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Keywords = lynch-like syndrome

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22 pages, 5295 KiB  
Article
Genomic Medicine in the Developing World: Cancer Spectrum, Cumulative Risk and Survival Outcomes for Lynch Syndrome Variant Heterozygotes with Germline Pathogenic Variants in the MLH1 and MSH2 Genes
by Lutricia Ndou, Ramadhani Chambuso, Ursula Algar, Adam Boutall, Paul Goldberg and Raj Ramesar
Biomedicines 2024, 12(12), 2906; https://doi.org/10.3390/biomedicines12122906 - 20 Dec 2024
Viewed by 996
Abstract
Background: Although genetic testing has improved our ability to diagnose Lynch syndrome (LS), there is still limited information on the extent of variations in the clinical and genetic landscape among LS variant heterozygotes (LSVH) in Africa. We sought to investigate the cancer [...] Read more.
Background: Although genetic testing has improved our ability to diagnose Lynch syndrome (LS), there is still limited information on the extent of variations in the clinical and genetic landscape among LS variant heterozygotes (LSVH) in Africa. We sought to investigate the cancer spectrum, cumulative risk, and survival outcomes of LSVH with pathogenic/likely pathogenic variants (P/LPVs) in the MLH1 and MSH2 genes using a LS registry in South Africa over the last 30 years. Methods: A retrospective study was conducted to retrieve demographic, clinical, and genetic data of all LSVH with P/LPVs in the MLH1 and MSH2 genes from our LS registry. Genetic data were analyzed according to cancer spectrum, cumulative risk, and crude survival. We used the Chi-squared and t-test to assess differences between groups, and Kaplan–Meier survival analyses were used to analyze the cumulative risk and crude survival outcomes. A p-value < 0.05 at a 95% confidence interval was considered statistically significant. Results: We analyzed a total of 577 LSVH from 109 families. About 450 (78%) and 127 (22%) LSVH harbored a disease-causing mutation in MLH1 and MSH2, respectively. A South African founder PV (MLH1:c.1528C>T) accounted for 74% (n = 426) of all LSVH. CRC was the most common diagnosed cancer in both MLH1 and MSH2 LSVH. MLH1 LSVH had a younger age at cancer diagnosis than MSH2 LSVH (43 vs. 47 years, respectively, p = 0.015). Extracolonic cancers were predominantly higher in female LSVH (n = 33, 35%) than in male LSVH (n = 8, 7%) with the MLH1:c.1528C>T founder PV. The cumulative risk of any cancer and CRC at any age was higher in MLH1 LSVH than in MSH2 LSVH (p = 0.020 and p = 0.036, respectively). LSVH with the MLH1:c.1528C>T PV had a better 10-year overall survival after the first cancer diagnosis, particularly for CRC. Conclusions: LSVH with P/LPVs in the MLH1 and MSH2 genes exhibited significant gene- and sex-specific differences in cancer spectrum, cumulative risk and survival outcomes. Cancer risk and survival estimates described in this study can be used to guide surveillance and genetic counselling for LSVH in our population. Full article
(This article belongs to the Section Molecular Genetics and Genetic Diseases)
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20 pages, 2015 KiB  
Article
Comprehensive Clinical Genetics, Molecular and Pathological Evaluation Efficiently Assist Diagnostics and Therapy Selection in Breast Cancer Patients with Hereditary Genetic Background
by Petra Nagy, János Papp, Vince Kornél Grolmusz, Anikó Bozsik, Tímea Pócza, Edit Oláh, Attila Patócs and Henriett Butz
Int. J. Mol. Sci. 2024, 25(23), 12546; https://doi.org/10.3390/ijms252312546 - 22 Nov 2024
Cited by 2 | Viewed by 1560
Abstract
Using multigene panel testing for the diagnostic evaluation of patients with hereditary breast and ovarian cancer (HBOC) syndrome often identifies clinically actionable variants in genes with varying levels of penetrance. High-penetrance genes (BRCA1, BRCA2, CDH1, PALB2, PTEN, [...] Read more.
