Lynch Syndrome: A Single Hereditary Cancer Syndrome or Multiple Syndromes Defined by Different Mismatch Repair Genes?

See “A ‘two-in-one hit’ model of shortcut carcinogenesis in MLH1 Lynch syndrome carriers,” by Ahadova A, Stenzinger A, Seppälä T, et al, on page 000, and “Molecular profile of MSH6-associated colorectal carcinomas shows distinct features from other Lynch syndrome–associated colorectal carcinomas,” by Helderman NC, van der Werf-’t Lam AS, Morreau H, et al, on page 000. See “A ‘two-in-one hit’ model of shortcut carcinogenesis in MLH1 Lynch syndrome carriers,” by Ahadova A, Stenzinger A, Seppälä T, et al, on page 000, and “Molecular profile of MSH6-associated colorectal carcinomas shows distinct features from other Lynch syndrome–associated colorectal carcinomas,” by Helderman NC, van der Werf-’t Lam AS, Morreau H, et al, on page 000. Lynch syndrome is the most common type of hereditary cancer syndrome, affecting 1 in 280–400 individuals.1Patel A.P. Wang M. Fahed A.C. et al.Association of rare pathogenic DNA variants for familial hypercholesterolemia, hereditary breast and ovarian cancer syndrome, and Lynch syndrome with disease risk in adults according to family history.JAMA Netw Open. 2020; 3e203959Crossref Scopus (44) Google Scholar, 2Grzymski J.J. Elhanan G. Morales Rosado J.A. et al.Population genetic screening efficiently identifies carriers of autosomal dominant diseases.Nat Med. 2020; 26: 1235-1239Crossref PubMed Scopus (76) Google Scholar, 3Win A.K. Jenkins M.A. Dowty J.G. et al.Prevalence and penetrance of major genes and polygenes for colorectal cancer.Cancer Epidemiol Biomarkers Prev. 2017; 26: 404-412Crossref PubMed Scopus (235) Google Scholar This predisposition to cancer is caused by inherited or germline pathogenic changes in the DNA mismatch repair (MMR) genes MLH1, MSH2, MSH6, and PMS2. In some cases, constitutional promoter methylation of MLH1 or MSH2 (secondary to an EPCAM 5′ deletion) is also identified.4Idos G. Valle L. Lynch syndrome. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews. Seattle: University of Washington. Available at:.https://www.ncbi.nlm.nih.gov/books/NBK1211/Google Scholar Despite the specific genetic alterations, patients with Lynch syndrome receive nearly identical clinical management in most countries. Recent evidence, including the results of 2 articles published in this issue of Gastroenterology,5Ahadova A. Stenzinger A. Seppälä T. et al.A “two-in-one hit“ model of shortcut carcinogenesis in MLH1 Lynch syndrome carriers.Gastroenterology. 2023; (XX:XXX–XXX)Abstract Full Text Full Text PDF Google Scholar,6Helderman N.C. van der Werf–’t Lam A.S. Morreau H. et al.Molecular profile of MSH6-associated colorectal carcinomas shows distinct features from other Lynch syndrome–associated colorectal carcinomas.Gastroenterology. 2023; (XX:XXX–XXX)Abstract Full Text Full Text PDF Google Scholar suggests that it may be time to reconsider the definition of Lynch syndrome (Figure 1). Specifically, the question is whether Lynch syndrome should still be viewed as a single cancer predisposition syndrome or should be recognized as 4 distinct syndromes associated with the different MMR genes. The risks of cancer (cumulative risks for various cancer types) differ among Lynch syndrome patients based on the specific altered MMR gene, leading to different cancer phenotypes, as demonstrated by retrospective and prospective observational data.7Dominguez-Valentin M. Sampson J.R. Seppälä T.T. et al.Cancer risks by gene, age, and gender in 6350 carriers of pathogenic mismatch repair variants: findings from the Prospective Lynch Syndrome Database.Genet Med. 2020; 22: 15-25Abstract Full Text Full Text PDF PubMed Scopus (238) Google Scholar, 8Bucksch K. Zachariae S. Aretz S. et al.Cancer risks in Lynch syndrome, Lynch-like syndrome, and familial colorectal cancer type X: a prospective cohort study.BMC Cancer. 2020; 20: 460Crossref PubMed Scopus (25) Google Scholar, 9Møller P. Seppälä T. Dowty J.G. et al.Colorectal cancer incidences in Lynch syndrome: a comparison of results from the prospective lynch syndrome database and the international mismatch repair consortium.Hered Cancer Clin Pract. 2022; 20: 36Crossref PubMed Scopus (6) Google Scholar, 10International Mismatch Repair ConsortiumVariation in the risk of colorectal cancer in families with Lynch syndrome: a retrospective cohort study.Lancet Oncol. 