Recent Discoveries in the Genetics of Familial Colorectal Cancer and Polyposis
Authors: Laura Valle
Journal: Clinical Gastroenterology and Hepatology (2016)

The development of genome-wide massively parallel sequencing, ie, whole-genome and whole-exome sequencing, and copy number approaches has raised high expectations for the identification of novel hereditary colorectal cancer genes. Although relatively successful for genes causing adenomatous polyposis syndromes, both autosomal dominant and recessive, the identification of genes associated with hereditary non-polyposis colorectal cancer has proven extremely challenging, mainly because of the absence of major high-penetrance genes and the difficulty in demonstrating the functional impact of the identified variants and their causal association with tumor development. Indeed, most, if not all, novel candidate non-polyposis colorectal cancer genes identified so far lack corroborative data in independent studies. Here we review the novel hereditary colorectal cancer genes and syndromes identified and the candidate genes proposed in recent years as well as discuss the challenges we face. The development of genome-wide massively parallel sequencing, ie, whole-genome and whole-exome sequencing, and copy number approaches has raised high expectations for the identification of novel hereditary colorectal cancer genes. Although relatively successful for genes causing adenomatous polyposis syndromes, both autosomal dominant and recessive, the identification of genes associated with hereditary non-polyposis colorectal cancer has proven extremely challenging, mainly because of the absence of major high-penetrance genes and the difficulty in demonstrating the functional impact of the identified variants and their causal association with tumor development. Indeed, most, if not all, novel candidate non-polyposis colorectal cancer genes identified so far lack corroborative data in independent studies. Here we review the novel hereditary colorectal cancer genes and syndromes identified and the candidate genes proposed in recent years as well as discuss the challenges we face. Colorectal cancer (CRC) is the third most common cancer in men (10.0% of all cancers) and the second most common in women (9.2%) worldwide.1Ferlay J. Ervik M. Dikshit R. et al.Cancer incidence and mortality worldwide: IARC CancerBase no. 11 [Internet]. International Agency for Research on Cancer, Lyon, France2013Google Scholar Most CRCs arise as a consequence of somatic genomic events that disrupt key cellular processes in individual colonic epithelial cells. The vast majority of CRCs develop from preexisting polyps; dysplasia is the true precursor lesion. Therefore, removal of polyps results in decrease of CRC incidence.2Winawer S.J. Zauber A.G. Ho M.N. et al.Prevention of colorectal cancer by colonoscopic polypectomy: the National Polyp Study Workgroup.N Engl J Med. 1993; 329: 1977-1981Crossref PubMed Scopus (0) Google Scholar Family history of cancer is one of the strongest predictors of CRC risk; this risk is higher with increasing number of affected relatives and when CRC occurs at young age.3Fuchs 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 (0) Google Scholar Crude estimates indicate that 20%–25% of all CRC patients have at least 1 relative affected with the disease, which may be explained by shared genetic and/or environmental factors.4Aaltonen L. Johns L. Jarvinen H. et al.Explaining the familial colorectal cancer risk associated with mismatch repair (MMR)-deficient and MMR-stable tumors.Clin Cancer Res. 2007; 13: 356-361Crossref PubMed Scopus (120) Google Scholar, 5Abdel-Rahman W.M. Peltomaki P. Lynch syndrome and related familial colorectal cancers.Crit Rev Oncog. 