Using multigene panel testing for the diagnostic evaluation of patients with hereditary breast and ovarian cancer (HBOC) syndrome often identifies clinically actionable variants in genes with varying levels of penetrance. High-penetrance genes (BRCA1, BRCA2, CDH1, PALB2, PTEN, STK11, TP53) inform specific clinical surveillance and therapeutic decisions, while recommendations for moderate-penetrance genes (ATM, BARD1, BRIP1, CHEK2, MLH1, MSH2, MSH6, PMS2, EPCAM, NF1, RAD51C, RAD51D) are more limited. A detailed disease history, including pedigree data, helps formulate the most appropriate and personalised management strategies. In this study, we evaluated the clinical benefits of comprehensive hereditary cancer gene panel testing and a pre-sent questionnaire in Hungarian patients with suspected HBOC syndrome. We prospectively enrolled 513 patients referred for HBOC testing. Of these, 463 met the genetic testing criteria, while 50 did not but were tested due to potential therapeutic indications. Additionally, a retrospective cohort of 47 patients who met the testing criteria but had previously only been tested for BRCA1/2 was also analysed. Among the 463 patients in the prospective cohort, 96 (20.7%) harboured pathogenic/likely pathogenic (P/LP) variants—67 in high-penetrance genes and 29 in moderate-penetrance genes. This ratio was similar in the retrospective cohort (6/47; 12.7%). In patients who did not meet the testing criteria, no mutations in high-penetrance genes were found, and only 3 of 50 (6%) harboured P/LP variants in moderate-penetrance genes. Secondary findings (P/LP variants in non-HBOC-associated genes) were identified in two patients. In the prospective cohort, P/LP variants in BRCA1 and BRCA2 were the most prevalent (56/96; 58.3%), and the extended testing doubled the P/LP detection ratio. Among moderate-penetrance genes, five cases (three in the prospective and two in the retrospective cohorts) had P/LP variants in Lynch syndrome-associated genes. Further immunohistochemistry analysis of breast tumour tissues helped clarify the causative role of these variants. Comprehensive clinical and molecular genetic evaluation is beneficial for the diagnosis and management of patients with P/LP variants in hereditary tumour-predisposing genes and can serve as a basis for effective therapy selection, such as PARP inhibitors or immunotherapy. Full article
(This article belongs to the Special Issue Molecular Mechanisms and Targeted Therapies of Breast Cancer)
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17 pages, 2334 KiB  
Article
Prospective Screening of Cancer Syndromes in Patients with Mesenchymal Tumors
by Ingegerd Öfverholm, Yingbo Lin, Julia Mondini, John Hardingz, Robert Bränström, Panagiotis Tsagkozis, Valtteri Wirta, Anna Gellerbring, Johan Lindberg, Venkatesh Chellappa, Markus Mayrhofer, Cecilia Haglund, Felix Haglund de Flon and Karin Wallander
Cancers 2024, 16(22), 3816; https://doi.org/10.3390/cancers16223816 - 13 Nov 2024
Viewed by 1703
Abstract
Background: The etiology of most mesenchymal tumors is unknown, and knowledge about syndromes with an increased risk of tumors in bone or soft tissue is sparse. Methods: We present a prospective germline analysis of 312 patients with tumors suspected of being sarcomas at [...] Read more.
Background: The etiology of most mesenchymal tumors is unknown, and knowledge about syndromes with an increased risk of tumors in bone or soft tissue is sparse. Methods: We present a prospective germline analysis of 312 patients with tumors suspected of being sarcomas at a tertiary sarcoma center. Germline and tumor whole genome sequencing, tumor transcriptome, and methylome analyses were performed. Results: Germline pathogenic or likely pathogenic variants associated with an increased risk of tumors were detected in 24 patients (8%), of which 11 (4%) harbored a detectable second hit in the tumor. Second hits were confirmed in genes with (NF1, RB1, TP53, EXT2, and SDHC) and without (ATM, CDC73, MLH1, MSH6, POLG, and KCNQ1) known association with mesenchymal tumor predisposition. Sarcomas from two Lynch syndrome patients showed mismatch repair deficiency, predicting a treatment response to immune checkpoint inhibitors (Level 1 biomarker