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10 pages, 569 KiB

Open AccessArticle

Identification of Lynch Syndrome Carriers among Patients with Small Bowel Adenocarcinoma

by Ariadna Sánchez, Luis Bujanda, Miriam Cuatrecasas, Alex Bofill, Cristina Alvarez-Urturi, Goretti Hernandez, Lara Aguilera, Sabela Carballal, Joan Llach, Cristina Herrera-Pariente, Mar Iglesias, Liseth Rivero-Sánchez, Gerhard Jung, Lorena Moreno, Teresa Ocaña, Carolina Bayarri, Maria Pellise, Antoni Castells, Sergi Castellví-Bel, Francesc Balaguer and Leticia Moreira Show full author list Hide full author list

Cancers 2021, 13(24), 6378; https://doi.org/10.3390/cancers13246378 - 20 Dec 2021

Viewed by 2499

Abstract

Background: Small bowel adenocarcinoma (SBA) is a rare disease which can be associated with Lynch syndrome (LS). LS tumors are characterized by the presence of microsatellite instability (MSI) and/or the loss of mismatch repair (MMR) protein expression. In SBA, the frequency of MMR [...] Read more.

Background: Small bowel adenocarcinoma (SBA) is a rare disease which can be associated with Lynch syndrome (LS). LS tumors are characterized by the presence of microsatellite instability (MSI) and/or the loss of mismatch repair (MMR) protein expression. In SBA, the frequency of MMR deficient (MMRd) tumors varies from 5% to 35%. This study aims to describe the prevalence of LS carriers among patients with MMRd small bowel adenocarcinomas. Methods: A multicenter retrospective study with identification and MMR testing of all consecutive SBA between 2004 and 2020 in a multicenter Spanish study. Demographical data, tumor characteristics, follow-up and survival information were collected. Germline testing was driven by identification of MMRd tumors. Results: A total of 94 individuals diagnosed with SBA were recruited. We observed 20 (21.3%) MMRd tumors. In 9/15 (60%) patients with MMRd tumors, a pathogenic variant was identified (three MLH1, four MSH2, one MSH6 and one PMS2). Accordingly, the prevalence of LS among all SBA cases was 10.1%. Conclusions: More than one-fifth of SBA display MMRd and in more than a half is due to LS. Our data supports the implementation of universal MMR tumor testing among SBA for the identification of LS families. Full article

(This article belongs to the Special Issue Lynch Syndrome)

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15 pages, 8682 KiB

Open AccessArticle

Machine Learning for Recurrence Prediction of Gynecologic Cancers Using Lynch Syndrome-Related Screening Markers

by Byung Wook Kim, Min Chul Choi, Min Kyu Kim, Jeong-Won Lee, Min Tae Kim, Joseph J. Noh, Hyun Park, Sang Geun Jung, Won Duk Joo, Seung Hun Song and Chan Lee

Cancers 2021, 13(22), 5670; https://doi.org/10.3390/cancers13225670 - 12 Nov 2021

Cited by 6 | Viewed by 2273

Abstract

To support the implementation of genome-based precision medicine, we developed machine learning models that predict the recurrence of patients with gynecologic cancer in using immune checkpoint inhibitors (ICI) based on clinical and pathologic characteristics, including Lynch syndrome-related screening markers such as immunohistochemistry (IHC) [...] Read more.

To support the implementation of genome-based precision medicine, we developed machine learning models that predict the recurrence of patients with gynecologic cancer in using immune checkpoint inhibitors (ICI) based on clinical and pathologic characteristics, including Lynch syndrome-related screening markers such as immunohistochemistry (IHC) and microsatellite instability (MSI) tests. To accomplish our goal, we reviewed the patient demographics, clinical data, and pathological results from their medical records. Then we identified seven potential characteristics (four MMR IHC [MLH1, MSH2, MSH6, and PMS2], MSI, Age 60, and tumor size). Following that, predictive models were built based on these variables using six machine learning algorithms: logistic regression (LR), support vector machine (SVM), naive Bayes (NB), random forest (RF), gradient boosting (GB), and extreme gradient boosting (EGB) (XGBoost). The experimental results showed that the RF-based model performed best at predicting gynecologic cancer recurrence, with AUCs of 0.818 and 0.826 for the 5-fold cross-validation (CV) and 5-fold CV with 10 repetitions, respectively. This study provides novel and baseline results about predicting the recurrence of gynecologic cancer in patients using ICI by using machine learning methods based on Lynch syndrome-related screening markers. Full article

(This article belongs to the Special Issue Lynch Syndrome)

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12 pages, 2225 KiB

Open AccessArticle

MiR-137 Targets the 3′ Untranslated Region of MSH2: Potential Implications in Lynch Syndrome-Related Colorectal Cancer

by Raffaella Liccardo, Raffaele Sessa, Silvia Trombetti, Marina De Rosa, Paola Izzo, Michela Grosso and Francesca Duraturo

Cancers 2021, 13(18), 4662; https://doi.org/10.3390/cancers13184662 - 17 Sep 2021

Cited by 3 | Viewed by 2433

Abstract

Mismatch Repair (MMR) gene dysregulation plays a fundamental role in Lynch Syndrome (LS) pathogenesis, a form of hereditary colorectal cancer. Loss or overexpression of key MMR genes leads to genome instability and tumorigenesis; however, the mechanisms controlling MMR gene expression are [...] Read more.