2008; 14 (discussion 23–31): 1-22Crossref PubMed Google Scholar, 6Lichtenstein P. Holm N.V. Verkasalo P.K. et al.Environmental and heritable factors in the causation of cancer: analyses of cohorts of twins from Sweden, Denmark, and Finland.N Engl J Med. 2000; 343: 78-85Crossref PubMed Scopus (0) Google Scholar It has been estimated that approximately 3%–6% of all CRC patients carry germline mutations associated with syndromic hereditary CRC. This genetic predisposition to CRC has been classically associated with germline mutations or epimutations in the DNA mismatch repair (MMR) genes MLH1, MSH2, MSH6, and PMS2 for non-polyposis cases and in APC and MUTYH (recessive inheritance) for adenomatous colonic polyposis. Other CRC predisposing syndromes, characterized by the presence of hamartomatous polyps, are caused by mutations in SMAD4, BMPR1A, STK11, and PTEN (Figure 1).7Valle L. Genetic predisposition to colorectal cancer: where we stand and future perspectives.World J Gastroenterol. 2014; 20: 9828-9849Crossref PubMed Scopus (8) Google Scholar Despite this knowledge, much of the genetic predisposition to CRC remains unexplained. This missing heritability may be in part multifactorial, ie, caused by the conjunction of moderate-risk or low-risk genetic variants, possibly in conjunction with environmental or lifestyle risk factors.8Bodmer W. Bonilla C. Common and rare variants in multifactorial susceptibility to common diseases.Nat Genet. 2008; 40: 695-701Crossref PubMed Scopus (694) Google Scholar It has been estimated that CRC low-penetrance variants, including the ones that have not been yet identified, may explain at most 5%–10% of the heritability to CRC.9Dunlop M.G. Tenesa A. Farrington S.M. et al.Cumulative impact of common genetic variants and other risk factors on colorectal cancer risk in 42,103 individuals.Gut. 2013; 62: 871-881Crossref PubMed Scopus (0) Google Scholar Recently, a model created to accurately determine the risk for CRC on the basis of common genetic CRC susceptibility loci showed that the accumulation of risk variants is significantly associated with increased risk of CRC in individuals with a family history of CRC.10Hsu L. Jeon J. Brenner H. et al.A model to determine colorectal cancer risk using common genetic susceptibility loci.Gastroenterology. 2015; 148: 1330-1339 e14Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar The identification of a bona fide germline pathogenic mutation that causes the increased risk and aggregation of CRC in a family has clear consequences in the clinical management of its members11Stoffel E.M. Boland C.R. Genetics and genetic testing in hereditary colorectal cancer.Gastroenterology. 2015; 149: 1191-1203 e2Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar; therefore, important efforts are being invested to identify novel genes that explain this predisposition, in particular in families with clear dominant inheritance of the disease. Here we aim to provide a review of the latest advances and discuss current challenges and future perspectives in this field. Before the development of high-throughput sequence capture methods and next-generation sequencing technologies, hereditary cancer studies were mainly based on genome-wide linkage analysis of large individual pedigrees or multiple pedigrees, followed by positional cloning and study of somatic analysis of mutations, which led to the identification of the previously mentioned hereditary CRC genes.12Leppert M. Dobbs M. Scambler P. et al.The gene for familial polyposis coli maps to the long arm of chromosome 5.Science. 1987; 238: 1411-1413Crossref PubMed Google Scholar, 13Nishisho I. Nakamura Y. Miyoshi Y. et al.Mutations of chromosome 5q21 genes in FAP and colorectal cancer patients.Science. 1991; 253: 665-669Crossref PubMed Google Scholar, 14Marra G. Boland C.R. Hereditary nonpolyposis colorectal cancer: the syndrome, the genes, and historical perspectives.J Natl Cancer Inst. 1995; 87: 1114-1125Crossref PubMed Google Scholar However, despite the enormous efforts made after the identification of the most prominent hereditary CRC genes, linkage analyses followed by positional cloning and/or sequencing of the genes (coding regions) located within the candidate linkage peaks seemed to be unable to identify additional causal genes,15Wiesner 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 (0) Google Scholar, 16Kemp 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 (0) Google Scholar, 17Skoglund J. Djureinovic T. Zhou X.L. et al.Linkage analysis in a large Swedish family supports the presence of a susceptibility locus for adenoma and colorectal cancer on chromosome 9q22.32-31.1.J Med Genet. 