according to the FDA (Federal Drug Administration) and ESMO (European Society for Medical Oncology)). None of the three CHEK2 carriers had a second hit in the tumor, suggesting a weak link to sarcoma. Conclusions: We conclude that second-hit analyses can be used in standard of care to identify syndrome-related tumors. This approach can help distinguish true manifestations of tumor syndromes from unrelated germline findings and enhance the understanding of germline predisposition in soft tissue tumors. Prospective screening using germline whole genome sequencing should be considered when comprehensive somatic sequencing is introduced into clinical practice. Full article
(This article belongs to the Special Issue Feature Papers in Section "Cancer Biomarkers" in 2023–2024)
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19 pages, 2114 KiB  
Article
Two Decades of Progress in Personalized Medicine of Colorectal Cancer in Serbia—Insights from the Institute for Oncology and Radiology of Serbia
by Milena Cavic, Neda Nikolic, Mladen Marinkovic, Ana Damjanovic, Ana Krivokuca, Miljana Tanic, Marko Radulovic, Aleksandra Stanojevic, Luka Pejnovic, Marija Djordjic Crnogorac, Ana Djuric, Miodrag Vukovic, Vanja Stevanovic, Jelena Kijac, Valentina Karadzic, Srdjan Nikolic, Suzana Stojanovic-Rundic, Radmila Jankovic and Jelena Spasic
Biomedicines 2024, 12(10), 2278; https://doi.org/10.3390/biomedicines12102278 - 8 Oct 2024
Cited by 2 | Viewed by 3110
Abstract
Background: It is projected that, by 2040, the number of new cases of colorectal cancer (CRC) will increase to 3.2 million, and the number of deaths to 1.6 million, highlighting the need for prevention strategies, early detection and adequate follow-up. In this study, [...] Read more.
Background: It is projected that, by 2040, the number of new cases of colorectal cancer (CRC) will increase to 3.2 million, and the number of deaths to 1.6 million, highlighting the need for prevention strategies, early detection and adequate follow-up. In this study, we aimed to provide an overview of the progress in personalized medicine of CRC in Serbia, with results and insights from the Institute for Oncology and Radiology of Serbia (IORS), and to propose guidance for tackling observed challenges in the future. Methods: Epidemiological data were derived from official global and national cancer registries and IORS electronic medical records. Germline genetic testing for Lynch syndrome was performed by Next Generation Sequencing. RAS and BRAF mutation analyses were performed using qPCR diagnostic kits. Results: Epidemiology and risk factors, prevention and early detection programs, as well as treatment options and scientific advances have been described in detail. Out of 103 patients who underwent germline testing for Lynch syndrome, 19 (18.4%) showed a mutation in MMR genes with pathogenic or likely pathogenic significance and 8 (7.8%) in other CRC-associated genes (APC, CHEK2, MUTYH). Of 6369 tested patients, 50.43% had a mutation in KRAS or NRAS genes, while 9.54% had the V600 mutation in the BRAF gene. Conclusions: Although significant improvements in CRC management have occurred globally in recent years, a strategic approach leading to population-based systemic solutions is required. The high incidence of young-onset CRC and the growing elderly population due to a rise in life expectancy will be especially important factors for countries with limited healthcare resources like Serbia. Full article
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12 pages, 1404 KiB  
Article
Comparing Clinicopathological and Immunohistochemical Features of Colorectal Carcinoma between Young and Old Age Groups
by Heyam Awad, Sanad Elshebli, Khaled Hasan, Yousef Eid, Fatima Obeidat, Mohammad Alzyoud, Basheer Alakhras and Faris AlShammas
Diagnostics 2024, 14(16), 1743; https://doi.org/10.3390/diagnostics14161743 - 11 Aug 2024
Cited by 1 | Viewed by 1584
Abstract
The incidence of colorectal carcinoma (CRC) is increasing among individuals younger than 50, and some studies suggest the presence of differences in CRC among old and young individuals regarding clinical and histopathological features. The aim of this study was to compare clinicopathological features, [...] Read more.
