Hereditary gastrointestinal cancers: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up†
Authors: N. Stjepanovic, L. Moreira, F. Carneiro, F. Balaguer, A. Cervantes, J. Balmaña, E. Martinelli
Journal: Annals of Oncology (2019)

Knowledge of genetic susceptibility to gastrointestinal cancers is constantly evolving with identification of new genes. Similarly, a better understanding of the genotype/phenotype relationship in patients with Lynch syndrome (LS) or familial adenomatous polyposis (FAP) is leading to more individualised surveillance recommendations. In addition, molecular profiling of patients with cancer has been shown to guide targeted therapies, such as immunotherapy. Specialists involved in the care of patients with gastrointestinal cancer should be familiar with the main hereditary cancer syndromes and refer patients to specialised cancer genetic units for adequate genetic counselling and to address specific concerns associated to each genetic susceptibility. These guidelines aim to summarise the evidence-based data on hereditary colorectal cancer (CRC), gastric cancer (GC) and pancreatic cancer (PC) and provide useful clinical recommendations for identification and management of patients with hereditary gastrointestinal cancers. LS accounts for 1%–3% of all CRC diagnoses [1.Lynch H.T. de la Chapelle A. Hereditary colorectal cancer.N Engl J Med. 2003; 348: 919-932Crossref PubMed Scopus (1536) Google Scholar]. It is caused by germline mutations in one of the mismatch repair (MMR) genes (MLH1, MSH2, MSH6 or PMS2) or epithelial cell adhesion molecule (EPCAM, which causes epigenetic silencing of MSH2) and has an autosomal dominant inheritance. More than 70% of mutations are identified in MLH1, MSH2 or EPCAM in tumours with microsatellite instability (MSI)-high. LS is characterised by an increased lifetime risk of CRC (30%–73%) and extracolonic malignancies such as endometrial (30%–51%), ovarian (4%–15%), gastric (up to 18%), small bowel (3%–5%), urinary tract (2%–20%), pancreatic (4%), brain or cutaneous gland tumours [2.Engel C. Loeffler M. Steinke V. et al.Risks of less common cancers in proven mutation carriers with Lynch syndrome.J Clin Oncol. 2012; 30: 4409-4415Crossref PubMed Scopus (187) Google Scholar, 3.Win A.K. Young J.P. Lindor N.M. et al.Colorectal and other cancer risks for carriers and noncarriers from families with a DNA mismatch repair gene mutation: a prospective cohort study.J Clin Oncol. 2012; 30: 958-964Crossref PubMed Scopus (227) Google Scholar, 4.Samadder N.J. Smith K.R. Wong J. et al.Cancer risk in families fulfilling the Amsterdam criteria for Lynch syndrome.JAMA Oncol. 2017; 3: 1697-1701Crossref PubMed Scopus (12) Google Scholar]. The carriers of pathogenic variants in MLH1 and MSH2 genes have a substantially higher risk of CRC cancer with younger age at diagnosis compared with carriers of MSH6 or PMS2 pathogenic variants. The cumulative incidence of endometrial and urinary tract cancers is higher in MSH2 carriers [5.Moller P. Seppala T. Bernstein I. et al.Cancer incidence and survival in Lynch syndrome patients receiving colonoscopic and gynaecological surveillance: first report from the prospective Lynch syndrome database.Gut. 2017; 66: 464-472Crossref PubMed Scopus (223) Google Scholar]. Data on cancer risk estimates for carriers of an EPCAM deletion is still limited. Historically, two LS clinical phenotypes have been described in those individuals with germline MMR gene pathogenic variants presenting with the combination of central nervous system tumours (Turcot syndrome) or combination of cutaneous gland tumours (Muir–Torre syndrome) [6.Hamilton S.R. Liu B. Parsons R.E. et al.The molecular basis of Turcot's syndrome.N Engl J Med. 1995; 332: 839-847Crossref PubMed Scopus (862) Google Scholar, 7.Misago N. Narisawa Y. Sebaceous neoplasms in Muir–Torre syndrome.Am J Dermatopathol. 2000; 22: 155-161Crossref PubMed Scopus (52) Google Scholar]. Recently, a third phenotype denominated constitutional or biallelic MMR deficiency (CMMRD) has been described in those individuals who are homozygous or compound heterozygotes for pathogenic variants in the MMR gene and is characterised by café-au-lait spots and childhood-onset tumours [8.Wimmer K. Kratz C.P. Vasen H.F. et al.Diagnostic criteria for constitutional mismatch repair deficiency syndrome: suggestions of the European consortium 'care for CMMRD' (C4CMMRD).J Med Genet. 