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Lynch Syndrome: State of the Art
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Lynch Syndrome: State of the Art

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Tumor Microenvironment".

Deadline for manuscript submissions: closed (1 February 2024) | Viewed by 16003

Special Issue Editors

Prof. Dr. Paola Izzo

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Guest Editor
Department of Molecular Medicine and Medical Biotechnology and CEINGE Biotecnologie Avanzate, University of Naples Federico II, 80131 Naples, Italy
Interests: Lynch syndrome; FAP; MAP; Cowden syndrome; aldolase; hemoglobinopathies; ZNF224; WT-1chronic myeloid leukemia; tyrosine kinase inhibitors
Special Issues, Collections and Topics in MDPI journals
Dr. Francesca Duraturo

E-Mail Website
Guest Editor
Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, 80131 Naples, Italy
Interests: Lynch syndrome; FAP; MAP; Cowden syndrome; PTEN hamartoma tumor syndrome; epithelial–mesenchymal transition; study of low risk-alleles; functional assay of unclassified MMR variants
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Lynch syndrome (LS) is an autosomal dominant genetic disorder associated with germline mutations in DNA mismatch repair (MMR) genes. The carriers of pathogenic mutations in these genes have an increased risk of developing a colorectal cancer and/or LS-associated cancer. The MMR complex loss determines at the somatic level (colorectal-cancer) a condition defined as microsatellite instability (MSI) or mismatch repair-deficiency (dMMR). Colorectal cancers with MSI or dMMR, but without detectable MMR genes germline mutations, were described many times in the literature, and they are termed Lynch-like syndrome (LLS). When this condition occurs in family clusters with strong inheritance for cancers, it becomes very important for the preventive management of LLS patients and their relatives to identify the genetic causes of cancer. To this regard, next-generation sequencing (NGS) applied to these cases with MSI but without pathogenic variants in MMR genes enables the simultaneous sequencing of a large number of hereditary cancer genes and, therefore, it allows the association with novel genes responsible for disease. Moreover, very important in these families LLS is also the correct interpretation of uncertain variants identified in MMR genes in order to clarify the real pathogenic significance and, thus, the role of variants in onset of tumor. However, MSI/dMMR status is not only routinely assessed in colorectal cancer for the initial screening of Lynch syndrome but, to date, it is also assessed in evaluation of cancer prognosis, and treatment decision-making. This Special Issue will highlight all these aspects of Lynch syndrome in order to advance our knowledge on the better pathway to follow for the management of Lynch syndrome patients.

Prof. Dr. Paola Izzo
Dr. Francesca Duraturo
Guest Editors

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Published Papers (6 papers)

