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• W2152555335 abstract "Colorectal cancer (CRC) has one of the most familial components of all human cancers. However, only a small fraction—up to 3%–5%—arise in the setting of the highly penetrant inherited syndromes, namely Lynch syndrome and adenomatous and hamartomatous polyposis syndromes.1Rustgi A.K. The genetics of hereditary colon cancer.Genes Dev. 2007; 21: 2525-2538Crossref PubMed Scopus (373) Google Scholar In the last 2 decades, it has been possible to identify the gene responsible for the vast majority of these disorders (MLH1, MSH2, MSH6, PMS2, APC, MYH, LKB1, SMAD4, BMPR1A, and PTEN).1Rustgi A.K. The genetics of hereditary colon cancer.Genes Dev. 2007; 21: 2525-2538Crossref PubMed Scopus (373) Google Scholar, 2Burt R. Neklason D.W. Genetic testing for inherited colon cancer.Gastroenterology. 2005; 128: 1696-1716Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar, 3Kahi C.J. Rex D.K. Imperiale T.F. Screening, surveillance, and primary prevention for colorectal cancer: a review of the recent literature.Gastroenterology. 2008; 135: 380-399Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar Aside from these, familial clustering occurs far more frequently than it would by chance, so additional genetic factors appear to confer risk. “Familial CRC” is distinguished from the above-mentioned, well-established hereditary syndromes that have a Mendelian inheritance pattern and accounts for 15%–20% of all CRC cases.2Burt R. Neklason D.W. Genetic testing for inherited colon cancer.Gastroenterology. 2005; 128: 1696-1716Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar, 4Piñol V. Andreu M. Castells A. et al.Gastrointestinal Oncology Group of the Spanish Gastroenterological AssociationFrequency of hereditary non-polyposis colorectal cancer and other colorectal cancer familial forms in Spain A multicenter, prospective, nation-wide study.Eur J Gastroenterol Hepatol. 2004; 16: 39-45Crossref PubMed Scopus (72) Google Scholar It is a heterogeneous condition that encompasses patients with unrecognized, true hereditary syndromes, as well as those with seemingly sporadic forms that aggregate in families. It is likely that CRC susceptibility in most of these individuals results from common, low-penetrance genes that confer predisposition to this neoplasm.1Rustgi A.K. The genetics of hereditary colon cancer.Genes Dev. 2007; 21: 2525-2538Crossref PubMed Scopus (373) Google Scholar, 5Houlston R.S. Peto J. The search for low-penetrance cancer susceptibility alleles.Oncogene. 2004; 23: 6471-6476Crossref PubMed Scopus (153) Google Scholar This review focuses specifically on this group of nonsyndromic familial CRC, dissecting its genetic background, unveiling the most efficient screening strategies, and revealing potential therapeutic implications. Because of the evolving definition and dynamic nature of this entity, most aspects of this review should be considered temporary; after gaining insight into the molecular basis of familial CRC, new predisposing syndromes will be identified, thereby narrowing the amalgam of patients belonging to the familial CRC category. A good analogy of the ephemeral nature of the familial CRC concept arises from the hereditary counterpart. In the last few years, it has been established that 40%–50% of families that meet the Amsterdam criteria for Lynch syndrome do not show evidence of a mismatch repair (MMR) defect, which is the hallmark of this disease. Relatives in such families have a lower incidence of CRC than those in families with Lynch syndrome, and the incidence of other cancers may not be increased. The designation of “familial CRC type X” has been proposed to describe this type of familial clustering of CRC.6Lindor N.M. Rabe K. Petersen G.M. et al.Lower cancer incidence in Amsterdam-I criteria families without mismatch repair deficiency: familial colorectal cancer type X.JAMA. 2005; 293: 1979-1985Crossref PubMed Scopus (476) Google Scholar, 7Llor X. Pons E. Xicola R.M. et al.Differential features of colorectal cancers fulfilling Amsterdam criteria without involvement of the mutator pathway.Clin Cancer Res. 