Abstract
Colorectal cancer (CRC) exhibits a strong familial risk with first-degree relatives of cases having a two to three times greater risk of developing CRC than the general population. An estimated 35% of CRC cases are due to genetic factors. Highly penetrant predisposing genes have been identified for several inherited CRC syndromes (e.g., FAP, Lynch syndrome, and juvenile polyposis) through genetic linkage studies. However, despite these considerable successes, mutations in these rare syndromes explain less than 6% of CRCs and only a small fraction of familial risk. While two recently described syndromes, MUTYH-associated polyposis, with its pattern of recessive inheritance, and familial CRC type X, account for additional genetic burden, they still account for only a small fraction of CRC risk. In the last few years, considerable effort has been directed toward the identification of common, low-penetrance mutations through the promising approach of genome-wide association studies (GWAS). With respect to CRC, 15 novel disease loci have been identified through GWAS including several genes involved in the TGFβ signaling pathway. The familial and population risks explained by these loci remain small, but it is expected that additional novel susceptibility markers will be identified as larger ongoing and pooled GWAS are completed. While the role of the majority of susceptibility genes identified through linkage studies and GWAS in energy balance remains unclear, a pattern is emerging of a possible link given that several TGFβ-related genes have been implicated in energy balance including susceptibility genes identified through linkage analyses or GWAS.
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References
Bulow S (1987) Familial polyposis coli. Dan Med Bull 34:1–15
Bussey HJ (1970) Gastrointestinal polyposis. Gut 11:970–978
Wennstrom J, Pierce ER, McKusick VA (1974) Hereditary benign and malignant lesions of the large bowel. Cancer 34(suppl):850–857
Rozen P, Macrae F (2006) Familial adenomatous polyposis: the practical applications of clinical and molecular screening. Fam Cancer 5:227–235
Lipton L, Tomlinson I (2006) The genetics of FAP and FAP-like syndromes. Fam Cancer 5:221–226
de la Chapelle A (2004) Genetic predisposition to colorectal cancer. Nat Rev Cancer 4:769–780
Knudsen AL, Bisgaard ML, Bulow S (2003) Attenuated familial adenomatous polyposis (AFAP). A review of the literature. Fam Cancer 2:43–55
Giardiello FM, Offerhaus JG (1995) Phenotype and cancer risk of various polyposis syndromes. Eur J Cancer 31A:1085–1087
Lynch HT, Smyrk T, McGinn T et al (1995) Attenuated familial adenomatous polyposis (AFAP). A phenotypically and genotypically distinctive variant of FAP. Cancer 76:2427–2433
Hamilton SR, Liu B, Parsons RE et al (1995) The molecular basis of Turcot’s syndrome. N Engl J Med 332:839–847
Chen CS, Phillips KD, Grist S et al (2006) Congenital hypertrophy of the retinal pigment epithelium (CHRPE) in familial colorectal cancer. Fam Cancer 5:397–404
Bodmer WF, Bailey CJ, Bodmer J et al (1987) Localization of the gene for familial adenomatous polyposis on chromosome 5. Nature 328:614–616
Groden J, Thliveris A, Samowitz W et al (1991) Identification and characterization of the familial adenomatous polyposis coli gene. Cell 66:589–600
Kinzler KW, Nilbert MC, Vogelstein B et al (1991) Identification of a gene located at chromosome 5q21 that is mutated in colorectal cancers. Science 251:1366–1370
Nishisho I, Nakamura Y, Miyoshi Y et al (1991) Mutations of chromosome 5q21 genes in FAP and colorectal cancer patients. Science 253:665–669
Fearnhead NS, Britton MP, Bodmer WF (2001) The ABC of APC. Hum Mol Genet 10:721–733
Bienz M (2002) The subcellular destinations of APC proteins. Nat Rev Mol Cell Biol 3:328–338
Nathke I (2004) APC at a glance. J Cell Sci 117:4873–4875
Goss KH, Groden J (2000) Biology of the adenomatous polyposis coli tumor suppressor. J Clin Oncol 18:1967–1979
Nathke IS (2004) The adenomatous polyposis coli protein: the Achilles heel of the gut epithelium. Annu Rev Cell Dev Biol 20:337–366
Watson SA (2001) Oncogenic targets of beta-catenin-mediated transcription in molecular pathogenesis of intestinal polyposis. Lancet 357:572–573
Nathke I (2006) Cytoskeleton out of the cupboard: colon cancer and cytoskeletal changes induced by loss of APC. Nat Rev Cancer 6:967–974
Nieuwenhuis MH, Vasen HF (2007) Correlations between mutation site in APC and phenotype of familial adenomatous polyposis (FAP): a review of the literature. Crit Rev Oncol Hematol 61:153–161
Galiatsatos P, Foulkes WD (2006) Familial adenomatous polyposis. Am J Gastroenterol 101:385–398
Guillem JG, Smith AJ, Calle JP, Ruo L (1999) Gastrointestinal polyposis syndromes. Curr Probl Surg 36:217–323
Laken SJ, Petersen GM, Gruber SB et al (1997) Familial colorectal cancer in Ashkenazim due to a hypermutable tract in APC. Nat Genet 17:79–83
Lefevre JH, Parc Y, Svrcek M et al (2009) APC, MYH, and the correlation genotype-phenotype in colorectal polyposis. Ann Surg Oncol 16:871–877