2014; 51: 355-365Crossref PubMed Scopus (226) Google Scholar, 9.Durno C.A. Sherman P.M. Aronson M. et al.Phenotypic and genotypic characterisation of biallelic mismatch repair deficiency (BMMR-D) syndrome.Eur J Cancer. 2015; 51: 977-983Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar]. Alterations in the MMR genes lead to accumulation of errors during DNA replication, especially in repetitive sequences known as microsatellites, causing MSI in the LS-related tumours. Due to the alterations in the MMR genes, the LS tumours may lack the expression of the corresponding MMR protein [tested by immunohistochemistry (IHC) staining]. MMR IHC testing on CRC tumours has a sensitivity and specificity of 94% and 88%, respectively, and is highly correlated to MSI status [10.Hampel H. Frankel W.L. Martin E. et al.Feasibility of screening for Lynch syndrome among patients with colorectal cancer.J Clin Oncol. 2008; 26: 5783-5788Crossref PubMed Scopus (605) Google Scholar]. Approximately 10% of CRCs display loss of expression of MLH1 and MSI due to somatic hypermethylation of the MLH1 promoter, often associated with BRAF V600E mutation in sporadic CRC. Therefore, if loss of MLH1 expression (alone or concurrently with loss of PMS2 expression) is observed, methylation analysis of the MLH1 promoter in the tumour and/or analysis for somatic BRAF V600E mutation should be carried out first [III, B]. Similarly, if loss of MLH1 expression (alone or concurrently with loss of PMS2 expression) is observed in GCs, hypermethylation of the MLH1 promoter should be ruled out first [III, B]. Double somatic mutations in CRC and endometrial cancer (EC) have recently been recognised by tumour sequencing. Tumours with double somatic mutations in MMR genes have a molecular phenotype that mimic LS cancers, as they present with MSI and lack the expression of MMR proteins [11.Hampel H. Pearlman R. Beightol M. et al.Assessment of tumor sequencing as a replacement for Lynch syndrome screening and current molecular tests for patients with colorectal cancer.JAMA Oncol. 2018; 4: 806-813Crossref PubMed Scopus (65) Google Scholar]. Therefore, somatic MMR gene testing for patients with unexplained abnormal tumour screening is suggested [III, B] [11.Hampel H. Pearlman R. Beightol M. et al.Assessment of tumor sequencing as a replacement for Lynch syndrome screening and current molecular tests for patients with colorectal cancer.JAMA Oncol. 2018; 4: 806-813Crossref PubMed Scopus (65) Google Scholar]. Clinical criteria used for identification of individuals at risk of LS, such as Amsterdam II criteria and revised Bethesda guidelines are based on age and family history of cancer (Table 1) [12.Vasen H.F. Watson P. Mecklin J.P. Lynch H.T. New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative group on HNPCC.Gastroenterology. 1999; 116: 1453-1456Abstract Full Text Full Text PDF PubMed Scopus (1952) Google Scholar, 13.Umar A. Boland C.R. Terdiman J.P. et al.Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability.J Natl Cancer Inst. 2004; 96: 261-268Crossref PubMed Scopus (2249) Google Scholar]. Due to the limited sensitivity and specificity of the clinical criteria, a broader CRC molecular screening with MMR IHC and/or MSI via polymerase chain reaction was proposed (Figure 1). The universal MMR IHC tumour testing in CRC patients has been shown to be more sensitive than the Bethesda guidelines for the identification of individuals at risk of LS (100% versus 87.8%) [14.Moreira L. Balaguer F. Lindor N. et al.Identification of Lynch syndrome among patients with colorectal cancer.JAMA. 2012; 308: 1555-1565Crossref PubMed Scopus (309) Google Scholar]. In addition, clinical criteria are gradually being surpassed by the evolving universal MMR IHC due to the role of MSI as a biomarker for predicting good response to treatment with immune checkpoint inhibitors in advanced cancer patients [15.Le D.T. Uram J.N. Wang H. et al.PD-1 blockade in tumors with mismatch-repair deficiency.N Engl J Med. 2015; 372: 2509-2520Crossref PubMed Scopus (4768) Google Scholar, 16.Overman M.J. McDermott R. Leach J.L. et al.Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study.Lancet Oncol. 2017; 18: 1182-1191Abstract Full Text Full Text PDF PubMed Scopus (986) Google Scholar]. Germline genetic testing can be considered in patients who fulfil the Amsterdam criteria, regardless of the MMR status. If multigene panel testing is available, MUTYH, POLE and POLD1 genes can be added to MMR genes, especially in those diagnosed at <50 years [III, C] [17.Pearlman R. Frankel W.L. Swanson B. et al.Prevalence and spectrum of germline cancer susceptibility gene mutations among patients with early-onset colorectal cancer.JAMA Oncol. 2017; 3: 464-471Crossref PubMed Scopus (243) Google Scholar, 18.Yurgelun M.B. Kulke M.H. Fuchs C.S. et al.Cancer susceptibility gene mutations in individuals with colorectal cancer.J Clin Oncol. 2017; 35: 1086-1095Crossref PubMed Scopus (176) Google Scholar].Table 1Amsterdam criteria II [12.Vasen H.F. Watson P. Mecklin J.P. Lynch H.T. New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative group on HNPCC.Gastroenterology. 1999; 116: 1453-1456Abstract Full Text Full Text PDF PubMed Scopus (1952) Google Scholar] and revised Bethesda [13.Umar A. Boland C.R. Terdiman J.P. et al.Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability.J Natl Cancer Inst. 2004; 96: 261-268Crossref PubMed Scopus (2249) Google Scholar] guidelinesAmsterdam criteria IIAt least three relatives must have a cancer associated with LS (colorectal, cancer of the endometrium, small bowel, ureter or renal pelvis); all of the following criteria should be present:•One must be a FDR of the other two•At least two successive generations must be affected•At least one relative with a cancer associated with LS should be diagnosed before age 50•FAP should be excluded in the CRC case(s) (if any)•Tumours should be verified whenever possibleRevised Bethesda guidelinesTumours from individuals should be tested for MSI in the following situations:•CRC diagnosed in a patient who is younger than 50 years of age•Presence of synchronous or metachronous colorectal or other LS-related tumoursaLS-related cancers include colorectal, endometrial, gastric, ovarian, pancreas, ureter and renal pelvis, biliary tract, brain (usually glioblastoma), small intestinal cancers, as well as sebaceous gland adenomas and keratoacanthomas., regardless of age•CRC with MSI-high histologybPresence of tumour infiltrating lymphocytes, Crohn's-like lymphocytic reaction, mucinous/signet ring differentiation or medullary growth pattern. CRC, colorectal cancer; FAP, familial adenomatous polyposis; FDR, first-degree relative; LS, Lynch syndrome; MSI, microsatellite instability. Adapted from Vasen et al. [12] and Umar et al. [13] with permission. diagnosed in a patient who is younger than 60 years of age•CRC diagnosed in a patient with one or more FDRs with an LS-related cancer, with one of the cancers being diagnosed below age 50•CRC diagnosed in a patient with two or more first- or second-degree relatives with LS-related cancer regardless of agea LS-related cancers include colorectal, endometrial, gastric, ovarian, pancreas, ureter and renal pelvis, biliary tract, brain (usually glioblastoma), small intestinal cancers, as well as sebaceous gland adenomas and keratoacanthomas.b Presence of tumour infiltrating lymphocytes, Crohn's-like lymphocytic reaction, mucinous/signet ring differentiation or medullary growth pattern.CRC, colorectal cancer; FAP, familial adenomatous polyposis; FDR, first-degree relative; LS, Lynch syndrome; MSI, microsatellite instability.Adapted from Vasen et al. [12.Vasen H.F. Watson P. Mecklin J.P. Lynch H.T. New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative group on HNPCC.Gastroenterology. 1999; 116: 1453-1456Abstract Full Text Full Text PDF PubMed Scopus (1952) Google Scholar] and Umar et al. [13.Umar A. Boland C.R. Terdiman J.P. et al.Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability.J Natl Cancer Inst. 2004; 96: 261-268Crossref PubMed Scopus (2249) Google Scholar] with permission. Open table in a new tab Similarly, MMR IHC and/or MSI screening followed by analysis of MLH1 promoter hypermethylation (if loss of expression of MLH1) is also recommended for women with EC, since 2%–3% of ECs are associated with LS [III, B] [19.Moller P. Seppala T. Bernstein I. et al.Incidence of and survival after subsequent cancers in carriers of pathogenic MMR variants with previous cancer: a report from the prospective Lynch syndrome database.Gut. 2017; 66: 1657-1664Crossref PubMed Scopus (65) Google Scholar]. For those individuals where no tumour tissue is available for molecular testing, prediction models that estimate the likelihood of finding an MMR gene pathogenic variant (i.e. PREMM model) constitute an effective clinical tool to consider referral for genetic testing [III, B] [20.Kastrinos F. Uno H. Ukaegbu C. et al.Development and validation of the PREMM5 Model for comprehensive risk assessment of Lynch syndrome.J Clin Oncol. 2017; 35: 2165-2172Crossref PubMed Scopus (62) Google Scholar]. Pathogenic genetic alterations might be frameshift, nonsense or splice site mutations that lead to truncating or unstable proteins, but large deletions and rearrangements are also common. Therefore, full germline genetic testing should include both DNA sequencing and large rearrangement analysis [III, A]. For individuals with LS, prevention and early detection of associated cancers by active surveillance can increase survival and improve quality of life. Thanks to advances in the genotype/phenotype correlation for LS patients, the surveillance protocol may be tailored according to the genetic alteration and family history of cancer (Table 2).Table 2LS surveillance recommendationsSiteTechniqueAge (years)Interval (years)ColorectumColonoscopy•MLH1/MSH2: 25aOr 5 years before the earliest CRC, if diagnosis <25 years.,bConsider later age for MSH6 carriers.•MSH6/PMS2: 351–2UterusTV US30–351Endometrial biopsyOvariesCA 125 + TV US30–351StomachUGI endoscopycConsider in high-incidence countries or family history of gastric cancer. Consider testing Helicobacter pylori30–351–3Other LS- associated cancersNonedConsider pancreatic/urinary tract cancer surveillance if family history. CA 125, cancer antigen 125; CRC, colorectal cancer; LS, Lynch syndrome; TV, transvaginal; UGI, upper gastrointestinal; US, ultrasound.a Or 5 years before the earliest CRC, if diagnosis <25 years.b Consider later age for MSH6 carriers.c Consider in high-incidence countries or family history of gastric cancer.d Consider pancreatic/urinary tract cancer surveillance if family history.CA 125, cancer antigen 125; CRC, colorectal cancer; LS, Lynch syndrome; TV, transvaginal; UGI, upper gastrointestinal; US, ultrasound. Open table in a new tab Accelerated adenoma-carcinoma sequence has been demonstrated in individuals with LS. Periodic colonoscopy surveillance allows the resection of polyps and identification of early-stage CRC. Colonoscopies carried out every 3 years have shown a CRC incidence and mortality reduction of 62% and 66%, respectively, while more frequent screening has been associated with earlier stage of CRC at diagnosis and up to 72% decrease in CRC mortality [21.Jarvinen H.J. Renkonen-Sinisalo L. Aktan-Collan K. et al.Ten years after mutation testing for Lynch syndrome: cancer incidence and outcome in mutation-positive and mutation-negative family members.J Clin Oncol. 2009; 27: 4793-4797Crossref PubMed Scopus (200) Google Scholar, 22.Vasen H.F. Abdirahman M. Brohet R. et al.One to 2-year surveillance intervals reduce risk of colorectal cancer in families with Lynch syndrome.Gastroenterology. 