2006; 43: e7Crossref PubMed Google Scholar, 18Neklason D.W. Kerber R.A. Nilson D.B. et al.Common familial colorectal cancer linked to chromosome 7q31: a genome-wide analysis.Cancer Res. 2008; 68: 8993-8997Crossref PubMed Scopus (0) Google Scholar, 19Papaemmanuil E. Carvajal-Carmona L. Sellick G.S. et al.Deciphering the genetics of hereditary non-syndromic colorectal cancer.Eur J Hum Genet. 2008; 16: 1477-1486Crossref PubMed Scopus (0) Google Scholar, 20Picelli S. Vandrovcova J. Jones S. et al.Genome-wide linkage scan for colorectal cancer susceptibility genes supports linkage to chromosome 3q.BMC Cancer. 2008; 8: 87Crossref PubMed Scopus (0) Google Scholar, 21Gray-McGuire C. Guda K. Adrianto I. et al.Confirmation of linkage to and localization of familial colon cancer risk haplotype on chromosome 9q22.Cancer Res. 2010; 70: 5409-5418Crossref PubMed Scopus (0) Google Scholar, 22Neklason D.W. Tuohy T.M. Stevens J. et al.Colorectal adenomas and cancer link to chromosome 13q22.1-13q31.3 in a large family with excess colorectal cancer.J Med Genet. 2010; 47: 692-699Crossref PubMed Scopus (0) Google Scholar, 23Saunders I.W. Ross J. Macrae F. et al.Evidence of linkage to chromosomes 10p15.3-p15.1, 14q24.3-q31.1 and 9q33.3-q34.3 in non-syndromic colorectal cancer families.Eur J Hum Genet. 2012; 20: 91-96Crossref PubMed Scopus (7) Google Scholar, 24Rudkjobing L.A. Eiberg H. Mikkelsen H.B. et al.The analysis of a large Danish family supports the presence of a susceptibility locus for adenoma and colorectal cancer on chromosome 11q24.Fam Cancer. 2015; 14: 393-400Crossref PubMed Google Scholar, 25Sanchez-Tome E. Rivera B. Perea J. et al.Genome-wide linkage analysis and tumoral characterization reveal heterogeneity in familial colorectal cancer type X.J Gastroenterol. 2015; 50: 657-666Crossref PubMed Google Scholar, 26Teerlink C. Nelson Q. Burt R. et al.Significant evidence of linkage for a gene predisposing to colorectal cancer and multiple primary cancers on 22q11.Clin Transl Gastroenterol. 2014; 5: e50Crossref PubMed Google Scholar, 27Kontham V. von Holst S. Lindblom A. Linkage analysis in familial non-Lynch syndrome colorectal cancer families from Sweden.PLoS One. 2013; 8: e83936Crossref PubMed Scopus (1) Google Scholar implying large heterogeneity, oligogenic or polygenic modes of inheritance, or unconventional mechanisms of gene inactivation among other possibilities. In the last decade, the rapid development of massively parallel sequencing–based approaches and genome-wide copy number techniques, associated with the decrease in their economic cost, restored hope for the identification of additional hereditary cancer genes. Among the approaches most commonly used for the identification of causal mutations in a genome-wide manner are whole-genome sequencing (WGS) and whole-exome sequencing (WES) and genome-wide, usually array-based, scanning of copy number alterations. These approaches are performed in isolated high-risk families (large pedigrees) or in multiple families or probands (often with an early age of cancer onset as an indicator of genetic predisposition) to identify a shared causal gene. Moreover, in some instances, combination of the above-mentioned methodologies, such as WES/WGS and linkage data, and/or combination of germline and somatic analyses are used to optimize the process. By using the above-mentioned approaches several novel genes have been proposed as responsible for hereditary CRC cases, in some instances also associated with polyposis. For some of the identified genes, the evidence gathered to date is robust, and their testing has been included in routine genetic diagnostics, whereas for others, the identification of additional pathogenic mutations in high-risk families is mandatory to provide the required evidence to consider the study of the gene in the clinical setting. By using a combination of WGS/WES and linkage analysis in probands with more than 10 adenomas by age 60 but no germline mutations in APC, MUTYH, or the MMR genes, Palles et al28Palles C. Cazier J.B. Howarth K.M. et al.Germline mutations affecting the proofreading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas.Nat Genet. 