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Research

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14 pages, 1334 KiB  
Article
Tumor Testing and Genetic Analysis to Identify Lynch Syndrome Patients in an Italian Colorectal Cancer Cohort
by Antonino Pantaleo, Giovanna Forte, Filomena Cariola, Anna Maria Valentini, Candida Fasano, Paola Sanese, Valentina Grossi, Antonia Lucia Buonadonna, Katia De Marco, Martina Lepore Signorile, Anna Filomena Guglielmi, Andrea Manghisi, Gianluigi Gigante, Raffaele Armentano, Vittoria Disciglio and Cristiano Simone
Cancers 2023, 15(20), 5061; https://doi.org/10.3390/cancers15205061 - 19 Oct 2023
Cited by 3 | Viewed by 1573
Abstract
Lynch syndrome (LS) is an inherited cancer susceptibility syndrome caused by germline mutations in a DNA mismatch repair (MMR) gene or in the EPCAM gene. LS is associated with an increased lifetime risk of colorectal cancer (CRC) and other malignancies. The screening algorithm [...] Read more.
Lynch syndrome (LS) is an inherited cancer susceptibility syndrome caused by germline mutations in a DNA mismatch repair (MMR) gene or in the EPCAM gene. LS is associated with an increased lifetime risk of colorectal cancer (CRC) and other malignancies. The screening algorithm for LS patient selection is based on the identification of CRC specimens that have MMR loss/high microsatellite instability (MSI-H) and are wild-type for BRAFV600. Here, we sought to clinically and molecularly characterize patients with these features. From 2017 to 2023, 841 CRC patients were evaluated for MSI and BRAFV600E mutation status, 100 of which showed MSI-H. Of these, 70 were wild-type for BRAFV600. Among these 70 patients, 30 were genetically tested for germline variants in hereditary cancer predisposition syndrome genes. This analysis showed that 19 of these 30 patients (63.3%) harbored a germline pathogenic or likely pathogenic variant in MMR genes, 2 (6.7%) harbored a variant of unknown significance (VUS) in MMR genes, 3 (10%) harbored a VUS in other cancer-related genes, and 6 (20%) were negative to genetic testing. These findings highlight the importance of personalized medicine for tailored genetic counseling, management, and surveillance of families with LS and other hereditary cancer syndromes. Full article
(This article belongs to the Special Issue Lynch Syndrome: State of the Art)
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29 pages, 4621 KiB  
Article
DNA Mismatch Repair Gene Variant Classification: Evaluating the Utility of Somatic Mutations and Mismatch Repair Deficient Colonic Crypts and Endometrial Glands
by Romy Walker, Khalid Mahmood, Julia Como, Mark Clendenning, Jihoon E. Joo, Peter Georgeson, Sharelle Joseland, Susan G. Preston, Bernard J. Pope, James M. Chan, Rachel Austin, Jasmina Bojadzieva, Ainsley Campbell, Emma Edwards, Margaret Gleeson, Annabel Goodwin, Marion T. Harris, Emilia Ip, Judy Kirk, Julia Mansour, Helen Mar Fan, Cassandra Nichols, Nicholas Pachter, Abiramy Ragunathan, Allan Spigelman, Rachel Susman, Michael Christie, Mark A. Jenkins, Rish K. Pai, Christophe Rosty, Finlay A. Macrae, Ingrid M. Winship and Daniel D. Buchananadd Show full author list remove Hide full author list
Cancers 2023, 15(20), 4925; https://doi.org/10.3390/cancers15204925 - 10 Oct 2023
Viewed by 2062
Abstract
Germline pathogenic variants in the DNA mismatch repair (MMR) genes (Lynch syndrome) predispose to colorectal (CRC) and endometrial (EC) cancer. Lynch syndrome specific tumor features were evaluated for their ability to support the ACMG/InSiGHT framework in classifying variants of uncertain clinical significance (VUS) [...] Read more.
Germline pathogenic variants in the DNA mismatch repair (MMR) genes (Lynch syndrome) predispose to colorectal (CRC) and endometrial (EC) cancer. Lynch syndrome specific tumor features were evaluated for their ability to support the ACMG/InSiGHT framework in classifying variants of uncertain clinical significance (VUS) in the MMR genes. Twenty-eight CRC or EC tumors from 25 VUS carriers (6xMLH1, 9xMSH2, 6xMSH6, 4xPMS2), underwent targeted tumor sequencing for the presence of microsatellite instability/MMR-deficiency (MSI-H/dMMR) status and identification of a somatic MMR mutation (second hit). Immunohistochemical testing for the presence of dMMR crypts/glands in normal tissue was also performed. The ACMG/InSiGHT framework reclassified 7/25 (28%) VUS to likely pathogenic (LP), three (12%) to benign/likely benign, and 15 (60%) VUS remained unchanged. For the seven re-classified LP variants comprising nine tumors, tumor sequencing confirmed MSI-H/dMMR (8/9, 88.9%) and a second hit (7/9, 77.8%). Of these LP reclassified variants where normal tissue was available, the presence of a dMMR crypt/gland was found in 2/4 (50%). Furthermore, a dMMR endometrial gland in a carrier of an MSH2 exon 1-6 duplication provides further support for an upgrade of this VUS to LP. Our study confirmed that identifying these Lynch syndrome features can improve MMR variant classification, enabling optimal clinical care. Full article
(This article belongs to the Special Issue Lynch Syndrome: State of the Art)
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24 pages, 1349 KiB  
Article
MyLynch: A Patient-Facing Clinical Decision Support Tool for Genetically-Guided Personalized Medicine in Lynch Syndrome
by Stephen T. Knapp, Anna Revette, Meghan Underhill-Blazey, Jill E. Stopfer, Chinedu I. Ukaegbu, Cole Poulin, Madison Parenteau, Sapna Syngal, Eunchan Bae, Timothy Bickmore, Heather Hampel, Gregory E. Idos, Giovanni Parmigiani, Matthew B. Yurgelun and Danielle Braun
Cancers 2023, 15(2), 391; https://doi.org/10.3390/cancers15020391 - 6 Jan 2023
Cited by 2 | Viewed by 2966
Abstract
Lynch syndrome (LS) is a hereditary cancer susceptibility condition associated with varying cancer risks depending on which of the five causative genes harbors a pathogenic variant; however, lifestyle and medical interventions provide options to lower those risks. We developed MyLynch, a patient-facing clinical [...] Read more.
