernandez Suarez A, Encarnación M, Pizarro A, Núñez Roldan A. APC germ-line mutations in southern Spanish patients with familial adenomatous polyposis: genotype-phenotype correlations and identification of eight novel mutations. Genet Test. 2005;9:37-40 pubmed..Intrafamilial phenotypic variability was observed in two families with mutations in exon/intron boundary, probably due to alternative splicing. ..
- Plawski A, Nowakowska D, Podralska M, Lipinski D, Steffen J, Slomski R. The AAPC case, with an early onset of colorectal cancer. Int J Colorectal Dis. 2007;22:449-51 pubmed..An atypical course of AAPC must be taken into consideration both in genetic counseling and in qualifying the patients with AAPC for the surgical treatment. ..
- Meniel V, Hay T, Douglas Jones A, Sansom O, Clarke A. Mutations in Apc and p53 synergize to promote mammary neoplasia. Cancer Res. 2005;65:410-6 pubmed..We therefore show clear synergy between these two mutations in mammary gland neoplasia and present data to suggest that at least one mechanism for this acceleration is the p53-dependent loss of Apc-deficient cells. ..
- McAlpine C, Barak Y, Matise I, Cormier R. Intestinal-specific PPARgamma deficiency enhances tumorigenesis in ApcMin/+ mice. Int J Cancer. 2006;119:2339-46 pubmed..Our results suggest that PPARgamma functions as a tumor resistance factor in the mouse intestine and warrant further investigation of the PPARgamma-dependent and independent actions of TZDs in cancer. ..
- Truta B, Allen B, Conrad P, Weinberg V, Miller G, Pomponio R, et al. A comparison of the phenotype and genotype in adenomatous polyposis patients with and without a family history. Fam Cancer. 2005;4:127-33 pubmed..However, germline APC mutations are detected far less frequently in patients without a family history. A small percentage of these cases may be secondary to biallelic germline MYH mutations. ..
- Kanter Smoler G, Björk J, Fritzell K, Engwall Y, Hallberg B, Karlsson G, et al. Novel findings in Swedish patients with MYH-associated polyposis: mutation detection and clinical characterization. Clin Gastroenterol Hepatol. 2006;4:499-506 pubmed
- Murphy S, McIlhatton B, Logan W, Porter K, Morrison P. A splice-site mutation in exon 4 of the APC gene in a family with attenuated familial adenomatous polyposis. Dig Dis Sci. 2007;52:2784-7 pubmed
- Rao C, Swamy M, Patlolla J, Kopelovich L. Suppression of familial adenomatous polyposis by CP-31398, a TP53 modulator, in APCmin/+ mice. Cancer Res. 2008;68:7670-5 pubmed publisher..Chemopreventive activity of other agents that restore tumor suppressor functions of mutant p53 in tumor cells is currently under investigation. ..
- Toyota M, Suzuki H, Yamamoto E, Imai K, Shinomura Y. [Gene mutation and DNA methylation in non-hereditary colon neoplasms]. Nihon Naika Gakkai Zasshi. 2007;96:226-30 pubmed
- Rozek L, Rennert G, Gruber S. APC E1317Q is not associated with Colorectal Cancer in a population-based case-control study in Northern Israel. Cancer Epidemiol Biomarkers Prev. 2006;15:2325-7 pubmed..Given the substantial size of our study and the consistency of our findings with the results of our meta-analyses, we conclude that it is unlikely that APC E1317Q is associated with a clinically meaningful risk of colorectal cancer. ..
- Bougatef K, Ouerhani S, Moussa A, Kourda N, Coulet F, Colas C, et al. Prevalence of mutations in APC, CTNNB1, and BRAF in Tunisian patients with sporadic colorectal cancer. Cancer Genet Cytogenet. 2008;187:12-8 pubmed publisher..The findings confirm the heterogeneity of APC gene alteration and also reveal a particular profile of this pathology among Tunisian patients that confirms the epidemiological data for this country. ..
- Nieuwenhuis M, Bulow S, Björk J, Jarvinen H, Bülow C, Bisgaard M, et al. Genotype predicting phenotype in familial adenomatous polyposis: a practical application to the choice of surgery. Dis Colon Rectum. 2009;52:1259-63 pubmed publisher..The risk of rectal cancer after primary colectomy was not significantly different between the three groups. ..
- Ng H, Novakovic B, Hiendleder S, Craig J, Roberts C, Saffery R. Distinct patterns of gene-specific methylation in mammalian placentas: implications for placental evolution and function. Placenta. 2010;31:259-68 pubmed publisher..Further studies, examining larger numbers of epigenetic modifications across phylogeny, are required to define the role of specific epigenetic modifications in the evolution of distinct placental structures. ..
- Jang Y, Lim S, Kim M, Chung H, Yoo H, Byeon J, et al. Three novel mutations of the APC gene in Korean patients with familial adenomatous polyposis. Cancer Genet Cytogenet. 2010;200:34-9 pubmed publisher..4612_4613delGA) were detected. The MUTYH mutation was not detected in any of the four FAP patients without an APC mutation. This finding of three novel mutations in a group of Korean FAP patients broadens the spectrum of APC mutations. ..