2005; 11: 7304-7310Crossref PubMed Scopus (109) Google Scholar Meanwhile, the gene(s) responsible for this new entity is/are unknown, and most patients will be included in the heterogeneous group of nonsyndromic familial CRC. However, there is little doubt that if 1 member of this group has the potential to become a new, well-defined, independent inherited disorder, it is familial CRC type X syndrome. The heterogeneous nature of nonsyndromic familial CRC suggests the coexistence of diverse pathogenic mechanisms. Potential genetic models range from a handful of modest risk alleles to a very large number of small risk alleles, which is the so-called polygenic model of complex diseases.8Koessler T. Oestergaard M.Z. Song H. et al.Common variants in mismatch repair genes and risk of colorectal cancer.Gut. 2008; 57: 1097-1101Crossref PubMed Scopus (43) Google Scholar Several candidate genes have been considered. In an initial approach, research efforts were made to investigate the involvement of more common, less penetrant genetic variants of known genes responsible for the well-established inherited CRC syndromes. Biallelic mutations in the MYH gene predispose to an attenuated form of adenomatous polyposis, referred to as MYH-associated polyposis.9Al-Tassan N. Chmiel N.H. Maynard J. et al.Inherited variants of MYH associated with somatic G:C→T:A mutations in colorectal tumors.Nat Genet. 2002; 30: 227-232Crossref PubMed Scopus (1059) Google Scholar, 10Sieber O.M. Lipton L. Crabtree M. et al.Multiple colorectal adenomas, classic adenomatous polyposis, and germ-line mutations in MYH.N Engl J Med. 2003; 348: 791-799Crossref PubMed Scopus (722) Google Scholar, 11Sampson J.R. Dolwani S. Jones S. et al.Autosomal recessive colorectal adenomatous polyposis due to inherited mutations of MYH.Lancet. 2003; 362: 39-41Abstract Full Text Full Text PDF PubMed Scopus (359) Google Scholar The MYH gene encodes a member of the base excision repair system, which contributes to the protection of cells against the mutagenic effects of aerobic metabolism. MYH is a DNA glycosylase that is responsible for the removal of adenines mispaired with 8-oxoguanine, one of the most mutagenic DNA products of oxidative DNA damage. Failure to correct these mispairs leads to somatic G:C→T:A transversions in target genes (ie, APC and KRAS).9Al-Tassan N. Chmiel N.H. Maynard J. et al.Inherited variants of MYH associated with somatic G:C→T:A mutations in colorectal tumors.Nat Genet. 2002; 30: 227-232Crossref PubMed Scopus (1059) Google Scholar, 12Castells A. MYH-associated polyposis: adenomas and hyperplastic polyps, partners in crime?.Gastroenterology. 2008; 135: 1857-1859Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar Recent studies have also demonstrated that germline MYH mutations predispose to CRC with an autosomal recessive pattern, accounting for 1% of such neoplasms.13Jenkins M.A. Croitoru M.E. Monga N. et al.Risk of colorectal cancer in monoallelic and biallelic carriers of MYH mutations: a population-based case-family study.Cancer Epidemiol Biomarkers Prev. 2006; 15: 312-314Crossref PubMed Scopus (143) Google Scholar, 14Croitoru M.E. Cleary S.P. Di Nicola N. et al.Association between biallelic and monoallelic germline MYH gene mutations and colorectal cancer risk.J Natl Cancer Inst. 2004; 96: 1631-1634Crossref PubMed Scopus (217) Google Scholar, 15Balaguer F. Castellvi-Bel S. Castells A. et al.Identification of MYH mutation carriers in colorectal cancer: a multicenter, case-control, population-based study.Clin Gastroenterol Hepatol. 2007; 5: 379-387Abstract Full Text Full Text PDF PubMed Scopus (134) Google Scholar Interestingly, in up to one third of these patients, no associated adenoma was found. In this setting, whereas biallelic MYH mutations are associated with a 93-fold increased risk of CRC, with an almost complete penetrance at 60 years of age, it has been suggested that monoallelic mutations may account for a small proportion of the excess familial CRC risk.15Balaguer F. Castellvi-Bel S. Castells A. et al.Identification of MYH mutation carriers in colorectal cancer: a multicenter, case-control, population-based study.Clin Gastroenterol Hepatol. 