Lynch syndrome (LS) is a hereditary cancer susceptibility condition associated with varying cancer risks depending on which of the five causative genes harbors a pathogenic variant; however, lifestyle and medical interventions provide options to lower those risks. We developed MyLynch, a patient-facing clinical decision support (CDS) web application that applies genetically-guided personalized medicine (GPM) for individuals with LS. The tool was developed in R Shiny through a patient-focused iterative design process. The knowledge base used to estimate patient-specific risk leveraged a rigorously curated literature review. MyLynch informs LS patients of their personal cancer risks, educates patients on relevant interventions, and provides patients with adjusted risk estimates, depending on the interventions they choose to pursue. MyLynch can improve risk communication between patients and providers while also encouraging communication among relatives with the goal of increasing cascade testing. As genetic panel testing becomes more widely available, GPM will play an increasingly important role in patient care, and CDS tools offer patients and providers tailored information to inform decision-making. MyLynch provides personalized cancer risk estimates and interventions to lower these risks for patients with LS. Full article
(This article belongs to the Special Issue Lynch Syndrome: State of the Art)
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27 pages, 4837 KiB  
Article
Large Cancer Pedigree Involving Multiple Cancer Genes including Likely Digenic MSH2 and MSH6 Lynch Syndrome (LS) and an Instance of Recombinational Rescue from LS
by Ingrid P. Vogelaar, Stephanie Greer, Fan Wang, GiWon Shin, Billy Lau, Yajing Hu, Sigurdis Haraldsdottir, Rocio Alvarez, Dennis Hazelett, Peter Nguyen, Francesca P. Aguirre, Maha Guindi, Andrew Hendifar, Jessica Balcom, Anna Leininger, Beth Fairbank, Hanlee Ji and Megan P. Hitchins
Cancers 2023, 15(1), 228; https://doi.org/10.3390/cancers15010228 - 30 Dec 2022
Cited by 1 | Viewed by 2942
Abstract
Lynch syndrome (LS), caused by heterozygous pathogenic variants affecting one of the mismatch repair (MMR) genes (MSH2, MLH1, MSH6, PMS2), confers moderate to high risks for colorectal, endometrial, and other cancers. We describe a four-generation, 13-branched pedigree in [...] Read more.
Lynch syndrome (LS), caused by heterozygous pathogenic variants affecting one of the mismatch repair (MMR) genes (MSH2, MLH1, MSH6, PMS2), confers moderate to high risks for colorectal, endometrial, and other cancers. We describe a four-generation, 13-branched pedigree in which multiple LS branches carry the MSH2 pathogenic variant c.2006G>T (p.Gly669Val), one branch has this and an additional novel MSH6 variant c.3936_4001+8dup (intronic), and other non-LS branches carry variants within other cancer-relevant genes (NBN, MC1R, PTPRJ). Both MSH2 c.2006G>T and MSH6 c.3936_4001+8dup caused aberrant RNA splicing in carriers, including out-of-frame exon-skipping, providing functional evidence of their pathogenicity. MSH2 and MSH6 are co-located on Chr2p21, but the two variants segregated independently (mapped in trans) within the digenic branch, with carriers of either or both variants. Thus, MSH2 c.2006G>T and MSH6 c.3936_4001+8dup independently confer LS with differing cancer risks among family members in the same branch. Carriers of both variants have near 100% risk of transmitting either one to offspring. Nevertheless, a female carrier of both variants did not transmit either to one son, due to a germline recombination within the intervening region. Genetic diagnosis, risk stratification, and counseling for cancer and inheritance were highly individualized in this family. The finding of multiple cancer-associated variants in this pedigree illustrates a need to consider offering multicancer gene panel testing, as opposed to targeted cascade testing, as additional cancer variants may be uncovered in relatives. Full article
(This article belongs to the Special Issue Lynch Syndrome: State of the Art)
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16 pages, 2493 KiB  
Article
Detection of Microsatellite Instability in Colonoscopic Biopsies and Postal Urine Samples from Lynch Syndrome Cancer Patients Using a Multiplex PCR Assay
by Rachel Phelps, Richard Gallon, Christine Hayes, Eli Glover, Philip Gibson, Ibrahim Edidi, Tom Lee, Sarah Mills, Adam Shaw, Rakesh Heer, Angela Ralte, Ciaron McAnulty, Mauro Santibanez-Koref, John Burn and Michael S. Jackson
Cancers 2022, 14(15), 3838; https://doi.org/10.3390/cancers14153838 - 8 Aug 2022
Cited by 4 | Viewed by 2710
Abstract
Identification of mismatch repair (MMR)-deficient colorectal cancers (CRCs) is recommended for Lynch syndrome (LS) screening, and supports targeting of immune checkpoint inhibitors. Microsatellite instability (MSI) analysis is commonly used to test for MMR deficiency. Testing biopsies prior to tumour resection can inform surgical [...] Read more.
Identification of mismatch repair (MMR)-deficient colorectal cancers (CRCs) is recommended for Lynch syndrome (LS) screening, and supports targeting of immune checkpoint inhibitors. Microsatellite instability (MSI) analysis is commonly used to test for MMR deficiency. Testing biopsies prior to tumour resection can inform surgical and therapeutic decisions, but can be limited by DNA quantity. MSI analysis of voided urine could also provide much needed surveillance for genitourinary tract cancers in LS. Here, we reconfigure an existing molecular inversion probe-based MSI and BRAF c.1799T > A assay to a multiplex PCR (mPCR) format, and demonstrate that it can sample >140 unique molecules per marker from <1 ng of DNA and classify CRCs with 96–100% sensitivity and specificity. We also show that it can detect increased MSI within individual and composite CRC biopsies from LS patients, and within preoperative urine cell free DNA (cfDNA) from two LS patients, one with an upper tract urothelial cancer, the other an undiagnosed endometrial cancer. Approximately 60–70% of the urine cfDNAs were tumour-derived. Our results suggest that mPCR sequence-based analysis of MSI and mutation hotspots in CRC biopsies could facilitate presurgery decision making, and could enable postal-based screening for urinary tract and endometrial tumours in LS patients. Full article
(This article belongs to the Special Issue Lynch Syndrome: State of the Art)
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Review