Bertario L, Russo A, Sala P et al (2003) Multiple approach to the exploration of genotype-phenotype correlations in familial adenomatous polyposis. J Clin Oncol 21:1698–1707
Caspari R, Friedl W, Mandl M et al (1994) Familial adenomatous polyposis: mutation at codon 1309 and early onset of colon cancer. Lancet 343:629–632
Enomoto M, Konishi M, Iwama T, Utsunomiya J, Sugihara KI, Miyaki M (2000) The relationship between frequencies of extracolonic manifestations and the position of APC germline mutation in patients with familial adenomatous polyposis. Jpn J Clin Oncol 30:82–88
Ficari F, Cama A, Valanzano R et al (2000) APC gene mutations and colorectal adenomatosis in familial adenomatous polyposis. Br J Cancer 82:348–353
Gayther SA, Wells D, SenGupta SB et al (1994) Regionally clustered APC mutations are associated with a severe phenotype and occur at a high frequency in new mutation cases of adenomatous polyposis coli. Hum Mol Genet 3:53–56
Nagase H, Miyoshi Y, Horii A et al (1992) Correlation between the location of germ-line mutations in the APC gene and the number of colorectal polyps in familial adenomatous polyposis patients. Cancer Res 52:4055–4057
Nugent KP, Phillips RK, Hodgson SV et al (1994) Phenotypic expression in familial adenomatous polyposis: partial prediction by mutation analysis. Gut 35:1622–1623
Brensinger JD, Laken SJ, Luce MC et al (1998) Variable phenotype of familial adenomatous polyposis in pedigrees with 3′ mutation in the APC gene. Gut 43:548–552
Friedl W, Uhlhaas S, Schulmann K et al (2002) Juvenile polyposis: massive gastric polyposis is more common in MADH4 mutation carriers than in BMPR1A mutation carriers. Hum Genet 111:108–111
Sieber OM, Segditsas S, Knudsen AL et al (2006) Disease severity and genetic pathways in attenuated familial adenomatous polyposis vary greatly but depend on the site of the germline mutation. Gut 55:1440–1448
Soravia C, Berk T, Madlensky L et al (1998) Genotype-phenotype correlations in attenuated adenomatous polyposis coli. Am J Hum Genet 62:1290–1301
Walon C, Kartheuser A, Michils G et al (1997) Novel germline mutations in the APC gene and their phenotypic spectrum in familial adenomatous polyposis kindreds. Hum Genet 100:601–605
Davies DR, Armstrong JG, Thakker N et al (1995) Severe Gardner syndrome in families with mutations restricted to a specific region of the APC gene. Am J Hum Genet 57:1151–1158
Friedl W, Caspari R, Sengteller M et al (2001) Can APC mutation analysis contribute to therapeutic decisions in familial adenomatous polyposis? Experience from 680 FAP families. Gut 48:515–521
Gebert JF, Dupon C, Kadmon M et al (1999) Combined molecular and clinical approaches for the identification of families with familial adenomatous polyposis coli. Ann Surg 229:350–361
Cetta F, Montalto G, Gori M, Curia MC, Cama A, Olschwang S (2000) Germline mutations of the APC gene in patients with familial adenomatous polyposis-associated thyroid carcinoma: results from a European cooperative study. J Clin Endocrinol Metab 85:286–292
Giardiello FM, Petersen GM, Piantadosi S et al (1997) APC gene mutations and extraintestinal phenotype of familial adenomatous polyposis. Gut 40:521–525
Dobbie Z, Spycher M, Mary JL et al (1996) Correlation between the development of extracolonic manifestations in FAP patients and mutations beyond codon 1403 in the APC gene. J Med Genet 33:274–280
Moser AR, Pitot HC, Dove WF (1990) A dominant mutation that predisposes to multiple intestinal neoplasia in the mouse. Science 247:322–324
Vasen HF, Mecklin JP, Khan PM, Lynch HT (1991) The International Collaborative Group on Hereditary Non-Polyposis Colorectal Cancer (ICG-HNPCC). Dis Colon Rectum 34:424–425
Rodriguez-Bigas MA, Boland CR, Hamilton SR et al (1997) A National Cancer Institute Workshop on Hereditary Nonpolyposis Colorectal Cancer Syndrome: meeting highlights and Bethesda guidelines. J Natl Cancer Inst 89:1758–1762
Umar A, Boland CR, Terdiman JP et al (2004) Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J Natl Cancer Inst 96:261–268
Dunlop MG, Farrington SM, Carothers AD et al (1997) Cancer risk associated with germline DNA mismatch repair gene mutations. Hum Mol Genet 6:105–110
Lynch HT, Smyrk T (1996) Hereditary nonpolyposis colorectal cancer (Lynch syndrome). An updated review. Cancer 78:1149–1167
Lynch HT, Smyrk TC, Watson P et al (1993) Genetics, natural history, tumor spectrum, and pathology of hereditary nonpolyposis colorectal cancer: an updated review. Gastroenterology 104:1535–1549
Lynch HT, de la Chapelle A (2003) Hereditary colorectal cancer. N Engl J Med 348:919–932
Gryfe R, Kim H, Hsieh ET et al (2000) Tumor microsatellite instability and clinical outcome in young patients with colorectal cancer. N Engl J Med 342:69–77
Seifert M, Reichrath J (2006) The role of the human DNA mismatch repair gene hMSH2 in DNA repair, cell cycle control and apoptosis: implications for pathogenesis, progression and therapy of cancer. J Mol Histol 37:301–307
Leach FS, Nicolaides NC, Papadopoulos N et al (1993) Mutations of a mutS homolog in hereditary nonpolyposis colorectal cancer. Cell 75:1215–1225