2007; 5: 379-387Abstract Full Text Full Text PDF PubMed Scopus (134) Google Scholar, 16Cleary S.P. Cotterchio M. Jenkins M.A. et al.Germline MYH mutations and colorectal cancer: a multi-site, population-based case-control study.Gastroenterology. 2009; 136: 1251-1260Abstract Full Text Full Text PDF PubMed Scopus (160) Google Scholar Lynch syndrome, also named hereditary nonpolyposis CRC, is an autosomal-dominant disorder clinically characterized by early onset CRC and the presence of multiple neoplasms affecting the colon, rectum, and other organs. It is associated with germline mutations in the MMR genes, mainly MSH2, MLH1, MSH6 and PMS2.1Rustgi A.K. The genetics of hereditary colon cancer.Genes Dev. 2007; 21: 2525-2538Crossref PubMed Scopus (373) Google Scholar, 17Pinol V. Castells A. Andreu M. et al.Accuracy of revised Bethesda guidelines, microsatellite instability, and immunohistochemistry for the identification of patients with hereditary nonpolyposis colorectal cancer.JAMA. 2005; 293: 1986-1994Crossref PubMed Scopus (446) Google Scholar Failure to correct DNA mispairings causes microsatellite instability (MSI), a phenomenon whereby a germline microsatellite undergoes a somatic gain or loss in repeat length. The accumulation of such errors may inactivate genes that are critical to cell integrity, including tumor suppressor genes, and facilitate carcinogenesis.1Rustgi A.K. The genetics of hereditary colon cancer.Genes Dev. 2007; 21: 2525-2538Crossref PubMed Scopus (373) Google Scholar Given that minor reductions in DNA repair capacity may alter the overall rate at which mutations accumulate, it has been hypothesized that polymorphisms in the MMR genes may increase the risk of developing CRC, particularly tumors with MSI, thus explaining a proportion of those nonsyndromic familial cases. Several polymorphisms have been implicated as susceptibility alleles in this setting, although their actual contribution to CRC risk remains controversial.8Koessler T. Oestergaard M.Z. Song H. et al.Common variants in mismatch repair genes and risk of colorectal cancer.Gut. 2008; 57: 1097-1101Crossref PubMed Scopus (43) Google Scholar Association studies have identified the MLH1 415G>C (D132H) variant, which confers clinically significant susceptibility to CRC.18Lipkin S.M. Rozek L.S. Rennert G. et al.The MLH1 D132H variant is associated with susceptibility to sporadic colorectal cancer.Nat Genet. 2004; 36: 694-699Crossref PubMed Scopus (91) Google Scholar In contrast with Lynch syndrome, tumors associated with this variant usually did not show MSI. Structural and functional analyses showed that the normal ATPase function of MLH1 is attenuated, but not eliminated, by the MLH1 D132H mutation.18Lipkin S.M. Rozek L.S. Rennert G. et al.The MLH1 D132H variant is associated with susceptibility to sporadic colorectal cancer.Nat Genet. 2004; 36: 694-699Crossref PubMed Scopus (91) Google Scholar On the other hand, the MLH1 -93G>A polymorphism is located in a potential transcription factor binding site of the core promoter region. Compared with control populations, homozygosity and heterozygosity for the MLH1 -93G>A variant allele is associated with MSI tumors (odds ratio [OR], 3.23; 95% confidence interval [CI], 1.65–6.30; and OR, 1.84; 95% CI, 1.20–2.83, respectively).19Raptis S. Mrkonjic M. Green R.C. et al.MLH1 -93G>A promoter polymorphism and the risk of microsatellite-unstable colorectal cancer.J Natl Cancer Inst. 2007; 99: 463-474Crossref PubMed Scopus (111) Google Scholar Finally, the MSH6 116G>A (G39E) polymorphism is also associated with increased risk of colon cancer among men (OR, 1.27; 95% CI, 1.04–1.54).20Campbell P.T. Curtin K. Ulrich C. et al.Mismatch repair polymorphisms and risk of colon cancer, tumor microsatellite instability, and interactions with lifestyle factors.Gut. 2009; 58: 661-667Crossref PubMed Scopus (92) Google Scholar Because MYH and MSH6 proteins function together during the DNA replication process, it has been proposed that a combination of germline mutations in both genes can contribute to an increased risk of CRC. In that vein, a recent study indicates