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14 pages, 1726 KiB  
Review
Hereditary Colorectal Cancer: State of the Art in Lynch Syndrome
by Antonio Nolano, Alessia Medugno, Silvia Trombetti, Raffaella Liccardo, Marina De Rosa, Paola Izzo and Francesca Duraturo
Cancers 2023, 15(1), 75; https://doi.org/10.3390/cancers15010075 - 23 Dec 2022
Cited by 14 | Viewed by 2557
Abstract
Hereditary non-polyposis colorectal cancer is also known as Lynch syndrome. Lynch syndrome is associated with pathogenetic variants in one of the mismatch repair (MMR) genes. In addition to colorectal cancer, the inefficiency of the MMR system leads to a greater predisposition to cancer [...] Read more.
Hereditary non-polyposis colorectal cancer is also known as Lynch syndrome. Lynch syndrome is associated with pathogenetic variants in one of the mismatch repair (MMR) genes. In addition to colorectal cancer, the inefficiency of the MMR system leads to a greater predisposition to cancer of the endometrium and other cancers of the abdominal sphere. Molecular diagnosis is performed to identify pathogenetic variants in MMR genes. However, for many patients with clinically suspected Lynch syndrome, it is not possible to identify a pathogenic variant in MMR genes. Molecular diagnosis is essential for referring patients to specific surveillance to prevent the development of tumors related to Lynch syndrome. This review summarizes the main aspects of Lynch syndrome and recent advances in the field and, in particular, emphasizes the factors that can lead to the loss of expression of MMR genes. Full article
(This article belongs to the Special Issue Lynch Syndrome: State of the Art)
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