Blackwell LJ, Martik D, Bjornson KP, Bjornson ES, Modrich P (1998) Nucleotide-promoted release of hMutSalpha from heteroduplex DNA is consistent with an ATP-dependent translocation mechanism. J Biol Chem 273:32055–32062
Gradia S, Acharya S, Fishel R (2000) The role of mismatched nucleotides in activating the hMSH2-hMSH6 molecular switch. J Biol Chem 275:3922–3930
Jiricny J, Marra G (2003) DNA repair defects in colon cancer. Curr Opin Genet Dev 13:61–69
Peltomaki P (2003) Role of DNA mismatch repair defects in the pathogenesis of human cancer. J Clin Oncol 21:1174–1179
Modrich P (2006) Mechanisms in eukaryotic mismatch repair. J Biol Chem 281:30305–30309
Aaltonen LA, Peltomaki P, Mecklin JP et al (1994) Replication errors in benign and malignant tumors from hereditary nonpolyposis colorectal cancer patients. Cancer Res 54:1645–1648
Ionov Y, Peinado MA, Malkhosyan S, Shibata D, Perucho M (1993) Ubiquitous somatic mutations in simple repeated sequences reveal a new mechanism for colonic carcinogenesis. Nature 363:558–561
Peltomaki P, Aaltonen LA, Sistonen P et al (1993) Genetic mapping of a locus predisposing to human colorectal cancer. Science 260:810–812
Thibodeau SN, Bren G, Schaid D (1993) Microsatellite instability in cancer of the proximal colon. Science 260:816–819
Fishel R, Lescoe MK, Rao MR et al (1993) The human mutator gene homolog MSH2 and its association with hereditary nonpolyposis colon cancer. Cell 75:1027–1038
Gill S, Lindor NM, Burgart LJ et al (2005) Isolated loss of PMS2 expression in colorectal cancers: frequency, patient age, and familial aggregation. Clin Cancer Res 11:6466–6471
Charbonnier F, Raux G, Wang Q et al (2000) Detection of exon deletions and duplications of the mismatch repair genes in hereditary nonpolyposis colorectal cancer families using multiplex polymerase chain reaction of short fluorescent fragments. Cancer Res 60:2760–2763
Nakagawa H, Yan H, Lockman J et al (2002) Allele separation facilitates interpretation of potential splicing alterations and genomic rearrangements. Cancer Res 62:4579–4582
Wagner A, Barrows A, Wijnen JT et al (2003) Molecular analysis of hereditary nonpolyposis colorectal cancer in the United States: high mutation detection rate among clinically selected families and characterization of an American founder genomic deletion of the MSH2 gene. Am J Hum Genet 72:1088–1100
Wijnen J, van der Klift H, Vasen H et al (1998) MSH2 genomic deletions are a frequent cause of HNPCC. Nat Genet 20:326–328
Yan H, Papadopoulos N, Marra G et al (2000) Conversion of diploidy to haploidy. Nature 403:723–724
Casey G, Lindor NM, Papadopoulos N et al (2005) Conversion analysis for mutation detection in MLH1 and MSH2 in patients with colorectal cancer. JAMA 293:799–809
Nicolaides NC, Carter KC, Shell BK, Papadopoulos N, Vogelstein B, Kinzler KW (1995) Genomic organization of the human PMS2 gene family. Genomics 30:195–206
Nicolaides NC, Kinzler KW, Vogelstein B (1995) Analysis of the 5′ region of PMS2 reveals heterogeneous transcripts and a novel overlapping gene. Genomics 29:329–334
Nakagawa H, Lockman JC, Frankel WL et al (2004) Mismatch repair gene PMS2: disease-causing germline mutations are frequent in patients whose tumors stain negative for PMS2 protein, but paralogous genes obscure mutation detection and interpretation. Cancer Res 64:4721–4727
De Vos M, Hayward BE, Picton S, Sheridan E, Bonthron DT (2004) Novel PMS2 pseudogenes can conceal recessive mutations causing a distinctive childhood cancer syndrome. Am J Hum Genet 74:954–964
Woods MO, Williams P, Careen A et al (2007) A new variant database for mismatch repair genes associated with Lynch syndrome. Hum Mutat 28:669–673
Cunningham JM, Kim CY, Christensen ER et al (2001) The frequency of hereditary defective mismatch repair in a prospective series of unselected colorectal carcinomas. Am J Hum Genet 69:780–790
Lindor NM, Burgart LJ, Leontovich O et al (2002) Immunohistochemistry versus microsatellite instability testing in phenotyping colorectal tumors. J Clin Oncol 20:1043–1048
Wahlberg SS, Schmeits J, Thomas G et al (2002) Evaluation of microsatellite instability and immunohistochemistry for the prediction of germ-line MSH2 and MLH1 mutations in hereditary nonpolyposis colon cancer families. Cancer Res 62:3485–3492
Hampel H, Frankel WL, Martin E et al (2005) Screening for the Lynch syndrome (hereditary nonpolyposis colorectal cancer). N Engl J Med 352:1851–1860
Hampel H, Frankel WL, Martin E et al (2008) Feasibility of screening for Lynch syndrome among patients with colorectal cancer. J Clin Oncol 26:5783–5788
Herman JG, Umar A, Polyak K et al (1998) Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma. Proc Natl Acad Sci USA 95:6870–6875
Gazzoli I, Loda M, Garber J, Syngal S, Kolodner RD (2002) A hereditary nonpolyposis colorectal carcinoma case associated with hypermethylation of the MLH1 gene in normal tissue and loss of heterozygosity of the unmethylated allele in the resulting microsatellite instability-high tumor. Cancer Res 62:3925–3928