Mismatch Repair (MMR) gene dysregulation plays a fundamental role in Lynch Syndrome (LS) pathogenesis, a form of hereditary colorectal cancer. Loss or overexpression of key MMR genes leads to genome instability and tumorigenesis; however, the mechanisms controlling MMR gene expression are unknown. One such gene, MSH2, exerts an important role, not only in MMR, but also in cell proliferation, apoptosis, and cell cycle control. In this study, we explored the functions and underlying molecular mechanisms of increased MSH2 expression related to a c.*226A>G variant in the 3′untranslated (UTR) region of MSH2 that had been previously identified in a subject clinically suspected of LS. Bioinformatics identified a putative binding site for miR-137 in this region. To verify miRNA targeting specificity, we performed luciferase gene reporter assays using a MSH2 3′UTR psiCHECK-2 vector in human SW480 cells over-expressing miR-137, which showed a drastic reduction in luciferase activity (p > 0.0001). This effect was abolished by site-directed mutagenesis of the putative miR-137 seed site. Moreover, in these cells we observed that miR-137 levels were inversely correlated with MSH2 expression levels. These results were confirmed by results in normal and tumoral tissues from the patient carrying the 3′UTR c.*226A>G variant in MSH2. Finally, miR-137 overexpression in SW480 cells significantly suppressed cell proliferation in a time- and dose-dependent manner (p < 0.0001), supporting a role for MSH2 in apoptosis and cell proliferation processes. Our findings suggest miR-137 helps control MSH2 expression via its 3′UTR and that dysregulation of this mechanism appears to promote tumorigenesis in colon cells. Full article

(This article belongs to the Special Issue Lynch Syndrome)

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14 pages, 1095 KiB

Open AccessArticle

Upper Gastrointestinal Lesions during Endoscopy Surveillance in Patients with Lynch Syndrome: A Multicentre Cohort Study

by Romain Chautard, David Malka, Elia Samaha, David Tougeron, Didier Barbereau, Olivier Caron, Gabriel Rahmi, Thierry Barrioz, Christophe Cellier, Sandrine Feau and Thierry Lecomte

Cancers 2021, 13(7), 1657; https://doi.org/10.3390/cancers13071657 - 1 Apr 2021

Cited by 8 | Viewed by 1787

Abstract

Background: Patients with Lynch syndrome are at increased risk of gastric and duodenal cancer. Upper gastrointestinal endoscopy surveillance is generally proposed, even though little data are available on upper gastrointestinal endoscopy in these patients. The aim of this retrospective study was to evaluate [...] Read more.

Background: Patients with Lynch syndrome are at increased risk of gastric and duodenal cancer. Upper gastrointestinal endoscopy surveillance is generally proposed, even though little data are available on upper gastrointestinal endoscopy in these patients. The aim of this retrospective study was to evaluate the prevalence and incidence of gastrointestinal lesions following upper gastrointestinal endoscopy examination in Lynch patients. Methods: A large, multicentre cohort of 172 patients with a proven germline mutation in one of the mismatch repair genes and at least one documented upper gastrointestinal endoscopy screening was assessed. Detailed information was collected on upper gastrointestinal endoscopy findings and the outcome of endoscopic follow-up. Results: Seventy neoplastic gastrointestinal lesions were diagnosed in 45 patients (26%) out of the 172 patients included. The median age at diagnosis of upper gastrointestinal lesions was 54 years. The prevalence of cancer at initial upper gastrointestinal endoscopy was 5% and the prevalence of precancerous lesions was 12%. Upper gastrointestinal lesions were more frequent after 40 years of age (p < 0.001). Helicobacter pylori infection was associated with an increased prevalence of gastric, but not duodenal, lesions (p < 0.001). Conclusions: Neoplastic upper gastrointestinal lesions are frequent in patients with Lynch syndrome, especially in those over 40 years of age. The results of our study suggest that Lynch patients should be considered for upper gastrointestinal endoscopic and Helicobacter pylori screening. Full article

(This article belongs to the Special Issue Lynch Syndrome)

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16 pages, 373 KiB

Open AccessArticle

Gynecological Surveillance and Surgery Outcomes in Dutch Lynch Syndrome Carriers

by Ellis L. Eikenboom, Helena C. van Doorn, Winand N. M. Dinjens, Hendrikus J. Dubbink, Willemina R. R. Geurts-Giele, Manon C. W. Spaander, Carli M. J. Tops, Anja Wagner and Anne Goverde

Cancers 2021, 13(3), 459; https://doi.org/10.3390/cancers13030459 - 26 Jan 2021

Cited by 3 | Viewed by 1941

Abstract

Lynch syndrome (LS) is caused by pathogenic germline variants in DNA mismatch repair (MMR) genes, predisposing female carriers for endometrial cancer (EC) and ovarian cancer (OC). Since gynecological LS surveillance guidelines are based on little evidence, we assessed its outcomes. Data regarding gynecological [...] Read more.