2013; 45: 136-144Crossref PubMed Scopus (285) Google Scholar identified mutations in the proofreading (exonuclease) domains of DNA polymerase epsilon (POLE; MIM# 174762) and delta (POLD1; MIM# 174761) in individuals/families with multiple colorectal adenomas and CRC, observing high risk of endometrial cancer in female POLD1 mutation carriers. The study of additional series of familial CRC and/or polyposis cases has provided conclusive evidence of the causal role of germline polymerase-proofreading mutations in the predisposition to CRC and polyposis, allowing a better definition of the syndrome and of its associated phenotype.29Valle L. Hernandez-Illan E. Bellido F. et al.New insights into POLE and POLD1 germline mutations in familial colorectal cancer and polyposis.Hum Mol Genet. 2014; 23: 3506-3512Crossref PubMed Scopus (39) Google Scholar, 30Rohlin A. Zagoras T. Nilsson S. et al.A mutation in POLE predisposing to a multi-tumour phenotype.Int J Oncol. 2014; 45: 77-81Crossref PubMed Scopus (0) Google Scholar, 31Elsayed F.A. Kets C.M. Ruano D. et al.Germline variants in POLE are associated with early onset mismatch repair deficient colorectal cancer.Eur J Hum Genet. 2015; 23: 1080-1084Crossref PubMed Scopus (0) Google Scholar, 32Spier I. Holzapfel S. Altmuller J. et al.Frequency and phenotypic spectrum of germline mutations in POLE and seven other polymerase genes in 266 patients with colorectal adenomas and carcinomas.Int J Cancer. 2015; 137: 320-331Crossref PubMed Scopus (25) Google Scholar, 33Aoude L.G. Heitzer E. Johansson P. et al.POLE mutations in families predisposed to cutaneous melanoma.Fam Cancer. 2015; 14: 621-628Crossref PubMed Scopus (0) Google Scholar, 34Jansen A.M. van Wezel T. van den Akker B.E. et al.Combined mismatch repair and POLE/POLD1 defects explain unresolved suspected Lynch syndrome cancers.Eur J Hum Genet. 2015; 24: 1089-1092Crossref PubMed Google Scholar, 35Bellido F. Pineda M. Aiza G. et al.POLE and POLD1 mutations in 529 kindred with familial colorectal cancer and/or polyposis: review of reported cases and recommendations for genetic testing and surveillance.Genet Med. 2016; 18: 325-332Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 36Rohlin A. Eiengard F. Lundstam U. et al.GREM1 and POLE variants in hereditary colorectal cancer syndromes.Genes Chromosomes Cancer. 2016; 55: 95-106Crossref PubMed Scopus (1) Google Scholar, 37Hansen M.F. Johansen J. Bjornevoll I. et al.A novel POLE mutation associated with cancers of colon, pancreas, ovaries and small intestine.Fam Cancer. 2015; 14: 437-448Crossref PubMed Scopus (0) Google Scholar Data gathered point to a highly penetrant autosomal syndrome characterized by attenuated or oligo-adenomatous colorectal polyposis, CRC, gastroduodenal (mostly duodenal) adenomas, and probably brain tumors. Moreover, female POLD1 mutation carriers are at very high risk of endometrial cancer and possibly at moderate risk of breast tumors.28Palles C. Cazier J.B. Howarth K.M. et al.Germline mutations affecting the proofreading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas.Nat Genet. 2013; 45: 136-144Crossref PubMed Scopus (285) Google Scholar, 29Valle L. Hernandez-Illan E. Bellido F. et al.New insights into POLE and POLD1 germline mutations in familial colorectal cancer and polyposis.Hum Mol Genet. 2014; 23: 3506-3512Crossref PubMed Scopus (39) Google Scholar, 31Elsayed F.A. Kets C.M. Ruano D. et al.Germline variants in POLE are associated with early onset mismatch repair deficient colorectal cancer.Eur J Hum Genet. 2015; 23: 1080-1084Crossref PubMed Scopus (0) Google Scholar, 32Spier I. Holzapfel S. Altmuller J. et al.Frequency and phenotypic spectrum of germline mutations in POLE and seven other polymerase genes in 266 patients with colorectal adenomas and carcinomas.Int J Cancer. 2015; 137: 320-331Crossref PubMed Scopus (25) Google Scholar, 35Bellido F. Pineda M. Aiza G. et al.POLE and POLD1 mutations in 529 kindred with familial colorectal cancer and/or polyposis: review of reported cases and recommendations for genetic testing and surveillance.Genet Med. 2016; 18: 325-332Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar The presence of other tumor types has also been reported in some families,28Palles C. Cazier J.B. Howarth K.M. et al.Germline mutations affecting the proofreading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas.Nat Genet. 