2021; 22: 1014-1022Abstract Full Text Full Text PDF Scopus (23) Google Scholar According to the Prospective Lynch Syndrome Database,7Dominguez-Valentin M. Sampson J.R. Seppälä T.T. et al.Cancer risks by gene, age, and gender in 6350 carriers of pathogenic mismatch repair variants: findings from the Prospective Lynch Syndrome Database.Genet Med. 2020; 22: 15-25Abstract Full Text Full Text PDF PubMed Scopus (238) Google Scholar germline pathogenic variants in MLH1 and MSH2 are associated primarily with increased risk of developing colorectal cancer (CRC) and endometrial cancer, while MSH6 and PMS2 alterations confer the highest risk for endometrial cancer. MLH1 and MSH2 are regarded as high penetrance genes, with a cumulative cancer risk of 64%–78% by age 70. MSH6 alterations primarily predispose women to cancer, with a cumulative cancer risk of 62% by age 70 compared with only 28% in men. While PMS2 pathogenic variants confer an overall cumulative cancer risk of 22%, similar to the general population risk (∼20% by age 74),11Ferlay J. Colombet M. Soerjomataram I. et al.Cancer statistics for the year 2020: an overview. Int J Cancer. Published online April 5, 2021.https://doi.org/10.1002/ijc.33588Google Scholar endometrial cancer has been identified as the tumor with the highest risk associated with PMS2.7Dominguez-Valentin M. Sampson J.R. Seppälä T.T. et al.Cancer risks by gene, age, and gender in 6350 carriers of pathogenic mismatch repair variants: findings from the Prospective Lynch Syndrome Database.Genet Med. 2020; 22: 15-25Abstract Full Text Full Text PDF PubMed Scopus (238) Google Scholar These findings led to recent changes in surveillance recommendations by several expert groups.12Seppälä T.T. Latchford A. Negoi I. et al.European guidelines from the EHTG and ESCP for Lynch syndrome: an updated third edition of the Mallorca guidelines based on gene and gender.Br J Surg. 2021; 108: 484-498Crossref PubMed Scopus (76) Google Scholar,13Kastrinos F. Ingram M.A. Silver E.R. et al.Gene-specific variation in colorectal cancer surveillance strategies for Lynch syndrome.Gastroenterology. 2021; 161: 453-462.e15Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar For years it was widely accepted that Lynch syndrome–associated CRC develops through the classic adenoma-carcinoma sequence. This understanding formed the basis for current surveillance recommendations, which advocate periodic colonoscopy screening with polypectomy. However, recent data consistently suggest that a significant proportion of Lynch syndrome patients develop CRC despite regular colonoscopy screening (as reviewed by Ahadova et al14Ahadova A. Seppälä T.T. Engel C. et al.The “unnatural“ history of colorectal cancer in Lynch syndrome: lessons from colonoscopy surveillance.Int J Cancer. 2021; 148: 800-811Crossref PubMed Scopus (25) Google Scholar). In fact, the incidence of CRC does not appear to decrease with the reduction of colonoscopy screening intervals from 2–3 years to annually.15Seppälä T. Pylvänäinen K. Evans D.G. et al.Colorectal cancer incidence in path_MLH1 carriers subjected to different follow-up protocols: a Prospective Lynch Syndrome Database report.Hered Cancer Clin Pract. 2017; 15: 18Crossref PubMed Scopus (34) Google Scholar, 16Engel C. Vasen H.F. Seppälä T. et al.No difference in colorectal cancer incidence or stage at detection by colonoscopy among 3 countries with different Lynch syndrome surveillance policies.Gastroenterology. 2018; 155: 1400-1409.e2Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar, 17Dominguez-Valentin M. Seppälä T.T. Sampson J.R. et al.Survival by colon cancer stage and screening interval in Lynch syndrome: a Prospective Lynch Syndrome Database report.Hered Cancer Clin Pract. 2019; 17: 28Crossref PubMed Scopus (21) Google Scholar Several nonexclusive hypotheses that may explain these observations have been proposed: 1) missed lesions, which translates into the importance of high quality colonoscopy screening in Lynch syndrome; 2) fast progression of adenomas; and 3) adenoma-free progression to cancer, either by submucosal growth or direct neoplastic transformation, likely from MMR-deficient (dMMR) crypt foci.14Ahadova A. Seppälä T.T. Engel C. et al.The “unnatural“ history of colorectal cancer in Lynch syndrome: lessons from colonoscopy surveillance.Int J Cancer. 