that CRC patients carrying monoallelic MYH mutations more frequently harbor concomitant MSH6 mutations than those without MYH mutations (11.5% vs 0%, respectively; P = .037; Giráldez et al, submitted manuscript). This observation supports the hypothesis that MYH and MSH6 function together; the combination of mutations may underlie an excess familial risk of CRC. Others susceptibility alleles include the TGFBR1*6A polymorphism. This is a relatively common variant of the TGFB1R gene (14% of the population carries ≥1 copy), and it has been consistently associated with increased incidences of colon, breast, and ovarian cancers. A combined analysis of 6 studies assessing CRC in 1,585 patients and 2,470 healthy control subjects indicated that TGFBR1*6A carriers were at increased risk of developing CRC (OR, 1.20; 95% CI, 1.01–1.43) and that the risk was especially high for TGFBR1*6A homozygotes (OR, 2.02; 95% CI, 1.18–3.48), revealing an allelic dosing effect.21Pasche B. Kaklamani V. Hou N. et al.TGFBR1*6A and cancer: a meta-analysis of 12 case-control studies.J Clin Oncol. 2004; 22: 756-758Crossref PubMed Scopus (72) Google Scholar Finally, the I1307K APC mutation, which creates a small, hypermutable region of the APC gene, has been found in 6% of Ashkenazi Jews and about 28% of Ashkenazim with a family history of CRC.22Laken S.J. Petersen G.M. Gruber S.B. et al.Familial colorectal cancer in Ashkenazim due to a hypermutable tract in APC.Nat Genet. 1997; 17: 79-83Crossref PubMed Scopus (522) Google Scholar In a more exploratory manner, several studies have attempted to identify loci harboring susceptibility alleles in populations of kindreds demonstrating familial clustering of CRC by employing the sibling pair method of linkage analysis. With this approach, it has been possible to map loci to several chromosomal regions including 9q22.2-31.223Wiesner G.L. Daley D. Lewis S. et al.A subset of familial colorectal neoplasia kindreds linked to chromosome 9q22.2-31.2.Proc Natl Acad Sci U S A. 2003; 100: 12961-12965Crossref PubMed Scopus (94) Google Scholar (further refined to 9q22.3324Kemp Z.E. Carvajal-Carmona L.G. Barclay E. et al.Evidence of linkage to chromosome 9q22.33 in colorectal cancer kindreds from the United Kingdom.Cancer Res. 2006; 66: 5003-5006Crossref PubMed Scopus (50) Google Scholar), 11q13.2-11q13.4, 11q22.1-23.1, and 14q23.1-14q24.1,25Djureinovic T. Skoglund J. Vandrovcova J. et al.A genome wide linkage analysis in Swedish families with hereditary non-familial adenomatous polyposis/non-hereditary non-polyposis colorectal cancer.Gut. 2006; 55: 362-366Crossref PubMed Scopus (26) Google Scholar which may contribute to disease predisposition in subsets of patients with nonsyndromic familial CRC. However, the definitive contribution of susceptibility loci has come with the recent publication of the results of massive genome-wide association studies by DNA microarray genotyping of a large number of tag single nucleotide polymorphisms (SNPs)26Tomlinson I. Webb E. Carvajal-Carmona L. et al.A genome-wide association scan of tag SNPs identifies a susceptibility variant for colorectal cancer at 8q24.21.Nat Genet. 2007; 39: 984-988Crossref PubMed Scopus (695) Google Scholar, 27Jaeger E. Webb E. Howarth K. et al.Common genetic variants at the CRAC1 (HMPS) locus on chromosome 15q13.3 influence colorectal cancer risk.Nat Genet. 2008; 40: 26-28Crossref PubMed Scopus (254) Google Scholar, 28Tomlinson I.P. Webb E. Carvajal-Carmona L. et al.A genome-wide association study identifies colorectal cancer susceptibility loci on chromosomes 10p14 and 8q23.3.Nat Genet. 2008; 40: 623-630Crossref PubMed Scopus (478) Google Scholar, 29Zanke B.W. Greenwood C.M. Rangrej J. et al.Genome-wide association scan identifies a colorectal cancer susceptibility locus on chromosome 8q24.Nat Genet. 2007; 39: 989-994Crossref PubMed Scopus (608) Google Scholar, 30Haiman C.A. Le Marchand L. Yamamato J. et al.A common genetic risk factor for colorectal and prostate cancer.Nat Genet. 2007; 39: 954-956Crossref PubMed Scopus (313) Google Scholar, 31Tenesa A. Farrington S.M. Prendergast J.G. et al.Genome-wide association scan identifies a colorectal cancer susceptibility locus on 11q23 and replicates risk loci at 8q24 and 18q21.Nat Genet. 