The incidence of colorectal carcinoma (CRC) is increasing among individuals younger than 50, and some studies suggest the presence of differences in CRC among old and young individuals regarding clinical and histopathological features. The aim of this study was to compare clinicopathological features, mismatch repair protein status, and expression of certain immunohistochemical stains between young and old groups. The study included 180 cases and found significant histological and immunohistochemical differences between the two groups. CRC in the young tends to be more right-sided and has a higher percentage of dMMR proteins, but less expression of p53 mutations. These features are commoner in Lynch syndrome, and more investigations to study the relationship between young-onset CRC and hereditary syndromes are needed. Young-onset CRC also tends to show higher expression of tumor cell PD-L1, which is an expected finding, as dMMR cases are more likely to be immunogenic. Two other significant differences are the higher percentage of mucinous carcinoma and the higher tumor grade in young-onset CRC. These two features suggest a more advanced disease with possibly worse outcomes; however, there is no difference in disease stage between the two age groups. Full article
(This article belongs to the Section Pathology and Molecular Diagnostics)
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10 pages, 813 KiB  
Article
Patterns and Frequency of Pathogenic Germline Mutations among Patients with Newly-Diagnosed Endometrial Cancer: The Jordanian Exploratory Cancer Genetics (Jo-ECAG) Endometrial Study
by Hikmat Abdel-Razeq, Hira Bani Hani, Baha Sharaf, Faris Tamimi, Hanan Khalil, Areej Abu Sheikha, Mais Alkyam, Sarah Abdel-Razeq, Tala Ghatasheh, Tala Radaideh and Suhaib Khater
Cancers 2024, 16(14), 2543; https://doi.org/10.3390/cancers16142543 - 15 Jul 2024
Viewed by 1732
Abstract
Most of endometrial cancers are sporadic, with 5% or less being attributed to inherited pathogenic germline mutations and mostly related to the Lynch syndrome. To our knowledge, this is the first study to investigate patterns and frequencies of germline mutations in patients with [...] Read more.
Most of endometrial cancers are sporadic, with 5% or less being attributed to inherited pathogenic germline mutations and mostly related to the Lynch syndrome. To our knowledge, this is the first study to investigate patterns and frequencies of germline mutations in patients with endometrial cancer in an Arab region. Consecutive patients with endometrial cancer (n = 130), regardless of their age and family history, were enrolled. Germline genetic testing, using an 84-gene panel, was performed on all. Almost half of the patient population (n = 64, 49.2%) was tested based on international guidelines, while the remaining patients (n = 66, 50.8%) were tested as part of an ongoing universal germline genetic testing program. Among the whole group, 18 (13.8%) patients had positive pathogenic or likely pathogenic (P/LP) germline variants. The most common variants encountered were in MLH1 (n = 4, 22.2%), PMS2 (n = 3, 16.7%), ATM, MSH2, MUTYH, and BRCA2 (n = 2, 11.1% each). In addition, three (2.3%) patients were found to have an increased risk allele of the APC gene. P/LP variants were more common among patients with carcinosarcoma and clear cell carcinoma, younger patients (age ≤ 50 years), and in patients with a non-metastatic disease. We conclude that germline genetic variants, mostly in genes related to the Lynch syndrome, are relatively common among Arab patients with endometrial cancer. Full article
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13 pages, 296 KiB  
Article
Mutations in Mismatch Repair Genes and Microsatellite Instability Status in Pancreatic Cancer
by Marina Emelyanova, Anna Ikonnikova, Alexander Pushkov, Elena Pudova, George Krasnov, Anna Popova, Ilya Zhanin, Darya Khomich, Ivan Abramov, Sergei Tjulandin, Dmitry Gryadunov and Ilya Pokataev
Cancers 2024, 16(11), 2111; https://doi.org/10.3390/cancers16112111 - 31 May 2024
Cited by 1 | Viewed by 2568
Abstract
Patients with pancreatic cancer (PC) showing mismatch repair (MMR) deficiency may benefit from immunotherapy. Microsatellite instability (MSI) is a hallmark of MMR deficiency (MMR-D). Here, we estimated the prevalence of MSI in PC, investigated germline and somatic mutations in the three MMR genes [...] Read more.