2010; 138: 2300-2306Abstract Full Text Full Text PDF PubMed Scopus (178) Google Scholar, 23.Dove-Edwin I. Sasieni P. Adams J. Thomas H.J. Prevention of colorectal cancer by colonoscopic surveillance in individuals with a family history of colorectal cancer: 16 year, prospective, follow-up study.BMJ. 2005; 331: 1047Crossref PubMed Scopus (158) Google Scholar]. Since the diagnosis of CRC before age 25 is unlikely in individuals with LS, and the CRC risk in MSH6 and PMS2 mutation carriers is substantially lower than for MLH1 and MSH2 ones, onset of colonoscopy surveillance is recommended at the age of 25 years for MLH1 and MSH2 mutation carriers and at the age of 35 years for MSH6 and PMS2 mutation carriers [III, C] [24.Moller P. Seppala T.T. Bernstein I. et al.Cancer risk and survival in path_MMR carriers by gene and gender up to 75 years of age: a report from the Prospective Lynch Syndrome Database.Gut. 2018; 67: 1306-1316Crossref PubMed Scopus (195) Google Scholar, 25.Ten Broeke S.W. van der Klift H.M. Tops C.M.J. et al.Cancer risks for PMS2-associated Lynch syndrome.J Clin Oncol. 2018; 36: 2961-2968Crossref PubMed Scopus (72) Google Scholar]. In all cases, age of onset in the youngest member of the family is to be considered and surveillance should be started 5 years earlier [V, B]. Surveillance colonoscopy every 1–2 years in asymptomatic individuals with LS is recommended [III, A] [5.Moller P. Seppala T. Bernstein I. et al.Cancer incidence and survival in Lynch syndrome patients receiving colonoscopic and gynaecological surveillance: first report from the prospective Lynch syndrome database.Gut. 2017; 66: 464-472Crossref PubMed Scopus (223) Google Scholar]. Chromoendoscopy with indigo carmine added to the standard colonoscopy has been shown to be substantially more effective than colonoscopy alone in LS individuals [26.Rahmi G. Lecomte T. Malka D. et al.Impact of chromoscopy on adenoma detection in patients with Lynch syndrome: a prospective, multicenter, blinded, tandem colonoscopy study.Am J Gastroenterol. 2015; 110: 288-298Crossref PubMed Scopus (38) Google Scholar]. High-quality colonoscopy carried out in dedicated centres is advised [IV, C]. There is no clear evidence to support upper gastrointestinal endoscopy surveillance in all LS patients. Consider testing and treating Helicobacter pylori (H. pylori) in all mutation carriers [27.Vasen H.F. Blanco I. Aktan-Collan K. et al.Revised guidelines for the clinical management of Lynch syndrome (HNPCC): recommendations by a group of European experts.Gut. 2013; 62: 812-823Crossref PubMed Scopus (477) Google Scholar]. In regions with high GC incidence and in families with a history of gastric neoplasms, surveillance with upper endoscopy may be considered every 1–3 years, starting at the age of 30–35 years [27.Vasen H.F. Blanco I. Aktan-Collan K. et al.Revised guidelines for the clinical management of Lynch syndrome (HNPCC): recommendations by a group of European experts.Gut. 2013; 62: 812-823Crossref PubMed Scopus (477) Google Scholar]. Routine surveillance of the small bowel in LS has a high rate of false-positive findings and it is not considered to be cost-efficient [IV, C]. Annual magnetic resonance imaging (MRI) and/or endoscopic ultrasound (EUS) surveillance in individuals with LS and one first-degree relative (FDR) affected with PC may be considered, although more supporting evidence is needed [IV, C] [28.Canto M.I. Harinck F. Hruban R.H. et al.International Cancer of the Pancreas Screening (CAPS) Consortium summit on the management of patients with increased risk for familial pancreatic cancer.Gut. 2013; 62: 339-347Crossref PubMed Scopus (445) Google Scholar]. Transvaginal ultrasound (TV US) has shown poor sensitivity and specificity for the diagnosis of EC in women with LS, while endometrial sampling could identify patients with premalignant endometrial lesions or asymptomatic endometrial carcinomas. Prophylactic hysterectomy and/or bilateral salpingo-oophorectomy reduce the incidence of EC and ovarian cancer in the LS population, although the survival benefit has not been demonstrated [29.Schmeler K.M. Lynch H.T. Chen L.M. et al.Prophylactic surgery to reduce the risk of gynecologic cancers in the Lynch syndrome.N Engl J Med. 2006; 354: 261-269Crossref PubMed Scopus (562) Google Scholar]. We recommend an annual gynaecological examination, TV US with cancer antigen 125 (CA 125) analysis and endometrial biopsy from age 30 to 35 years [IV, C]. Prophylactic hysterectomy with bilateral oophorectomy is an option that might be discussed and considered for mutation carriers who have completed childbearing or are postmenopausal [IV, C]. Urine cytology surveillance in individuals with LS has a poor sensitivity (29%) and a high rate of false-positive results, while the benefit of the US screening is unknown [30.Myrhoj T. Andersen M.B. Bernstein I. Screening for urinary tract cancer with urine cytology in Lynch syndrome and familial colorectal cancer.Fam Cancer. 