2013; 45: 136-144Crossref PubMed Scopus (285) Google Scholar, 30Rohlin A. Zagoras T. Nilsson S. et al.A mutation in POLE predisposing to a multi-tumour phenotype.Int J Oncol. 2014; 45: 77-81Crossref PubMed Scopus (0) Google Scholar, 32Spier I. Holzapfel S. Altmuller J. et al.Frequency and phenotypic spectrum of germline mutations in POLE and seven other polymerase genes in 266 patients with colorectal adenomas and carcinomas.Int J Cancer. 2015; 137: 320-331Crossref PubMed Scopus (25) Google Scholar, 33Aoude L.G. Heitzer E. Johansson P. et al.POLE mutations in families predisposed to cutaneous melanoma.Fam Cancer. 2015; 14: 621-628Crossref PubMed Scopus (0) Google Scholar, 37Hansen M.F. Johansen J. Bjornevoll I. et al.A novel POLE mutation associated with cancers of colon, pancreas, ovaries and small intestine.Fam Cancer. 2015; 14: 437-448Crossref PubMed Scopus (0) Google Scholar fitting with a defect in a mechanism of correction of DNA errors. The polymerase-proofreading–associated phenotype may appear as non-polyposis CRC syndrome,29Valle L. Hernandez-Illan E. Bellido F. et al.New insights into POLE and POLD1 germline mutations in familial colorectal cancer and polyposis.Hum Mol Genet. 2014; 23: 3506-3512Crossref PubMed Scopus (39) Google Scholar, 35Bellido F. Pineda M. Aiza G. et al.POLE and POLD1 mutations in 529 kindred with familial colorectal cancer and/or polyposis: review of reported cases and recommendations for genetic testing and surveillance.Genet Med. 2016; 18: 325-332Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar and in some instances, presence of mismatch repair defects in the tumors has been reported.31Elsayed F.A. Kets C.M. Ruano D. et al.Germline variants in POLE are associated with early onset mismatch repair deficient colorectal cancer.Eur J Hum Genet. 2015; 23: 1080-1084Crossref PubMed Scopus (0) Google Scholar, 34Jansen A.M. van Wezel T. van den Akker B.E. et al.Combined mismatch repair and POLE/POLD1 defects explain unresolved suspected Lynch syndrome cancers.Eur J Hum Genet. 2015; 24: 1089-1092Crossref PubMed Google Scholar Tumors developed in the context of polymerase-proofreading mutations, both germline and somatic, show a hypermutated phenotype, leading to more than a million base substitutions in some tumors, with a tumor mutational spectrum characterized by increased proportion of G:C to T:A and A:T to C:G transversions.38Briggs S. Tomlinson I. Germline and somatic polymerase epsilon and delta mutations define a new class of hypermutated colorectal and endometrial cancers.J Pathol. 2013; 230: 148-153Crossref PubMed Scopus (77) Google Scholar, 39The Cancer Genome Atlas NetworkComprehensive molecular characterization of human colon and rectal cancer.Nature. 2012; 487: 330-337Crossref PubMed Scopus (2139) Google Scholar Similar to microsatellite instability (MSI), the presence of somatic mutations in POLE has been recently associated with favorable prognosis in sporadic tumors,40Rayner E. van Gool I.C. Palles C. et al.A panoply of errors: polymerase proofreading domain mutations in cancer.Nat Rev Cancer. 2016; 16: 71-81Crossref PubMed Scopus (0) Google Scholar but whether this also applies to tumors arising in germline mutation carriers remains unsolved. By performing WES in 51 adenomatous polyposis and CRC patients from 48 families, Weren et al41Weren R.D. Ligtenberg M.J. Kets C.M. et al.A germline homozygous mutation in the base-excision repair gene NTHL1 causes adenomatous polyposis and colorectal cancer.Nat Genet. 