2021; 148: 800-811Crossref PubMed Scopus (25) Google Scholar,18Monahan K.J. Swinyard O. Latchford A. Biology of pre-cancers and opportunities for cancer interception—lesson from colorectal cancer susceptibility syndromes. Cancer Prev Res (Phila). Published online March 30, 2023.https://doi.org/10.1158/1940-6207.CAPR-22-0500Google Scholar Engel et al19Engel C. Ahadova A. Seppälä T.T. et al.Associations of pathogenic variants in MLH1, MSH2, and MSH6 with risk of colorectal adenomas and tumors and with somatic mutations in patients with Lynch syndrome.Gastroenterology. 2020; 158: 1326-1333Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar conducted a study to assess the cumulative risk of colorectal cancer (CRC) and incident adenomas among MLH1, MSH2, and MSH6 carriers 10 years after their initial colonoscopy. The risk of CRC was similar among MLH1 and MSH2 Lynch syndrome patients, but heterozygous carriers of MLH1 pathogenic variants had a significantly lower risk of developing adenomas compared with MSH2 and MSH6 heterozygotes. The authors suggested an alternative hypothesis to the APC-driven adenoma-carcinoma sequence based on those findings and the significantly higher prevalence of somatic CTNNB1 (β-catenin) mutations in MLH1-related CRCs vs MSH2-related Lynch syndrome CRCs (50% vs 7%, respectively) or MSH6 Lynch syndrome CRCs,19Engel C. Ahadova A. Seppälä T.T. et al.Associations of pathogenic variants in MLH1, MSH2, and MSH6 with risk of colorectal adenomas and tumors and with somatic mutations in patients with Lynch syndrome.Gastroenterology. 2020; 158: 1326-1333Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar observations that have now been validated by Helderman et al.6Helderman N.C. van der Werf–’t Lam A.S. Morreau H. et al.Molecular profile of MSH6-associated colorectal carcinomas shows distinct features from other Lynch syndrome–associated colorectal carcinomas.Gastroenterology. 2023; (XX:XXX–XXX)Abstract Full Text Full Text PDF Google Scholar This proposed pathway of colorectal carcinogenesis omits the adenoma (nonflat polypoid morphology) phase and is linked to the existence of somatic CTNNB1 mutations, which are rare in sporadic CRC and mutually exclusive to APC mutations. In this issue of Gastroenterology, Ahadova et al5Ahadova A. Stenzinger A. Seppälä T. et al.A “two-in-one hit“ model of shortcut carcinogenesis in MLH1 Lynch syndrome carriers.Gastroenterology. 2023; (XX:XXX–XXX)Abstract Full Text Full Text PDF Google Scholar propose a mechanistic hypothesis that explains their previous findings. It is based on the observation that MLH1 and CTNNB1 are in the same 5-Mb region of chromosome 3p22.1-p22.2, and that the entire region is lost via the most common mechanism of somatic second-hit inactivation in MLH1-associated Lynch syndrome cancers: copy-neutral loss of heterozygosity. For the loss of heterozygosity event to confer 2 carcinogenic hits simultaneously, it would need to affect non-neoplastic colon cells that already harbor a mono-allelic somatic CTNNB1 mutation, a phenomenon that occurs in approximately 2 out of 100 normal colon crypts. According to the provided data, this mechanism, called “two-in-one hit” by the authors, might account for about 40% of MLH1 Lynch syndrome CRCs and would explain the frequent short or absent adenoma phase in MLH1-associated colorectal carcinogenesis in Lynch syndrome. In this context, colonoscopy screening would aim for early diagnosis rather than prevention. Another source of heterogeneity within Lynch syndrome relies on the different functions of the different MMR heterodimers, which seem to determine the mutational characteristics of the associated tumors, as has been demonstrated by Helderman et al6Helderman N.C. van der Werf–’t Lam A.S. Morreau H. et al.Molecular profile of MSH6-associated colorectal carcinomas shows distinct features from other Lynch syndrome–associated colorectal carcinomas.Gastroenterology. 