Miyakura Y, Sugano K, Akasu T et al (2004) Extensive but hemiallelic methylation of the hMLH1 promoter region in early-onset sporadic colon cancers with microsatellite instability. Clin Gastroenterol Hepatol 2:147–156
Suter CM, Martin DI, Ward RL (2004) Germline epimutation of MLH1 in individuals with multiple cancers. Nat Genet 36:497–501
Goecke T, Schulmann K, Engel C et al (2006) Genotype-phenotype comparison of German MLH1 and MSH2 mutation carriers clinically affected with Lynch syndrome: a report by the German HNPCC Consortium. J Clin Oncol 24:4285–4292
Kastrinos F, Stoffel EM, Balmana J, Steyerberg EW, Mercado R, Syngal S (2008) Phenotype comparison of MLH1 and MSH2 mutation carriers in a cohort of 1,914 individuals undergoing clinical genetic testing in the United States. Cancer Epidemiol Biomarkers Prev 17:2044–2051
Vasen HF, Wijnen JT, Menko FH et al (1996) Cancer risk in families with hereditary nonpolyposis colorectal cancer diagnosed by mutation analysis. Gastroenterology 110:1020–1027
Parc Y, Boisson C, Thomas G, Olschwang S (2003) Cancer risk in 348 French MSH2 or MLH1 gene carriers. J Med Genet 40:208–213
Farrington SM, Lin-Goerke J, Ling J et al (1998) Systematic analysis of hMSH2 and hMLH1 in young colon cancer patients and controls. Am J Hum Genet 63:749–759
Bisgaard ML, Jager AC, Myrhoj T, Bernstein I, Nielsen FC (2002) Hereditary non-polyposis colorectal cancer (HNPCC): phenotype-genotype correlation between patients with and without identified mutation. Hum Mutat 20:20–27
Vasen HF, Stormorken A, Menko FH et al (2001) MSH2 mutation carriers are at higher risk of cancer than MLH1 mutation carriers: a study of hereditary nonpolyposis colorectal cancer families. J Clin Oncol 19:4074–4080
Peltomaki P, Gao X, Mecklin JP (2001) Genotype and phenotype in hereditary nonpolyposis colon cancer: a study of families with different vs. shared predisposing mutations. Fam Cancer 1:9–15
Ribic CM, Sargent DJ, Moore MJ et al (2003) Tumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer. N Engl J Med 349:247–257
Vilar E, Scaltriti M, Balmana J et al (2008) Microsatellite instability due to hMLH1 deficiency is associated with increased cytotoxicity to irinotecan in human colorectal cancer cell lines. Br J Cancer 99:1607–1612
Bertagnolli MM, Niedzwiecki D, Compton CC et al (2009) Microsatellite instability predicts improved response to adjuvant therapy with irinotecan, fluorouracil, and leucovorin in stage III colon cancer: Cancer and Leukemia Group B Protocol 89803. J Clin Oncol 27:1814–1821
Kim GP, Colangelo LH, Wieand HS et al (2007) Prognostic and predictive roles of high-degree microsatellite instability in colon cancer: a National Cancer Institute-National Surgical Adjuvant Breast and Bowel Project Collaborative Study. J Clin Oncol 25:767–772
Al-Tassan N, Chmiel NH, Maynard J et al (2002) Inherited variants of MYH associated with somatic G:C– > T:A mutations in colorectal tumors. Nat Genet 30:227–232
Sieber OM, Lipton L, Crabtree M et al (2003) Multiple colorectal adenomas, classic adenomatous polyposis, and germ-line mutations in MYH. N Engl J Med 348:791–799
Croitoru ME, Cleary SP, Di Nicola N et al (2004) Association between biallelic and monoallelic germline MYH gene mutations and colorectal cancer risk. J Natl Cancer Inst 96:1631–1634
Nielsen M, Joerink-van de Beld MC, Jones N et al (2009) Analysis of MUTYH genotypes and colorectal phenotypes in patients with MUTYH-associated polyposis. Gastroenterology 136:471–476
Lubbe SJ, Di Bernardo MC, Chandler IP, Houlston RS (2009) Clinical implications of the colorectal cancer risk associated with MUTYH mutation. J Clin Oncol 27:3975–3980
Cleary SP, Cotterchio M, Jenkins MA et al (2009) Germline MutY human homologue mutations and colorectal cancer: a multisite case–control study. Gastroenterology 136:1251–1260
Tenesa A, Campbell H, Barnetson R, Porteous M, Dunlop M, Farrington SM (2006) Association of MUTYH and colorectal cancer. Br J Cancer 95:239–242
Sampson JR, Dolwani S, Jones S et al (2003) Autosomal recessive colorectal adenomatous polyposis due to inherited mutations of MYH. Lancet 362:39–41
Enholm S, Hienonen T, Suomalainen A et al (2003) Proportion and phenotype of MYH-associated colorectal neoplasia in a population-based series of Finnish colorectal cancer patients. Am J Pathol 163:827–832
Wang L, Baudhuin LM, Boardman LA et al (2004) MYH mutations in patients with attenuated and classic polyposis and with young-onset colorectal cancer without polyps. Gastroenterology 127:9–16
Venesio T, Molatore S, Cattaneo F, Arrigoni A, Risio M, Ranzani GN (2004) High frequency of MYH gene mutations in a subset of patients with familial adenomatous polyposis. Gastroenterology 126:1681–1685
Farrington SM, Tenesa A, Barnetson R et al (2005) Germline susceptibility to colorectal cancer due to base-excision repair gene defects. Am J Hum Genet 77:112–119
Poulsen ML, Bisgaard ML (2008) MUTYH associated polyposis (MAP). Curr Genomics 9:420–435