Lynch syndrome (LS) is caused by pathogenic germline variants in DNA mismatch repair (MMR) genes, predisposing female carriers for endometrial cancer (EC) and ovarian cancer (OC). Since gynecological LS surveillance guidelines are based on little evidence, we assessed its outcomes. Data regarding gynecological tumors, surveillance, and (risk-reducing) surgery were collected from female LS carriers diagnosed in our center since 1993. Of 505 female carriers, 104 had a gynecological malignancy prior to genetic LS diagnosis. Of 264 carriers eligible for gynecological management, 164 carriers gave informed consent and had available surveillance data: 38 MLH1, 25 MSH2, 82 MSH6, and 19 PMS2 carriers (median follow-up 5.6 years). Surveillance intervals were within advised time in >80%. Transvaginal ultrasound, endometrial sampling, and CA125 measurements were performed in 76.8%, 35.9%, and 40.6%, respectively. Four symptomatic ECs, one symptomatic OC, and one asymptomatic EC were diagnosed. Endometrial hyperplasia was found in eight carriers, of whom three were symptomatic. Risk-reducing surgery was performed in 73 (45.5%) carriers (median age 51 years), revealing two asymptomatic ECs. All ECs were diagnosed in FIGO I. Gynecological management in LS carriers varied largely, stressing the need for uniform, evidence-based guidelines. Most ECs presented early and symptomatically, questioning the surveillance benefit in its current form. Full article

(This article belongs to the Special Issue Lynch Syndrome)

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15 pages, 1612 KiB

Open AccessArticle

Molecular Basis of Mismatch Repair Protein Deficiency in Tumors from Lynch Suspected Cases with Negative Germline Test Results

by Alisa Olkinuora, Annette Gylling, Henrikki Almusa, Samuli Eldfors, Anna Lepistö, Jukka-Pekka Mecklin, Taina Tuulikki Nieminen and Päivi Peltomäki

Cancers 2020, 12(7), 1853; https://doi.org/10.3390/cancers12071853 - 9 Jul 2020

Cited by 7 | Viewed by 4992

Abstract

Some 10–50% of Lynch-suspected cases with abnormal immunohistochemical (IHC) staining remain without any identifiable germline mutation of DNA mismatch repair (MMR) genes. MMR proteins form heterodimeric complexes, giving rise to distinct IHC patterns when mutant. Potential reasons for not finding a germline mutation [...] Read more.

Some 10–50% of Lynch-suspected cases with abnormal immunohistochemical (IHC) staining remain without any identifiable germline mutation of DNA mismatch repair (MMR) genes. MMR proteins form heterodimeric complexes, giving rise to distinct IHC patterns when mutant. Potential reasons for not finding a germline mutation include involvement of an MMR gene not predicted by the IHC pattern, epigenetic mechanism of predisposition, primary mutation in another DNA repair or replication-associated gene, and double somatic MMR gene mutations. We addressed these possibilities by germline and tumor studies in 60 Lynch-suspected cases ascertained through diagnostics (n = 55) or research (n = 5). All cases had abnormal MMR protein staining in tumors but no point mutation or large rearrangement of the suspected MMR genes in the germline. In diagnostic practice, MSH2/MSH6 (MutS Homolog 2/MutS Homolog 6) deficiency prompts MSH2 mutation screening; in our study, 3/11 index individuals (27%) with this IHC pattern revealed pathogenic germline mutations in MSH6. Individuals with isolated absence of MSH6 are routinely screened for MSH6 mutations alone; we found a predisposing mutation in MSH2 in 1/7 such cases (14%). Somatic deletion of the MSH2-MSH6 region, joint loss of MSH6 and MSH3 (MutS Homolog 3) proteins, and hindered MSH2/MSH6 dimerization offered explanations to misleading IHC patterns. Constitutional epimutation hypothesis was pursued in the MSH2 and/or MSH6-deficient cases plus 38 cases with MLH1 (MutL Homolog 1)-deficient tumors; a primary MLH1 epimutation was identified in one case with an MLH1-deficient tumor. We conclude that both MSH2 and MSH6 should be screened in MSH2/6- and MSH6-deficient cases. In MLH1-deficient cases, constitutional epimutations of MLH1 warrant consideration. Full article