2023; (XX:XXX–XXX)Abstract Full Text Full Text PDF Google Scholar in this issue of Gastroenterology. Although Lynch syndrome-associated CRCs show similar mutational patterns, gene-specific characteristics have been depicted. MSH6 Lynch syndrome CRCs harbor more dMMR signature-associated single-nucleotide variants and fewer dMMR signature-associated indels than MLH1 and PMS2 Lynch syndrome CRCs. MSH2-deficient Lynch syndrome CRCs, in contrast, harbor high numbers of both dMMR signature–associated single-nucleotide variants and indels. These differences are the result of the different roles of MMR heterodimers in DNA repair and their overlapping functions. These new findings agree with the well known fact that some MSH6-deficient tumors display low levels of MSI, or even micro-satellite stability, when using standard MSI detection techniques.20Hendriks Y.M. Wagner A. Morreau H. et al.Cancer risk in hereditary nonpolyposis colorectal cancer due to MSH6 mutations: impact on counseling and surveillance.Gastroenterology. 2004; 127: 17-25Abstract Full Text Full Text PDF PubMed Scopus (344) Google Scholar,21Wu Y. Berends M.J. Mensink R.G. et al.Association of hereditary nonpolyposis colorectal cancer-related tumors displaying low microsatellite instability with MSH6 germline mutations.Am J Hum Genet. 1999; 65: 1291-1298Abstract Full Text Full Text PDF PubMed Scopus (275) Google Scholar As a consequence of this different mutation spectrum, MSH6 Lynch syndrome patients might be less sensitive to frame-shift peptide neo-antigen–based vaccines compared with the other Lynch syndrome patients. In conclusion, it may be appropriate to consider categorizing Lynch syndrome as 4 distinct syndromes based on the specific altered MMR gene, as occurs for the recessive syndromes associated with MUTYH, NTHL1, and MBD4 base excision repair glycosylases. The varying carcinogenic mechanisms and associated cancer risks indicate the need for gene-specific surveillance recommendations in Lynch syndrome. Moreover, the growing understanding of gene-specific differences will likely affect treatment options and efficacy of Lynch syndrome vaccines. Studies of larger sample series are needed to definitively confirm the differences in mutational features identified across Lynch syndrome tumors and to evaluate the associated clinical consequences. Prospective data demonstrating the presence of MLH1 and CTNNB1 double inactivation in a relevant proportion of MLH1 Lynch syndrome interval cancers, as well as characterization of gene-specific tumor immune context coupled with correlations with prognosis and response to immunotherapies, will provide further insight. Laura Valle’s academic activity is funded by the Spanish Ministry of Science and Innovation (Agencia Estatal de Investigación), co-funded by FEDER funds—A Way to Build Europe (PID2020-112595RB-I00); Instituto de Salud Carlos III (CIBERONC CB16/12/00234); and Government of Catalonia (AGAUR 2021SGR01112, CERCA Program for institutional support). A “Two-in-One Hit” Model of Shortcut Carcinogenesis in MLH1 Lynch Syndrome CarriersGastroenterologyPreviewThe clinical presentation of Lynch syndrome (LS), the most common inherited cancer syndrome, varies depending on the affected mismatch repair (MMR) gene. Although both MLH1 and MSH2 carriers have a high risk of colorectal cancer (CRC) under regular surveillance, MSH2 carriers have a significantly higher risk of developing adenomas compared with MLH1 carriers.1 A CRC pathway presumably skipping the adenoma phase has been previously associated with somatic CTNNB1 mutations.2 About 50% of MLH1-associated CRCs display CTNNB1 mutations, whereas MSH2-associated CRCs are rarely CTNNB1 mutant and more commonly show somatic APC mutations. Full-Text PDF Molecular Profile of MSH6-Associated Colorectal Carcinomas Shows Distinct Features From Other Lynch Syndrome–Associated Colorectal CarcinomasGastroenterologyPreviewLynch syndrome (LS) is the most common hereditary colorectal cancer (CRC) syndrome and is caused by pathogenic constitutional variants in 1 of the mismatch repair (MMR) genes, including MLH1, MSH2 (EPCAM), MSH6, and PMS2. Although generally referred to as 1 entity, LS exhibits a highly heterogeneous phenotype, exemplified by major differences in cancer penetrance between MMR gene variant carriers.1 These differences imply that the quality of colonoscopy, optimal surveillance intervals, treatment, preventive strategies, and other aspects of care likely differ between LS subgroups. Full-Text PDF Open Access