Jenkins MA, Croitoru ME, Monga N et al (2006) Risk of colorectal cancer in monoallelic and biallelic carriers of MYH mutations: a population-based case-family study. Cancer Epidemiol Biomarkers Prev 15:312–314
Jones N, Vogt S, Nielsen M et al (2009) Increased colorectal cancer incidence in obligate carriers of heterozygous mutations in MUTYH. Gastroenterology 137:489–494, 94 e1; quiz 725–6
Fleischmann C, Peto J, Cheadle J, Shah B, Sampson J, Houlston RS (2004) Comprehensive analysis of the contribution of germline MYH variation to early-onset colorectal cancer. Int J Cancer 109:554–558
Gismondi V, Meta M, Bonelli L et al (2004) Prevalence of the Y165C, G382D and 1395delGGA germline mutations of the MYH gene in Italian patients with adenomatous polyposis coli and colorectal adenomas. Int J Cancer 109:680–684
Lu AL, Li X, Gu Y, Wright PM, Chang DY (2001) Repair of oxidative DNA damage: mechanisms and functions. Cell Biochem Biophys 35:141–170
Yamane A, Shinmura K, Sunaga N et al (2003) Suppressive activities of OGG1 and MYH proteins against G:C to T:A mutations caused by 8-hydroxyguanine but not by benzo[a]pyrene diol epoxide in human cells in vivo. Carcinogenesis 24:1031–1037
Tudek B (2007) Base excision repair modulation as a risk factor for human cancers. Mol Aspects Med 28:258–275
Frosina G (2007) Tumor suppression by DNA base excision repair. Mini Rev Med Chem 7:727–743
Dallosso AR, Dolwani S, Jones N et al (2008) Inherited predisposition to colorectal adenomas caused by multiple rare alleles of MUTYH but not OGG1, NUDT1, NTH1 or NEIL 1, 2 or 3. Gut 57:1252–1255
Croitoru ME, Cleary SP, Berk T et al (2007) Germline MYH mutations in a clinic-based series of Canadian multiple colorectal adenoma patients. J Surg Oncol 95:499–506
O’Shea AM, Cleary SP, Croitoru MA et al (2008) Pathological features of colorectal carcinomas in MYH-associated polyposis. Histopathology 53:184–194
Lipton L, Halford SE, Johnson V et al (2003) Carcinogenesis in MYH-associated polyposis follows a distinct genetic pathway. Cancer Res 63:7595–7599
Aretz S, Uhlhaas S, Goergens H et al (2006) MUTYH-associated polyposis: 70 of 71 patients with biallelic mutations present with an attenuated or atypical phenotype. Int J Cancer 119:807–814
Nielsen M, Poley JW, Verhoef S et al (2006) Duodenal carcinoma in MUTYH-associated polyposis. J Clin Pathol 59:1212–1215
Nielsen M, Hes FJ, Nagengast FM et al (2007) Germline mutations in APC and MUTYH are responsible for the majority of families with attenuated familial adenomatous polyposis. Clin Genet 71:427–433
Wijnen JT, Vasen HF, Khan PM et al (1998) Clinical findings with implications for genetic testing in families with clustering of colorectal cancer. N Engl J Med 339:511–518
Newcomb PA, Baron J, Cotterchio M et al (2007) Colon Cancer Family Registry: an international resource for studies of the genetic epidemiology of colon cancer. Cancer Epidemiol Biomarkers Prev 16:2331–2343
Lindor NM, Rabe K, Petersen GM et al (2005) Lower cancer incidence in Amsterdam-I criteria families without mismatch repair deficiency: familial colorectal cancer type X. JAMA 293:1979–1985
Renkonen E, Zhang Y, Lohi H et al (2003) Altered expression of MLH1, MSH2, and MSH6 in predisposition to hereditary nonpolyposis colorectal cancer. J Clin Oncol 21:3629–3637
Schiemann U, Muller-Koch Y, Gross M et al (2004) Extended microsatellite analysis in microsatellite stable, MSH2 and MLH1 mutation-negative HNPCC patients: genetic reclassification and correlation with clinical features. Digestion 69:166–176
Mueller-Koch Y, Vogelsang H, Kopp R et al (2005) Hereditary non-polyposis colorectal cancer: clinical and molecular evidence for a new entity of hereditary colorectal cancer. Gut 54:1733–1740
Dove-Edwin I, de Jong AE, Adams J et al (2006) Prospective results of surveillance colonoscopy in dominant familial colorectal cancer with and without Lynch syndrome. Gastroenterology 130:1995–2000
Valle L, Perea J, Carbonell P et al (2007) Clinicopathologic and pedigree differences in amsterdam I-positive hereditary nonpolyposis colorectal cancer families according to tumor microsatellite instability status. J Clin Oncol 25:781–786
Llor X, Pons E, Xicola RM et al (2005) Differential features of colorectal cancers fulfilling Amsterdam criteria without involvement of the mutator pathway. Clin Cancer Res 11:7304–7310
Abdel-Rahman WM, Ollikainen M, Kariola R et al (2005) Comprehensive characterization of HNPCC-related colorectal cancers reveals striking molecular features in families with no germline mismatch repair gene mutations. Oncogene 24:1542–1551
Sanchez-de-Abajo A, de la Hoya M, van Puijenbroek M et al (2007) Molecular analysis of colorectal cancer tumors from patients with mismatch repair proficient hereditary nonpolyposis colorectal cancer suggests novel carcinogenic pathways. Clin Cancer Res 13:5729–5735
Minoo P, Baker K, Goswami R et al (2006) Extensive DNA methylation in normal colorectal mucosa in hyperplastic polyposis. Gut 55:1467–1474
Chen HM, Fang JY (2009). Genetics of the hamartomatous polyposis syndromes: a molecular review. Int J Colorectal Dis 24:865–874