Patients with pancreatic cancer (PC) showing mismatch repair (MMR) deficiency may benefit from immunotherapy. Microsatellite instability (MSI) is a hallmark of MMR deficiency (MMR-D). Here, we estimated the prevalence of MSI in PC, investigated germline and somatic mutations in the three MMR genes (MLH1, MSH2, and MSH6), and assessed the relationship between MMR genes mutations and MSI status in PC. Clinical specimens from PC patients were analyzed using targeted next-generation sequencing, including paired normal and tumor specimens from 155 patients, tumor-only specimens from 86 patients, and normal-only specimens from 379 patients. The MSI status of 235 PCs was assessed via PCR. Pathogenic/likely pathogenic (P/LP) germline variants in the MMR genes were identified in 1.1% of patients, while somatic variants were found in 2.6% of patients. No MSI-H tumors were detected. One patient carried two variants (P (VAF = 0.57) and LP (VAF = 0.25)) simultaneously; however, their germline/somatic status remains unknown due to the investigation focusing solely on the tumor and MSI analysis was not performed for this patient. MSI is rare in PC, even in tumors with MMR genes mutations. Our findings underscore the importance of assessing tumor MMR-D status in PC patients with confirmed Lynch syndrome when deciding whether to prescribe immunotherapy. Full article
(This article belongs to the Special Issue Advanced Research in Pancreatic Ductal Adenocarcinoma)
5 pages, 4476 KiB  
Case Report
Sebaceomas in a Muir–Torre-like Phenotype in a Patient with MUTYH-Associated Polyposis
by Julia Guarrera, James C. Prezzano and Kathleen A. Mannava
Dermatopathology 2024, 11(1), 124-128; https://doi.org/10.3390/dermatopathology11010011 - 4 Mar 2024
Cited by 1 | Viewed by 2141
Abstract
This case report describes a case of a patient with MUTYH-associated polyposis (MAP), who presented with multiple sebaceomas in a Muir–Torre-like phenotype. MAP is caused by mutations in MUTYH, a base excision repair gene responsible for detecting and repairing the 8-oxo-G:A transversion caused [...] Read more.
This case report describes a case of a patient with MUTYH-associated polyposis (MAP), who presented with multiple sebaceomas in a Muir–Torre-like phenotype. MAP is caused by mutations in MUTYH, a base excision repair gene responsible for detecting and repairing the 8-oxo-G:A transversion caused by reactive oxygen species. MAP is associated with an increased risk of developing adenomatous polyps and colorectal cancer. Muir–Torre syndrome is a clinical phenotype of Lynch syndrome, which presents with multiple cutaneous sebaceous neoplasms. Lynch syndrome, like MAP, increases the likelihood of developing colorectal cancer but with a different pathogenesis and mode of inheritance. This case demonstrates that in a patient presenting with multiple sebaceous neoplasms, further workup and genetic testing may be indicated, not only for Muir–Torre and Lynch syndrome but also for MAP. Full article
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19 pages, 523 KiB  
Article
Prevalence of Variants of Uncertain Significance in Patients Undergoing Genetic Testing for Hereditary Breast and Ovarian Cancer and Lynch Syndrome
by Pavlina Chrysafi, Chinmay T. Jani, Margaret Lotz, Omar Al Omari, Harpreet Singh, Katherine Stafford, Lipisha Agarwal, Arashdeep Rupal, Abdul Qadir Dar, Abby Dangelo and Prudence Lam
Cancers 2023, 15(24), 5762; https://doi.org/10.3390/cancers15245762 - 8 Dec 2023
Cited by 5 | Viewed by 3507
Abstract
Hereditary Breast and Ovarian Cancer (HBOC) and Lynch Syndrome (LS) are the most common inherited cancer syndromes identified with genetic testing. Testing, though, commonly reveals variants of uncertain significance (VUSs). This is a retrospective observational study designed to determine the prevalence of pathogenic [...] Read more.
Hereditary Breast and Ovarian Cancer (HBOC) and Lynch Syndrome (LS) are the most common inherited cancer syndromes identified with genetic testing. Testing, though, commonly reveals variants of uncertain significance (VUSs). This is a retrospective observational study designed to determine the prevalence of pathogenic mutations and VUSs in patients tested for HBOC and/or LS and to explore the characteristics of the VUS population. Patients 18–80 years old that met NCCN criteria for HBOC and/or LS genetic screening were tested between 2006 and 2020 at Mount Auburn Hospital in Cambridge, Massachusetts. A total of 663 patients were included in the study, with a mean age of 50 years old and 90% being females. Pathogenic mutations were identified in 12.5% and VUSs in 28.3%. VUS prevalence was associated with race (p-value = 0.019), being particularly higher in Asian populations. Patients with a personal history of breast cancer or family history of breast or ovarian cancer were more likely to have a VUS (personal breast: OR: 1.55; CI: 1.08–2.25; family breast: OR: 1.68; CI: 1.08–2.60, family ovarian OR: 2.29; CI: 1.04–5.45). In conclusion, VUSs appear to be detected in almost one third patients tested for cancer genetic syndromes, and thus future work is warranted to determine their significance in cancer development. Full article
(This article belongs to the Special Issue Genetics and Epigenetics of Gynecological Cancer)
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20 pages, 1347 KiB  
Review
Early-Onset Ovarian Cancer <30 Years: What Do We Know about Its Genetic Predisposition?