2015; 47: 668-671Crossref PubMed Scopus (54) Google Scholar identified 3 Dutch families with homozygous truncating mutations in the NTHL1 gene (MIM# 616415), fitting with a recessive disorder. All 3 families carried the same NTHL1 mutation in homozygosis, c.268C>T (p.Gln90*). Like MUTYH, a known recessive adenomatous polyposis gene, NTHL1 encodes a glycosylase involved in base excision repair, the primary pathway for the repair of oxidative DNA damage. In comparison with the MUTYH protein, NTHL1 targets a broader range of DNA lesions,42Cooke M.S. Evans M.D. Dizdaroglu M. et al.Oxidative DNA damage: mechanisms, mutation, and disease.Faseb J. 2003; 17: 1195-1214Crossref PubMed Scopus (1474) Google Scholar and the tumors developed by NTHL1 mutation carriers show an increase in C:G>T:A transitions rather than C:G>A:T transversions,41Weren R.D. Ligtenberg M.J. Kets C.M. et al.A germline homozygous mutation in the base-excision repair gene NTHL1 causes adenomatous polyposis and colorectal cancer.Nat Genet. 2015; 47: 668-671Crossref PubMed Scopus (54) Google Scholar as has been observed in double knockout mice.43Chan M.K. Ocampo-Hafalla M.T. Vartanian V. et al.Targeted deletion of the genes encoding NTH1 and NEIL1 DNA N-glycosylases reveals the existence of novel carcinogenic oxidative damage to DNA.DNA Repair (Amst). 2009; 8: 786-794Crossref PubMed Scopus (0) Google Scholar Despite the recent description of the syndrome and the publication of only 4 families carrying biallelic NTHL1 mutations, the NTHL1-associated phenotype may be not only characterized by the presence of attenuated adenomatous polyposis and CRC but represents a multi-tumor syndrome41Weren R.D. Ligtenberg M.J. Kets C.M. et al.A germline homozygous mutation in the base-excision repair gene NTHL1 causes adenomatous polyposis and colorectal cancer.Nat Genet. 2015; 47: 668-671Crossref PubMed Scopus (54) Google Scholar, 44Rivera B. Castellsague E. Bah I. et al.Biallelic NTHL1 mutations in a woman with multiple primary tumors.N Engl J Med. 2015; 373: 1985-1986Crossref PubMed Scopus (0) Google Scholar whose precise tumor spectrum remains to be defined. Hereditary mixed polyposis syndrome (MIM# 601228) is an unusual disease associated with polyps of multiple and mixed morphologies, including serrated lesions, Peutz-Jeghers polyps, juvenile polyps, conventional adenomas, and CRC, in the absence of any identifiable extracolonic features.45Whitelaw S.C. Murday V.A. Tomlinson I.P. et al.Clinical and molecular features of the hereditary mixed polyposis syndrome.Gastroenterology. 1997; 112: 327-334Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar Between 1999 and 2008 linkage analyses performed in Ashkenazi families with hereditary mixed polyposis allowed to map a mixed polyposis gene (also known as CRAC1) to chromosome 15q13.3 and to identify a shared haplotype within the region, suggesting a single founder mutation.46Jaeger E.E. Woodford-Richens K.L. Lockett M. et al.An ancestral Ashkenazi haplotype at the HMPS/CRAC1 locus on 15q13-q14 is associated with hereditary mixed polyposis syndrome.Am J Hum Genet. 2003; 72: 1261-1267Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar, 47Jaeger 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 (216) Google Scholar, 48Tomlinson I. Rahman N. Frayling I. et al.Inherited susceptibility to colorectal adenomas and carcinomas: evidence for a new predisposition gene on 15q14-q22.Gastroenterology. 1999; 116: 789-795Abstract Full Text Full Text PDF PubMed Google Scholar However, no novel, potentially pathogenic mutations in the genes located in the region were identified. The use of a custom oligonucleotide array to search for copy number variation in the region identified the presence of a heterozygous single-copy duplication of about 40 kilobases (kb) centered on chr15:30.77 Mb present in the affected members of the studied families. The change was a simple tandem tail-head duplication with the insertion of a 30 base pair sequence of unknown origin and no homology to known sequences between the duplicons. The duplication extended from intron 2 of SCG5 to a site just upstream of the GREM1 CpG island and is associated with greatly increased, allele-specific GREM1 expression.49Jaeger E. Leedham S. Lewis A. et al.Hereditary mixed polyposis syndrome is caused by a 40-kb upstream duplication that leads to increased and ectopic expression of the BMP antagonist GREM1.Nat Genet. 