Liaw D, Marsh DJ, Li J et al (1997) Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome. Nat Genet 16:64–67
Marsh DJ, Coulon V, Lunetta KL et al (1998) Mutation spectrum and genotype-phenotype analyses in Cowden disease and Bannayan-Zonana syndrome, two hamartoma syndromes with germline PTEN mutation. Hum Mol Genet 7:507–515
Marsh DJ, Kum JB, Lunetta KL et al (1999) PTEN mutation spectrum and genotype-phenotype correlations in Bannayan-Riley-Ruvalcaba syndrome suggest a single entity with Cowden syndrome. Hum Mol Genet 8:1461–1472
Eng C (2000) Will the real Cowden syndrome please stand up: revised diagnostic criteria. J Med Genet 37:828–830
Maehama T, Dixon JE (1999) PTEN: a tumour suppressor that functions as a phospholipid phosphatase. Trends Cell Biol 9:125–128
Inoki K, Corradetti MN, Guan KL (2005) Dysregulation of the TSC-mTOR pathway in human disease. Nat Genet 37:19–24
Zhou XP, Waite KA, Pilarski R et al (2003) Germline PTEN promoter mutations and deletions in Cowden/Bannayan-Riley-Ruvalcaba syndrome result in aberrant PTEN protein and dysregulation of the phosphoinositol-3-kinase/Akt pathway. Am J Hum Genet 73:404–411
Nelen MR, Padberg GW, Peeters EA et al (1996) Localization of the gene for Cowden disease to chromosome 10q22-23. Nat Genet 13:114–116
Pilarski R, Eng C (2004) Will the real Cowden syndrome please stand up (again)? Expanding mutational and clinical spectra of the PTEN hamartoma tumour syndrome. J Med Genet 41:323–326
Foley TR, McGarrity TJ, Abt AB (1988) Peutz-Jeghers syndrome: a clinicopathologic survey of the “Harrisburg family” with a 49-year follow-up. Gastroenterology 95:1535–1540
Bourke B, Broderick A, Bohane T (2006) Peutz-Jeghers syndrome and management recommendations. Clin Gastroenterol Hepatol 4:1550; author reply
Hemminki A, Markie D, Tomlinson I et al (1998) A serine/threonine kinase gene defective in Peutz-Jeghers syndrome. Nature 391:184–187
Jenne DE, Reimann H, Nezu J et al (1998) Peutz-Jeghers syndrome is caused by mutations in a novel serine threonine kinase. Nat Genet 18:38–43
Amos CI, Keitheri-Cheteri MB, Sabripour M et al (2004) Genotype-phenotype correlations in Peutz-Jeghers syndrome. J Med Genet 41:327–333
Giardiello FM, Brensinger JD, Tersmette AC et al (2000) Very high risk of cancer in familial Peutz-Jeghers syndrome. Gastroenterology 119:1447–1453
Yoon KA, Ku JL, Choi HS et al (2000) Germline mutations of the STK11 gene in Korean Peutz-Jeghers syndrome patients. Br J Cancer 82:1403–1406
Brosens LA, van Hattem WA, Jansen M, de Leng WW, Giardiello FM, Offerhaus GJ (2007) Gastrointestinal polyposis syndromes. Curr Mol Med 7:29–46
Jass JR, Williams CB, Bussey HJ, Morson BC (1988) Juvenile polyposis—a precancerous condition. Histopathology 13:619–630
Chow E, Macrae F (2005) A review of juvenile polyposis syndrome. J Gastroenterol Hepatol 20:1634–1640
Howe JR, Roth S, Ringold JC et al (1998) Mutations in the SMAD4/DPC4 gene in juvenile polyposis. Science 280:1086–1088
Howe JR, Bair JL, Sayed MG et al (2001) Germline mutations of the gene encoding bone morphogenetic protein receptor 1A in juvenile polyposis. Nat Genet 28:184–187
Zhou XP, Woodford-Richens K, Lehtonen R et al (2001) Germline mutations in BMPR1A/ALK3 cause a subset of cases of juvenile polyposis syndrome and of Cowden and Bannayan-Riley-Ruvalcaba syndromes. Am J Hum Genet 69:704–711
Aretz S, Stienen D, Uhlhaas S et al (2007) High proportion of large genomic deletions and a genotype phenotype update in 80 unrelated families with juvenile polyposis syndrome. J Med Genet 44:702–709
van Hattem WA, Brosens LA, de Leng WW et al (2008) Large genomic deletions of SMAD4, BMPR1A and PTEN in juvenile polyposis. Gut 57:623–627
Sweet K, Willis J, Zhou XP et al (2005) Molecular classification of patients with unexplained hamartomatous and hyperplastic polyposis. JAMA 294:2465–2473
Howe JR, Haidle JL, Lal G et al (2007) ENG mutations in MADH4/BMPR1A mutation negative patients with juvenile polyposis. Clin Genet 71:91–92
Sayed MG, Ahmed AF, Ringold JR et al (2002) Germline SMAD4 or BMPR1A mutations and phenotype of juvenile polyposis. Ann Surg Oncol 9:901–906
Cao X, Eu KW, Kumarasinghe MP, Li HH, Loi C, Cheah PY (2006) Mapping of hereditary mixed polyposis syndrome (HMPS) to chromosome 10q23 by genomewide high-density single nucleotide polymorphism (SNP) scan and identification of BMPR1A loss of function. J Med Genet 43:e13
O’Riordan JM, O’Donoghue D, Green A et al (2011) Hereditary mixed polyposis syndrome due to a BMPR1A mutation. Colorectal Dis 12:570–573
Cheah PY, Wong YH, Chau YP et al (2009) Germline bone morphogenesis protein receptor 1A mutation causes colorectal tumorigenesis in hereditary mixed polyposis syndrome. Am J Gastroenterol 104:3027–3033
Manolio TA (2010) Genomewide association studies and assessment of the risk of disease. N Engl J Med 363:166–176
Hindorff LA, Junkins HA, Hall PN, Mehta JP, Manolio TA (2011). A Catalog of published genome-wide association studies. Available at: www.genome.gov/gwastudies.