2008; 40: 631-637Crossref PubMed Scopus (485) Google Scholar, 32Broderick P. Carvajal-Carmona L. Pittman A.M. et al.A genome-wide association study shows that common alleles of SMAD7 influence colorectal cancer risk.Nat Genet. 2007; 39: 1315-1317Crossref PubMed Scopus (433) Google Scholar (Table 1). Following this approach, it has been possible to identify loci at chromosomal regions 8q23.3, 8q24.21, 10p14, 11q23.1, 15q13.3, and 18q21.1 that account for ∼3% of the excess familial risk of CRC. Although the increase in risk associated with each individual SNP is modest, the loci might have additive or synergistic effects that increase risk in carriers of multiple SNPs. In considering all 6 SNPs (Table 1), there has been no evidence of interactive effects between them, suggesting that each locus makes an independent contribution to CRC risk. Risk increases along with the numbers of variant alleles for the 6 loci (ORper allele, 1.19; 95% CI, 1.15–1.23), up to ∼5-fold for individuals who carry ≥7 risk alleles31Tenesa A. Farrington S.M. Prendergast J.G. et al.Genome-wide association scan identifies a colorectal cancer susceptibility locus on 11q23 and replicates risk loci at 8q24 and 18q21.Nat Genet. 2008; 40: 631-637Crossref PubMed Scopus (485) Google Scholar, 33Pittman A.M. Webb E. Carvajal-Carmona L. et al.Refinement of the basis and impact of common 11q23.1 variation to the risk of developing colorectal cancer.Hum Mol Genet. 2008; 17: 3720-3727Crossref PubMed Scopus (62) Google Scholar (Figure 1).Table 1Risk of Colorectal Cancer Associated With Susceptibility Alleles Identified in Genome-Wide Association StudiesSNPGeneChromosomal regionPer alleleaResults are expressed as odds ratio (95% confidence interval).Heterozygous gene carriersaResults are expressed as odds ratio (95% confidence interval).Homozygous gene carriersaResults are expressed as odds ratio (95% confidence interval).Referencers16892766EIF3H8q23.31.25 (1.19–1.32)1.27 (1.20–1.34)1.43 (1.13–1.82)Tomlinson et al28Tomlinson I.P. Webb E. Carvajal-Carmona L. et al.A genome-wide association study identifies colorectal cancer susceptibility loci on chromosomes 10p14 and 8q23.3.Nat Genet. 2008; 40: 623-630Crossref PubMed Scopus (478) Google Scholarrs6983267 (rs7014346)8q24.211.24 (1.17–1.33)1.35 (1.20–1.53)1.57 (1.38–1.80)Tomlinson et al26Tomlinson I. Webb E. Carvajal-Carmona L. et al.A genome-wide association scan of tag SNPs identifies a susceptibility variant for colorectal cancer at 8q24.21.Nat Genet. 2007; 39: 984-988Crossref PubMed Scopus (695) Google Scholar1.17 (1.12–1.23)NANAZanke et al29Zanke B.W. Greenwood C.M. Rangrej J. et al.Genome-wide association scan identifies a colorectal cancer susceptibility locus on chromosome 8q24.Nat Genet. 2007; 39: 989-994Crossref PubMed Scopus (608) Google Scholar1.22 (1.12–1.321.04 (0.90–1.20)1.47 (1.25–1.74)Haiman et al30Haiman C.A. Le Marchand L. Yamamato J. et al.A common genetic risk factor for colorectal and prostate cancer.Nat Genet. 2007; 39: 954-956Crossref PubMed Scopus (313) Google Scholar1.19 (1.15–1.23)NANATenesa et al31Tenesa A. Farrington S.M. Prendergast J.G. et al.Genome-wide association scan identifies a colorectal cancer susceptibility locus on 11q23 and replicates risk loci at 8q24 and 18q21.Nat Genet. 2008; 40: 631-637Crossref PubMed Scopus (485) Google Scholarrs1079566810p140.89 (0.86–0.91)0.87 (0.83–0.91)0.80 (0.74–0.86)Tomlinson et al28Tomlinson I.P. Webb E. Carvajal-Carmona L. et al.A genome-wide association study identifies colorectal cancer susceptibility loci on chromosomes 10p14 and 8q23.3.Nat Genet. 2008; 40: 623-630Crossref PubMed Scopus (478) Google Scholarrs380284211q23.11.11 (1.08–1.15)NANATenesa et al31Tenesa A. Farrington S.M. Prendergast J.G. et al.Genome-wide association scan identifies a colorectal cancer susceptibility locus on 11q23 and replicates risk loci at 8q24 and 18q21.Nat Genet. 2008; 40: 631-637Crossref PubMed Scopus (485) Google Scholar1.17 (1.12–1.22)1.18 (1.11–1.25)1.35 (1.22–1.49)Pittman et al33Pittman A.M. Webb E. Carvajal-Carmona L. et al.Refinement of the basis and impact of common 11q23.1 variation to the risk of developing colorectal cancer.Hum Mol Genet. 