(This article belongs to the Special Issue Lynch Syndrome)

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32 pages, 1834 KiB

Open AccessArticle

Comprehensive Constitutional Genetic and Epigenetic Characterization of Lynch-Like Individuals

by Estela Dámaso, Maribel González-Acosta, Gardenia Vargas-Parra, Matilde Navarro, Judith Balmaña, Teresa Ramon y Cajal, Noemí Tuset, Bryony A. Thompson, Fátima Marín, Anna Fernández, Carolina Gómez, Àngela Velasco, Ares Solanes, Sílvia Iglesias, Gisela Urgel, Consol López, Jesús del Valle, Olga Campos, Maria Santacana, Xavier Matias-Guiu, Conxi Lázaro, Laura Valle, Joan Brunet, Marta Pineda and Gabriel Capellá Show full author list Hide full author list

Cancers 2020, 12(7), 1799; https://doi.org/10.3390/cancers12071799 - 5 Jul 2020

Cited by 13 | Viewed by 4117

Abstract

The causal mechanism for cancer predisposition in Lynch-like syndrome (LLS) remains unknown. Our aim was to elucidate the constitutional basis of mismatch repair (MMR) deficiency in LLS patients throughout a comprehensive (epi)genetic analysis. One hundred and fifteen LLS patients harboring MMR-deficient tumors and [...] Read more.

The causal mechanism for cancer predisposition in Lynch-like syndrome (LLS) remains unknown. Our aim was to elucidate the constitutional basis of mismatch repair (MMR) deficiency in LLS patients throughout a comprehensive (epi)genetic analysis. One hundred and fifteen LLS patients harboring MMR-deficient tumors and no germline MMR mutations were included. Mutational analysis of 26 colorectal cancer (CRC)-associated genes was performed. Pathogenicity of MMR variants was assessed by splicing and multifactorial likelihood analyses. Genome-wide methylome analysis was performed by the Infinium Human Methylation 450K Bead Chip. The multigene panel analysis revealed the presence of two MMR gene truncating mutations not previously found. Of a total of 15 additional MMR variants identified, five -present in 6 unrelated individuals- were reclassified as pathogenic. In addition, 13 predicted deleterious variants in other CRC-predisposing genes were found in 12 probands. Methylome analysis detected one constitutional MLH1 epimutation, but no additional differentially methylated regions were identified in LLS compared to LS patients or cancer-free individuals. In conclusion, the use of an ad-hoc designed gene panel combined with pathogenicity assessment of variants allowed the identification of deleterious MMR mutations as well as new LLS candidate causal genes. Constitutional epimutations in non-LS-associated genes are not responsible for LLS. Full article

(This article belongs to the Special Issue Lynch Syndrome)

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Review

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37 pages, 540 KiB

Open AccessReview

How Should We Test for Lynch Syndrome? A Review of Current Guidelines and Future Strategies

by Richard Gallon, Peter Gawthorpe, Rachel L. Phelps, Christine Hayes, Gillian M. Borthwick, Mauro Santibanez-Koref, Michael S. Jackson and John Burn

Cancers 2021, 13(3), 406; https://doi.org/10.3390/cancers13030406 - 22 Jan 2021

Cited by 29 | Viewed by 5821

Abstract

International guidelines for the diagnosis of Lynch syndrome (LS) recommend molecular screening of colorectal cancers (CRCs) to identify patients for germline mismatch repair (MMR) gene testing. As our understanding of the LS phenotype and diagnostic technologies have advanced, there is a need to [...] Read more.

International guidelines for the diagnosis of Lynch syndrome (LS) recommend molecular screening of colorectal cancers (CRCs) to identify patients for germline mismatch repair (MMR) gene testing. As our understanding of the LS phenotype and diagnostic technologies have advanced, there is a need to review these guidelines and new screening opportunities. We discuss the barriers to implementation of current guidelines, as well as guideline limitations, and highlight new technologies and knowledge that may address these. We also discuss alternative screening strategies to increase the rate of LS diagnoses. In particular, the focus of current guidance on CRCs means that approximately half of Lynch-spectrum tumours occurring in unknown male LS carriers, and only one-third in female LS carriers, will trigger testing for LS. There is increasing pressure to expand guidelines to include molecular screening of endometrial cancers, the most frequent cancer in female LS carriers. Furthermore, we collate the evidence to support MMR deficiency testing of other Lynch-spectrum tumours to screen for LS. However, a reliance on tumour tissue limits preoperative testing and, therefore, diagnosis prior to malignancy. The recent successes of functional assays to detect microsatellite instability or MMR deficiency in non-neoplastic tissues suggest that future diagnostic pipelines could become independent of tumour tissue. Full article

(This article belongs to the Special Issue Lynch Syndrome)

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