2008; 7: 303-307Crossref PubMed Scopus (49) Google Scholar]. We only recommend urinary tract surveillance under a research protocol [IV, C]. The Colorectal Adenoma/Carcinoma Prevention Programme 2 (CAPP2) has shown a 60% reduction in the incidence of CRC- and other LS-associated tumours among those individuals treated with 600 mg daily aspirin taken for at least 2 years versus placebo [31.Burn J. Gerdes A.M. Macrae F. et al.Long-term effect of aspirin on cancer risk in carriers of hereditary colorectal cancer: an analysis from the CAPP2 randomised controlled trial.Lancet. 2011; 378: 2081-2087Abstract Full Text Full Text PDF PubMed Scopus (677) Google Scholar]. Aspirin may be considered as a cancer prevention measure in individuals with LS, although the optimal dose has still not been determined and is the objective of the ongoing CAPP3 study that compares daily aspirin at 600, 300 and 100 mg [I, C]. Smoking and obesity increase the risk of adenomas and CRC in LS [32.Oines M. Helsingen L.M. Bretthauer M. Emilsson L. Epidemiology and risk factors of colorectal polyps.Best Pract Res Clin Gastroenterol. 2017; 31: 419-424Crossref PubMed Scopus (44) Google Scholar]. Patients are advised to refrain from smoking and stay within normal weight range [III, C]. It has been shown that there was an increased risk of metachronous CRC after partial colectomy and that the quality of life was similar after partial and total colectomy with ileorectal anastomosis (IRA) [19.Moller P. Seppala T. Bernstein I. et al.Incidence of and survival after subsequent cancers in carriers of pathogenic MMR variants with previous cancer: a report from the prospective Lynch syndrome database.Gut. 2017; 66: 1657-1664Crossref PubMed Scopus (65) Google Scholar]. Therefore, an extended colectomy may be an option in patients with LS undergoing primary surgery for CRC, especially in younger patients [IV, C]. Presence of MSI is a demonstrated prognostic factor and remains controversial as predictive for current chemotherapy (ChT) regimens in CRC and GC. Current evidence does not allow definitive recommendations regarding ChT regimens based on the MMR or MSI status [33.Sinicrope F.A. Shi Q. Allegra C.J. et al.Association of DNA mismatch repair and mutations in BRAF and KRAS with survival after recurrence in stage III colon cancers: a secondary analysis of 2 randomized clinical trials.JAMA Oncol. 2017; 3: 472-480Crossref PubMed Scopus (50) Google Scholar]. The MMR- or MSI-deficient status may be useful to determine the subset of stage II CRC patients who present a low risk of recurrence and in whom an adjuvant ChT may not be necessary [II, C] [34.Tejpar S. Saridaki Z. Delorenzi M. et al.Microsatellite instability, prognosis and drug sensitivity of stage II and III colorectal cancer: more complexity to the puzzle.J Natl Cancer Inst. 2011; 103: 841-844Crossref PubMed Scopus (45) Google Scholar]. Several studies have demonstrated that MMR-deficient tumours harbour a high mutational load, and express numerous neoantigens that makes them sensitive to immunotherapy. Two immune checkpoint inhibitors have demonstrated substantial responses in patients with advanced MMR-deficient cancers and have received accelerated approval by the United States Food and Drug Administration (FDA): pembrolizumab for any MMR-deficient solid tumour and nivolumab for colorectal MMR-deficient tumours [15.Le D.T. Uram J.N. Wang H. et al.PD-1 blockade in tumors with mismatch-repair deficiency.N Engl J Med. 2015; 372: 2509-2520Crossref PubMed Scopus (4768) Google Scholar, 16.Overman M.J. McDermott R. Leach J.L. et al.Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study.Lancet Oncol. 