Zanke BW, Greenwood CM, Rangrej J et al (2007) Genome-wide association scan identifies a colorectal cancer susceptibility locus on chromosome 8q24. Nat Genet 39:989–994
Broderick P, Carvajal-Carmona L, Pittman AM et al (2007) A genome-wide association study shows that common alleles of SMAD7 influence colorectal cancer risk. Nat Genet 39:1315–1317
Tomlinson I, Webb E, Carvajal-Carmona L et al (2007) A genome-wide association scan of tag SNPs identifies a susceptibility variant for colorectal cancer at 8q24.21. Nat Genet 39:984–988
Jaeger E, Webb E, Howarth K et al (2008) Common genetic variants at the CRAC1 (HMPS) locus on chromosome 15q13.3 influence colorectal cancer risk. Nat Genet 40:26–28
Tomlinson IP, Webb E, Carvajal-Carmona L et al (2008) A genome-wide association study identifies colorectal cancer susceptibility loci on chromosomes 10p14 and 8q23.3. Nat Genet 40:623–630
Tenesa A, Farrington SM, Prendergast JG et al (2008) Genome-wide association scan identifies a colorectal cancer susceptibility locus on 11q23 and replicates risk loci at 8q24 and 18q21. Nat Genet 40:631–637
Houlston RS, Webb E, Broderick P et al (2008) Meta-analysis of genome-wide association data identifies four new susceptibility loci for colorectal cancer. Nat Genet 40:1426–1435
Houlston RS, Cheadle J, Dobbins SE et al (2010) Meta-analysis of three genome-wide association studies identifies susceptibility loci for colorectal cancer at 1q41, 3q26.2, 12q13.13 and 20q13.33. Nat Genet 42:973–977
Tenesa A, Dunlop MG (2009) New insights into the aetiology of colorectal cancer from genome-wide association studies. Nat Rev Genet 10:353–358
Massague J, Seoane J, Wotton D (2005) Smad transcription factors. Genes Dev 19:2783–2810
Massague J (2008) TGFbeta in cancer. Cell 134:215–230
Blobe GC, Schiemann WP, Lodish HF (2000) Role of transforming growth factor beta in human disease. N Engl J Med 342:1350–1358
Amundadottir LT, Sulem P, Gudmundsson J et al (2006) A common variant associated with prostate cancer in European and African populations. Nat Genet 38:652–658
Freedman ML, Haiman CA, Patterson N et al (2006) Admixture mapping identifies 8q24 as a prostate cancer risk locus in African-American men. Proc Natl Acad Sci USA 103:14068–14073
Haiman CA, Patterson N, Freedman ML et al (2007) Multiple regions within 8q24 independently affect risk for prostate cancer. Nat Genet 39:638–644
Haiman CA, Le Marchand L, Yamamato J et al (2007) A common genetic risk factor for colorectal and prostate cancer. Nat Genet 39:954–956
Yeager M, Xiao N, Hayes RB et al (2008) Comprehensive resequence analysis of a 136 kb region of human chromosome 8q24 associated with prostate and colon cancers. Hum Genet 124:161–170
Pomerantz MM, Beckwith CA, Regan MM et al (2009) Evaluation of the 8q24 prostate cancer risk locus and MYC expression. Cancer Res 69:5568–5574
Ahmadiyeh N, Pomerantz MM, Grisanzio C et al (2010) 8q24 prostate, breast, and colon cancer risk loci show tissue-specific long-range interaction with MYC. Proc Natl Acad Sci USA 107:9742–9746
Editorial (2010) On beyond GWAS. Nat Genet 42:551
The International HapMap Consortium (2003) The International HapMap Project. Nature 426:789–796
Hindorff LA, Sethupathy P, Junkins HA et al (2009) Potential etiologic and functional implications of genome-wide association loci for human diseases and traits. Proc Natl Acad Sci USA 106:9362–9367
Talseth-Palmer BA, Brenne IS, Ashton KA et al (2011) Colorectal cancer susceptibility loci on chromosome 8q23.3 and 11q23.1 as modifiers for disease expression in lynch syndrome. J Med Genet 48:279–284
Wijnen JT, Brohet RM, van Eijk R et al (2009) Chromosome 8q23.3 and 11q23.1 variants modify colorectal cancer risk in Lynch syndrome. Gastroenterology 136:131–137
Le Marchand L, Wilkens LR (2008) Design considerations for genomic association studies: importance of gene-environment interactions. Cancer Epidemiol Biomarkers Prev 17:263–267
Potter JD (1999) Colorectal cancer: molecules and populations. J Natl Cancer Inst 91:916–932
Evans DM, Marchini J, Morris AP, Cardon LR (2006) Two-stage two-locus models in genome-wide association. PLoS Genet 2:e157
Zamani N, Brown CW (2011) Emerging roles for the transforming growth factor-{beta} superfamily in regulating adiposity and energy expenditure. Endocr Rev 32(3):387–403
Derynck R, Akhurst RJ (2007) Differentiation plasticity regulated by TGF-beta family proteins in development and disease. Nat Cell Biol 9:1000–1004
Ross SE, Hemati N, Longo KA et al (2000) Inhibition of adipogenesis by Wnt signaling. Science 289:950–953