2008; 17: 3720-3727Crossref PubMed Scopus (62) Google Scholarrs4779584CRAC1(HMPS) region15q13.31.23 (1.14–1.34)1.17 (1.06–1.30)1.70 (1.35–2.14)Jaeger et al27Jaeger E. Webb E. Howarth K. et al.Common genetic variants at the CRAC1 (HMPS) locus on chromosome 15q13.3 influence colorectal cancer risk.Nat Genet. 2008; 40: 26-28Crossref PubMed Scopus (254) Google Scholarrs4939827SMAD718q21.10.85 (0.80–0.91)0.84 (0.75–0.94)0.73 (0.64–0.83)Broderick et al32Broderick P. Carvajal-Carmona L. Pittman A.M. et al.A genome-wide association study shows that common alleles of SMAD7 influence colorectal cancer risk.Nat Genet. 2007; 39: 1315-1317Crossref PubMed Scopus (433) Google Scholar1.20 (1.16–1.24)NANATenesa et al31Tenesa A. Farrington S.M. Prendergast J.G. et al.Genome-wide association scan identifies a colorectal cancer susceptibility locus on 11q23 and replicates risk loci at 8q24 and 18q21.Nat Genet. 2008; 40: 631-637Crossref PubMed Scopus (485) Google ScholarNA, not available.a Results are expressed as odds ratio (95% confidence interval). Open table in a new tab NA, not available. In addition to identifying the cumulative effect on the risk of developing CRC, the large-scale genotyping efforts may contribute substantially to further characterize subsets of patients with different clinical presentations, response to treatment, or prognosis. In that sense, it has been possible to identify SNPs associated with tumor site (rs10795668,28Tomlinson I.P. Webb E. Carvajal-Carmona L. et al.A genome-wide association study identifies colorectal cancer susceptibility loci on chromosomes 10p14 and 8q23.3.Nat Genet. 2008; 40: 623-630Crossref PubMed Scopus (478) Google Scholar rs3802842,31Tenesa A. Farrington S.M. Prendergast J.G. et al.Genome-wide association scan identifies a colorectal cancer susceptibility locus on 11q23 and replicates risk loci at 8q24 and 18q21.Nat Genet. 2008; 40: 631-637Crossref PubMed Scopus (485) Google Scholar, 33Pittman A.M. Webb E. Carvajal-Carmona L. et al.Refinement of the basis and impact of common 11q23.1 variation to the risk of developing colorectal cancer.Hum Mol Genet. 2008; 17: 3720-3727Crossref PubMed Scopus (62) Google Scholar and rs493982731) and age at diagnosis (rs1689276628). Interestingly, it has been suggested recently that some of these risk alleles may also act as modifiers in Lynch syndrome mutation carriers.34Wijnen J.T. Brohet R.M. Eijk R.V. et al.Chromosome 8q23.3 and 11q23.1 variants modify colorectal cancer risk in Lynch syndrome.Gastroenterology. 2009; 136: 131-137Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar From this standpoint, results from ongoing studies, which are aimed at establishing genotype–phenotype correlations, could identify new approaches for CRC prevention and treatment (see below). First-degree relatives of patients with CRC have a 2- to 3-fold increased risk of developing this neoplasm, compared with the overall population (reviewed by Burt and Neklason2Burt R. Neklason D.W. Genetic testing for inherited colon cancer.Gastroenterology. 2005; 128: 1696-1716Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar; Figure 1). Likewise, it has been found that CRC risk in persons with an affected first-degree relative is approximately the same at age 40 as the general population at age 50.35Fuchs C.S. Giovannucci E.L. Colditz G.A. et al.A prospective study of family history and the risk of colorectal cancer.N Engl J Med. 1994; 331: 1669-1674Crossref PubMed Scopus (665) Google Scholar From a clinical perspective, the familial risk of CRC depends mainly on the number of relatives, the kinship, and the age of cancer diagnosis. If ≥2 first-degree relatives had CRC, the risk for family members is consistently higher than if only 1 first-degree relative was affected. The risk is even higher if the index case was diagnosed at a younger age, increasing approximately 3- or 4-fold if the diagnosis was made between 45 and 55 years, or before 45 years of age, respectively.36St John D.J. McDermott F.T. Hopper J.L. et al.Cancer risk in relatives