2017; 18: 1182-1191Abstract Full Text Full Text PDF PubMed Scopus (986) Google Scholar]. This syndrome represents up to 40% of families who fulfil the Amsterdam criteria for hereditary non-polyposis colon cancer but do not harbour a tumour MMR deficiency or an underlying germline MMR gene alteration [35.Lindor 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 (460) Google Scholar]. Risk of cancer in these families seems to be limited to the colorectum, and colonoscopy surveillance at 3–5-year intervals, starting at age 40 or 10 years earlier than the age at diagnosis of the youngest case in the family may be considered [IV, C]. Patients with biallelic mutations in one of the MMR genes are usually affected with childhood cancers. There is a high-incidence of CRC, adenomatous polyposis and small bowel tumours, haematological tumours (leukaemia or lymphoma), brain, endometrium and urinary tract tumours. Two expert consensuses have proposed a surveillance approach that includes semestral blood work and abdominal US, annual brain MRI, upper endoscopy and colonoscopy and consideration of annual whole-body MRI. Both consensuses acknowledge the lack of robust evidence and the need for more research [36.Tabori U. Hansford J.R. Achatz M.I. et al.Clinical management and tumor surveillance recommendations of inherited mismatch repair deficiency in childhood.Clin Cancer Res. 2017; 23: e32-e37Crossref PubMed Scopus (75) Google Scholar, 37.Vasen H.F. Ghorbanoghli Z. Bourdeaut F. et al.Guidelines for surveillance of individuals with constitutional mismatch repair-deficiency proposed by the European Consortium "Care for CMMR-D" (C4CMMR-D).J Med Genet. 2014; 51: 283-293Crossref PubMed Scopus (132) Google Scholar]. This refers to patients who resemble LS due to the presence of MMR deficiency or MSI (excluding MLH1 hypermethylation) but lack a germline mutation. In these cases, MMR genetic testing on tumour DNA would recognise that 50%–70% of these cases harbour biallelic somatic mutations that might explain the abnormal IHC and/or MSI results [38.Haraldsdottir S. Hampel H. Tomsic J. et al.Colon and endometrial cancers with mismatch repair deficiency can arise from somatic, rather than germline, mutations.Gastroenterology. 2014; 147: 1308-1316Abstract Full Text Full Text PDF PubMed Scopus (233) Google Scholar]. Therefore, ruling out a sporadic somatic biallelic inactivation of these genes would spare an intensive surveillance of Lynch-associated tumours in relatives considered potentially at risk. Colorectal polyposis is a group of syndromes characterised by multiple polyps in the large intestine and an increased risk of CRC, as well as extraintestinal manifestations. Depending on the histology of the polyps, they are classified into adenomatous, serrated polyposis and hamartomatous polyposis. FAP is an autosomal dominant inherited disorder associated with germline mutations in the adenomatous polyposis coli (APC) gene and characterised by the presence of multiple colorectal adenomas. In its classical form, FAP patients have a near 100% risk of developing CRC at an early age if prophylactic colectomy is not carried out. It represents <1% of all cases of CRC and constitutes the most frequent cause of polyposis with a known genetic cause [39.Karstensen J.G. Burisch J. Pommergaard H.C. et al.Colorectal cancer in individuals with familial adenomatous polyposis, based on analysis of the Danish polyposis registry.Clin Gastroenterol Hepatol. 2019; ([Epub ahead of print])Abstract Full Text Full Text PDF Scopus (5) Google Scholar]. Clinical diagnosis is based on two main phenotypes, the classical form characterised by >100 adenomas along the entire colon, and the attenuated phenotype that presents between 10 and 100 adenomas, preferentially localised in the right colon and with a later onset. It is associated with a broad spectrum of extracolonic tumours, including hepatoblastoma in children, duodenal, pancreatic, thyroid and brain cancers. Germline mutation in the APC gene is found in 80% of the classical FAP and only in 10% of attenuated cases [40.Grover S. Kastrinos F. Steyerberg E.W. et al.Prevalence and phenotypes of APC and MUTYH mutations in patients with multiple colorectal adenomas.JAMA. 2012; 308: 485-492Crossref PubMed Scopus (121) Google Scholar]. Mutations located between codons 1250 and 1464 of the APC gene have been associated with more se