by Klara Horackova, Marketa Janatova, Petra Kleiblova, Zdenek Kleibl and Jana Soukupova
Int. J. Mol. Sci. 2023, 24(23), 17020; https://doi.org/10.3390/ijms242317020 - 30 Nov 2023
Cited by 13 | Viewed by 3146
Abstract
Ovarian cancer (OC) is one of the leading causes of cancer-related deaths in women. Most patients are diagnosed with advanced epithelial OC in their late 60s, and early-onset adult OC diagnosed ≤30 years is rare, accounting for less than 5% of all OC [...] Read more.
Ovarian cancer (OC) is one of the leading causes of cancer-related deaths in women. Most patients are diagnosed with advanced epithelial OC in their late 60s, and early-onset adult OC diagnosed ≤30 years is rare, accounting for less than 5% of all OC cases. The most significant risk factor for OC development are germline pathogenic/likely pathogenic variants (GPVs) in OC predisposition genes (including BRCA1, BRCA2, BRIP1, RAD51C, RAD51D, Lynch syndrome genes, or BRIP1), which contribute to the development of over 20% of all OC cases. GPVs in BRCA1/BRCA2 are the most prevalent. The presence of a GPV directs tailored cancer risk-reducing strategies for OC patients and their relatives. Identification of OC patients with GPVs can also have therapeutic consequences. Despite the general assumption that early cancer onset indicates higher involvement of hereditary cancer predisposition, the presence of GPVs in early-onset OC is rare (<10% of patients), and their heritability is uncertain. This review summarizes the current knowledge on the genetic predisposition to early-onset OC, with a special focus on epithelial OC, and suggests other alternative genetic factors (digenic, oligogenic, polygenic heritability, genetic mosaicism, imprinting, etc.) that may influence the development of early-onset OC in adult women lacking GPVs in known OC predisposition genes. Full article
(This article belongs to the Special Issue Gynecological Cancer 2023)
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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 7 | Viewed by 2274
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
Cited by 1 | Viewed by 2808
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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9 pages, 898 KiB  
Case Report
Germline Variants in MLH1 and ATM Genes in a Young Patient with MSI-H in a Precancerous Colonic Lesion
by Antonio Nolano, Giovanni Battista Rossi, Valentina D’Angelo, Raffaella Liccardo, Marina De Rosa, Paola Izzo and Francesca Duraturo
Int. J. Mol. Sci. 2023, 24(6), 5970; https://doi.org/10.3390/ijms24065970 - 22 Mar 2023
Cited by 2 | Viewed by 5599
Abstract
Lynch syndrome (LS) is an autosomal dominant inherited disorder that primarily predisposes individuals to colorectal and endometrial cancer. It is associated with pathogenic variants in DNA mismatch repair (MMR) genes. In this study, we report the case of a 16-year-old boy who developed [...] Read more.
Lynch syndrome (LS) is an autosomal dominant inherited disorder that primarily predisposes individuals to colorectal and endometrial cancer. It is associated with pathogenic variants in DNA mismatch repair (MMR) genes. In this study, we report the case of a 16-year-old boy who developed a precancerous colonic lesion and had a clinical suspicion of LS. The proband was found to have a somatic MSI-H status. Analysis of the coding sequences and flanking introns of the MLH1 and MSH2 genes by Sanger sequencing led to the identification of the variant of uncertain significance, namely, c.589-9_589-6delGTTT in the MLH1 gene. Further investigation revealed that this variant was likely pathogenetic. Subsequent next-generation sequencing panel analysis revealed the presence of two variants of uncertain significance in the ATM gene. We conclude that the phenotype of our index case is likely the result of a synergistic effect of these identified variants. Future studies will allow us to understand how risk alleles in different colorectal-cancer-prone genes interact with each other to increase an individual’s risk of developing cancer. Full article
(This article belongs to the Special Issue Cancer Biomarker: Current Status and Future Perspectives)
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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 2 | Viewed by 3629
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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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 25 | Viewed by 3528
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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