of patients with common colorectal cancer.Ann Intern Med. 1993; 118: 785-790Crossref PubMed Scopus (338) Google Scholar Finally, CRC in second- or third-degree relatives also increases the likelihood of developing this neoplasm, but only by about 50% greater than the average risk of general population37Slattery M.L. Kerber R.A. Family history of cancer and colon cancer risk: the Utah Population Database.J Natl Cancer Inst. 1994; 86: 1618-1626Crossref PubMed Scopus (186) Google Scholar (Figure 1). These associations have been demonstrated not only for CRC, but also for colorectal adenomas. In the National Polyp Study, the risk of CRC in siblings and parents of patients with adenoma was 1.78 (95% CI, 1.18–2.67).38Winawer S.J. Zauber A.G. Gerdes H. et al.Risk of colorectal cancer in the families of patients with adenomatous polyps National Polyp Study Workgroup.N Engl J Med. 1996; 334: 82-87Crossref PubMed Scopus (299) Google Scholar This estimate increased to 2.59 (95% CI, 1.46–4.58) when the adenoma was diagnosed before the age of 60 years. These results were confirmed in another study in which the risk of adenomatous polyps in first degree-relatives of patients with CRC, compared with controls, was 1.5 (95% CI, 1.0–2.4) when any adenoma was considered and 2.6 (95% CI, 1.3–5.1) when the analysis was limited to advanced adenomas (size ≥1 cm or villous component).39Pariente A. Milan C. Lafon J. et al.Colonoscopic screening in first-degree relatives of patients with 'sporadic' colorectal cancer: a case-control study The Association Nationale des Gastroenterologues des Hopitaux and Registre Bourguignon des Cancers Digestifs (INSERM CRI 9505).Gastroenterology. 1998; 115: 7-12Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar Although there is evidence for familial risk stratification, all screening recommendations for these individuals must be considered empiric at the current time because of the lack of prospective controlled studies with mortality end points in this setting.2Burt R. Neklason D.W. Genetic testing for inherited colon cancer.Gastroenterology. 2005; 128: 1696-1716Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar In general, the presence of familial risk has prompted more aggressive screening strategies than those recommended in the average risk population, and beginning at a younger age (Figure 2). According to the recently published guidelines for CRC screening,40Levin B. Lieberman D.A. McFarland B. et al.Screening and surveillance for the early detection of colorectal cancer and adenomatous polyps, 2008: a joint guideline from the American Cancer Society, the US Multi-Society Task Force on Colorectal Cancer, and the American College of Radiology.CA Cancer J Clin. 2008; 58: 130-160Crossref PubMed Scopus (1361) Google Scholar persons with a first-degree relative who developed CRC before the age of 60, or ≥2 first-degree relatives who developed CRC at any age should undergo colonoscopy every 5 years starting at age 40 years or 10 years before the youngest case in the family. On the other hand, individuals with a first-degree relative that developed CRC at an age ≥60 years or 2 second-degree relatives with CRC can undergo any screening option at the same intervals recommended for the average-risk population, but starting at an age of 40 years (Figure 2).40Levin B. Lieberman D.A. McFarland B. et al.Screening and surveillance for the early detection of colorectal cancer and adenomatous polyps, 2008: a joint guideline from the American Cancer Society, the US Multi-Society Task Force on Colorectal Cancer, and the American College of Radiology.CA Cancer J Clin. 2008; 58: 130-160Crossref PubMed Scopus (1361) Google Scholar Although there is evidence of an anticipation phenomenon in individuals with affected first-degree relatives,35Fuchs C.S. Giovannucci E.L. Colditz G.A. et al.A prospective study of family history and the risk of colorectal cancer.N Engl J Med. 1994; 331: 1669-1674Crossref PubMed Scopus (665) Google Scholar thus justifying the beginning of screening at a younger age, there is no indication that other differences in natural history may exist, which would have reinforced a more intensive strategy regarding procedures and/or intervals between examinations. In addition, the sensitivities and specificities of any given screening method in individuals at risk of familial CRC do not differ from those of the average risk population,2Burt R. Neklason D.W. Genetic testing for inherited colon cancer.Gastroenterology. 