Sciarretta S, Ferrucci A, Ciavarella GM et al (2007) Markers of inflammation and fibrosis are related to cardiovascular damage in hypertensive patients with metabolic syndrome. Am J Hypertens 20:784–791
Rosmond R, Chagnon M, Bouchard C, Bjorntorp P (2003) Increased abdominal obesity, insulin and glucose levels in nondiabetic subjects with a T29C polymorphism of the transforming growth factor-beta1 gene. Horm Res 59:191–194
Spencer M, Yao-Borengasser A, Unal R et al (2010) Adipose tissue macrophages in insulin-resistant subjects are associated with collagen VI and fibrosis and demonstrate alternative activation. Am J Physiol Endocrinol Metab 299:E1016–E1027
Alessi MC, Bastelica D, Morange P et al (2000) Plasminogen activator inhibitor 1, transforming growth factor-beta1, and BMI are closely associated in human adipose tissue during morbid obesity. Diabetes 49:1374–1380
Porreca E, Di Febbo C, Vitacolonna E et al (2002) Transforming growth factor-beta1 levels in hypertensive patients: association with body mass index and leptin. Am J Hypertens 15:759–765
Herder C, Zierer A, Koenig W, Roden M, Meisinger C, Thorand B (2009) Transforming growth factor-beta1 and incident type 2 diabetes: results from the MONICA/KORA case-cohort study, 1984–2002. Diabetes Care 32:1921–1923
Samad F, Pandey M, Loskutoff DJ (1998) Tissue factor gene expression in the adipose tissues of obese mice. Proc Natl Acad Sci USA 95:7591–7596
Tseng YH, Kokkotou E, Schulz TJ et al (2008) New role of bone morphogenetic protein 7 in brown adipogenesis and energy expenditure. Nature 454:1000–1004
Taha MF, Valojerdi MR, Mowla SJ (2006) Effect of bone morphogenetic protein-4 (BMP-4) on adipocyte differentiation from mouse embryonic stem cells. Anat Histol Embryol 35:271–278
Bowers RR, Kim JW, Otto TC, Lane MD (2006) Stable stem cell commitment to the adipocyte lineage by inhibition of DNA methylation: role of the BMP-4 gene. Proc Natl Acad Sci USA 103:13022–13027
Dani C, Smith AG, Dessolin S et al (1997) Differentiation of embryonic stem cells into adipocytes in vitro. J Cell Sci 110(Pt 11):1279–1285
Tang QQ, Otto TC, Lane MD (2004) Commitment of C3H10T1/2 pluripotent stem cells to the adipocyte lineage. Proc Natl Acad Sci USA 101:9607–9611
Matsuzawa Y, Funahashi T, Nakamura T (1999) Molecular mechanism of metabolic syndrome X: contribution of adipocytokines adipocyte-derived bioactive substances. Ann N Y Acad Sci 892:146–154
Son JW, Kim MK, Park YM et al (2011) Association of serum bone morphogenetic protein 4 levels with obesity and metabolic syndrome in non-diabetic individuals. Endocr J 58(1):39–46
Huang H, Song TJ, Li X et al (2009) BMP signaling pathway is required for commitment of C3H10T1/2 pluripotent stem cells to the adipocyte lineage. Proc Natl Acad Sci USA 106:12670–12675
Mohamed-Ali V, Pinkney JH, Coppack SW (1998) Adipose tissue as an endocrine and paracrine organ. Int J Obes Relat Metab Disord 22:1145–1158
Bowers RR, Lane MD (2007) A role for bone morphogenetic protein-4 in adipocyte development. Cell Cycle 6:385–389
Skillington J, Choy L, Derynck R (2002) Bone morphogenetic protein and retinoic acid signaling cooperate to induce osteoblast differentiation of preadipocytes. J Cell Biol 159:135–146
Chen D, Ji X, Harris MA et al (1998) Differential roles for bone morphogenetic protein (BMP) receptor type IB and IA in differentiation and specification of mesenchymal precursor cells to osteoblast and adipocyte lineages. J Cell Biol 142:295–305
Sottile V, Seuwen K (2000) Bone morphogenetic protein-2 stimulates adipogenic differentiation of mesenchymal precursor cells in synergy with BRL 49653 (rosiglitazone). FEBS Lett 475:201–204
Hata K, Nishimura R, Ikeda F et al (2003) Differential roles of Smad1 and p38 kinase in regulation of peroxisome proliferator-activating receptor gamma during bone morphogenetic protein 2-induced adipogenesis. Mol Biol Cell 14:545–555
ten Dijke P, Yamashita H, Sampath TK et al (1994) Identification of type I receptors for osteogenic protein-1 and bone morphogenetic protein-4. J Biol Chem 269:16985–16988
Bottcher Y, Unbehauen H, Kloting N et al (2009) Adipose tissue expression and genetic variants of the bone morphogenetic protein receptor 1A gene (BMPR1A) are associated with human obesity. Diabetes 58:2119–2128
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Casey, G. (2012). Genetics of Colon Cancer Susceptibility. In: Markowitz, S., Berger, N. (eds) Energy Balance and Gastrointestinal Cancer. Energy Balance and Cancer, vol 4. Springer, Boston, MA. https://doi.org/10.1007/978-1-4614-2367-6_2
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