2012; 44: 699-703Crossref PubMed Scopus (80) Google Scholar To date, the GREM1 40-kb upstream duplication has only been found in the Ashkenazi Jewish descendants of a single founder. However, the phenotype is not restricted to mixed polyposis, which has led to recommend genetic testing of the GREM1 founder duplication to all Ashkenazi Jewish subjects with multiple colorectal polyps and those fulfilling the criteria for non-polyposis CRC.50Laitman Y. Jaeger E. Katz L. et al.GREM1 germline mutation screening in Ashkenazi Jewish patients with familial colorectal cancer.Genet Res (Camb). 2015; 97: e11Crossref PubMed Google Scholar Recently, a disease-causing tandem-repeat duplication of 16 kb in the regulatory region of GREM1 (7.7 kb upstream of the gene) was identified in a non-Ashkenazi family with attenuated polyposis with some indications of polyp morphology similar to a juvenile and a metaplastic type.36Rohlin A. Eiengard F. Lundstam U. et al.GREM1 and POLE variants in hereditary colorectal cancer syndromes.Genes Chromosomes Cancer. 2016; 55: 95-106Crossref PubMed Scopus (1) Google Scholar Likewise, a duplication of the whole GREM1 gene was identified in a single early-onset CRC patient without features of mixed polyposis.51Venkatachalam R. Verwiel E.T. Kamping E.J. et al.Identification of candidate predisposing copy number variants in familial and early-onset colorectal cancer patients.Int J Cancer. 2011; 129: 1635-1642Crossref PubMed Scopus (27) Google Scholar Moreover, it has been demonstrated that a common GREM1 variant affecting an enhancer, rs16969681, is also associated with CRC susceptibility, conferring approximately 20% differential risk in the general population.52Lewis A. Freeman-Mills L. de la Calle-Mustienes E. et al.A polymorphic enhancer near GREM1 influences bowel cancer risk through differential CDX2 and TCF7L2 binding.Cell Rep. 2014; 8: 983-990Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar Serrated polyposis is a clinically defined syndrome with multiple serrated polyps in the colorectum and increased CRC risk. The true prevalence of serrated polyposis syndrome (SPS), as defined by the World Health Organization (WHO) criteria, is unclear because of the risk of bias across studies, but it is likely to be below 0.09% as derived from primary colonoscopy screening programs.53van Herwaarden Y.J. Verstegen M.H. Dura P. et al.Low prevalence of serrated polyposis syndrome in screening populations: a systematic review.Endoscopy. 2015; 47: 1043-1049Crossref PubMed Google Scholar Moreover, the risk to develop CRC (approximately 1.9% in 5 years), lower than it had been first estimated, largely depends on presence of serrated polyps containing dysplasia, advanced adenomas, and/or combined WHO criteria 1 and 3.54IJspeert J.E. Rana S.A. Atkinson N.S. et al.Clinical risk factors of colorectal cancer in patients with serrated polyposis syndrome: a multicentre cohort analysis.Gut. 2015; ([Epub ahead of print])Google Scholar, 55Carballal S. Rodriguez-Alcalde D. Moreira L. et al.Colorectal cancer risk factors in patients with serrated polyposis syndrome: a large multicentre study.Gut. 2015; ([Epub ahead of print])PubMed Google Scholar For years, researchers have unsuccessfully tried to identify the genetic cause(s) of this clinical entity by agnostic approaches or studying genes that cause other colonic polyposis syndromes.56Clendenning M. Young J.P. Walsh M.D. et al.Germline mutations in the polyposis-associated genes BMPR1A, SMAD4, PTEN, MUTYH and GREM1 are not common in individuals with serrated polyposis syndrome.PLoS One. 2013; 8: e66705Crossref PubMed Scopus (0) Google Scholar By carrying out WES in 20 unrelated subjects with multiple sessile serrated adenomas (16 fulfilled the WHO criteria of SPS), Gala et al57Gala M.K. Mizukami Y. Le L.P. et al.Germline mutations in oncogene-induced senescence pathways are associated with multiple sessile serrated adenomas.Gastroenterology. 2014; 146: 520-529Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar identified germline mutations in genes that regulate senescence, ATM, PIF1, TELO2, XAF1, and RBL1, in 5 patients and nonsense mutations in RNF43, a regulator of ATM/ATR DNA damage response, in 2 of the 20 studied patients (ages at diagnosis, 51 and 52). The protein encoded by RNF43 is a RING-type E3 ubiquiting ligase, which is thought to negatively regulate Wnt signaling.58Loregger A. G