2005; 128: 1696-1716Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar so the same screening guidelines are likely to apply for those at risk of nonsyndromic familial CRC. A better genotype–phenotype characterization of patients with CRC that is based on the number of low-penetrance risk alleles (or some specific combinations of them) may provide further insight in familial risk stratification and, consequently, contribute to a more rational approach for establishing screening strategies. Many studies have demonstrated that family history of CRC increases the risk of developing the disease by 2- or 3-fold.35Fuchs C.S. Giovannucci E.L. Colditz G.A. et al.A prospective study of family history and the risk of colorectal cancer.N Engl J Med. 1994; 331: 1669-1674Crossref PubMed Scopus (665) Google Scholar, 37Slattery M.L. Kerber R.A. Family history of cancer and colon cancer risk: the Utah Population Database.J Natl Cancer Inst. 1994; 86: 1618-1626Crossref PubMed Scopus (186) Google Scholar, 41Johns L.E. Houlston R.S. A systematic review and meta-analysis of familial colorectal cancer risk.Am J Gastroenterol. 2001; 96: 2992-3003Crossref PubMed Google Scholar However, there is controversy over whether a family history of CRC affects the outcome of patients with established disease. A recent study42Chan J.A. Meyerhardt J.A. Niedzwiecki D. et al.Association of family history with cancer recurrence and survival among patients with stage III colon cancer.JAMA. 2008; 299: 2515-2523Crossref PubMed Scopus (65) Google Scholar demonstrated that a family history of CRC is associated with a significant reduction in cancer recurrence and death among patients with stage III colon cancer receiving adjuvant chemotherapy. In fact, compared with patients without a family history, the adjusted hazard ratio among those with ≥1 affected first-degree relatives was 0.72 (95% CI, 0.54–0.96) for disease-free survival, 0.74 (95% CI, 0.55–0.99) for recurrence-free survival, and 0.75 (95% CI, 0.54–1.05) for overall survival. This reduction in risk of cancer recurrence or death associated with a family history decreased further with an increasing number of affected first-degree relatives, but was independent of tumor MMR status.42Chan J.A. Meyerhardt J.A. Niedzwiecki D. et al.Association of family history with cancer recurrence and survival among patients with stage III colon cancer.JAMA. 2008; 299: 2515-2523Crossref PubMed Scopus (65) Google Scholar Results of this study support the hypothesis that a relatively common, although less penetrant genetic predisposition, may not only influence cancer risk but also patient survival. If these results are confirmed by other studies of similar characteristics, family history of CRC could become a new, valuable predictor to identify those patients who would mostly benefit from adjuvant chemotherapy, saving resources and avoiding preventable toxicity. By contrast, molecular characterization of the subset of patients with family history of CRC might lead to the identification of novel genetic features predictive of response to chemotherapy. Although it is likely that syndromic entities with a Mendelian inheritance may emerge from the heterogeneous category of familial CRC, predisposition to such a neoplasm in this setting seems to be due to common, low-penetrance genetic components. Genetic testing involving the identified susceptibility genes or others could soon become part of the clinical armamentarium for assessing CRC risk and determining the optimal diagnostic, therapeutic, and preventive approaches. Indeed, identification of individuals at increased risk based on their genotype may allow one to tailor screening recommendations and propose specific therapeutic strategies." @default.
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