scholarly journals Novel Implications in Molecular Diagnosis of Lynch Syndrome

2017 ◽  
Vol 2017 ◽  
pp. 1-12 ◽  
Author(s):  
Raffaella Liccardo ◽  
Marina De Rosa ◽  
Paola Izzo ◽  
Francesca Duraturo
Keyword(s):  
Lynch Syndrome ◽  
Clinical Manifestations ◽  
Mendelian Inheritance ◽  
Dna Mismatch ◽  
Variants Of Unknown Significance ◽  
Mmr Genes ◽  
Risk Alleles ◽  
Detection Analysis ◽  
Unknown Significance ◽  
Analytical Strategies

About 10% of total colorectal cancers are associated with known Mendelian inheritance, as Familial Adenomatous Polyposis (FAP) and Lynch syndrome (LS). In these cancer types the clinical manifestations of disease are due to mutations in high-risk alleles, with a penetrance at least of 70%. The LS is associated with germline mutations in the DNA mismatch repair (MMR) genes. However, the mutation detection analysis of these genes does not always provide informative results for genetic counseling of LS patients. Very often, the molecular analysis reveals the presence of variants of unknown significance (VUSs) whose interpretation is not easy and requires the combination of different analytical strategies to get a proper assessment of their pathogenicity. In some cases, these VUSs may make a more substantial overall contribution to cancer risk than the well-assessed severe Mendelian variants. Moreover, it could also be possible that the simultaneous presence of these genetic variants in several MMR genes that behave as low risk alleles might contribute in a cooperative manner to increase the risk of hereditary cancer. In this paper, through a review of the recent literature, we have speculated a novel inheritance model in the Lynch syndrome; this could pave the way toward new diagnostic perspectives.

scholarly journals Lynch syndrome: current status of CRC in Biotechnological and Biomedical fields

2021 ◽  
Author(s):  
Arnaud Martino Capuzzo
Keyword(s):  
Lynch Syndrome ◽  
Upper Urinary Tract ◽  
Current Status ◽  
Precise Description ◽  
Dna Mismatch ◽  
Mmr Genes ◽  
Detection Analysis ◽  
Long Time ◽  
Surveillance Programs ◽  
Cancer Types

Lynch syndrome (LS) is an autosomal dominant genetic condition caused by mutations in the DNA mismatch repair (MMR) genes in the germline. Colorectal cancer and/or LS-associated cancer are more likely in people who carry pathogenic mutations in these genes. Cancers of the endometrium, small intestine, stomach, pancreas, and biliary tract, ovarian, brain, upper urinary tract, and skin are among the cancer types linked to LS. The criteria for a clinical diagnosis of LS, as well as the processes for genetic testing to identify carriers of pathogenetic mutations in MMR genes, have been known for a long time. The precise description of the pathogenicity associated with MMR genetic variants is critical in the mutation detection analysis, especially in order to enroll mutation carriers in endoscopic surveillance programs that are more suited to them. As a result, this may aid in the improvement of LS-related cancer prevention efforts. In this review, we discuss recent advances in the molecular genetics of LS.

scholarly journals Lynch Syndrome: Current Status of CRC in Biotechnological and Biomedical Fields

2021 ◽  
Author(s):  
Arnaud Martino Capuzzo
Keyword(s):  
Lynch Syndrome ◽  
Upper Urinary Tract ◽  
Current Status ◽  
Precise Description ◽  
Dna Mismatch ◽  
Mmr Genes ◽  
Detection Analysis ◽  
Long Time ◽  
Surveillance Programs ◽  
Cancer Types

Lynch syndrome (LS) is an autosomal dominant genetic condition caused by mutations in the DNA mismatch repair (MMR) genes in the germline. Colorectal cancer and/or LS-associated cancer are more likely in people who carry pathogenic mutations in these genes. Cancers of the endometrium, small intestine, stomach, pancreas, and biliary tract, ovarian, brain, upper urinary tract, and skin are among the cancer types linked to LS. The criteria for a clinical diagnosis of LS, as well as the processes for genetic testing to identify carriers of pathogenetic mutations in MMR genes, have been known for a long time. The precise description of the pathogenicity associated with MMR genetic variants is critical in the mutation detection analysis, especially in order to enroll mutation carriers in endoscopic surveillance programs that are more suited to them. As a result, this may aid in the improvement of LS-related cancer prevention efforts. In this review, we discuss recent advances in the molecular genetics of LS.

scholarly journals Insertion of an SVA Element in MSH2 as a Novel Cause of Lynch Syndrome

2020 ◽  
Author(s):  
Ciyu Yang ◽  
Yirong Li ◽  
Magan Trottier ◽  
Michael Farrell ◽  
Vikas Rai ◽  
...  
Keyword(s):  
Lynch Syndrome ◽  
Pcr Analysis ◽  
Rt Pcr ◽  
Dna Mismatch ◽  
Mmr Genes ◽  
Antisense Orientation ◽  
The Family ◽  
Long Range Pcr ◽  
Early Onset Colorectal Cancer ◽  
Generation Sequencing

Germline mutations in the DNA mismatch repair (MMR) genes cause Lynch syndrome (LS). Insertions of retrotransposons in MMR genes have been reported as a rare cause of LS. Here, we present a novel SINE-VNTR-Alu (SVA) insertion in exon 12 of MSH2 in an individual with early-onset colorectal cancer and strong LS family history. RT-PCR analysis indicated a larger aberrant MSH2 transcript in one of the family members. MSK-IMPACT next-generation sequencing testing and long-range PCR revealed an insertion in MSH2 exon 12 at the c.1972 position in an antisense orientation. The insertion was further characterized as an SVA element approximately 3 kb in length, belonging to the SVA_F1 family of retrotransposons.

scholarly journals Clinical and genetic aspects of differential diagnostics of hereditary non-polyposis colorectal cancer

2019 ◽  
Vol 6 (2) ◽  
pp. 21-27
Author(s):  
A. V. Semyanikhina ◽  
A. O. Rasulov ◽  
L. N. Lyubchenko
Keyword(s):  
Colorectal Cancer ◽  
Colon Cancer ◽  
Lynch Syndrome ◽  
Mismatch Repair ◽  
Heterogeneous Group ◽  
Differential Diagnostics ◽  
Genetic Characteristics ◽  
Dna Mismatch ◽  
Mmr Genes ◽  
Long Time

Lynch syndrome was synonymous with hereditary non-polyposis colorectal cancer for a long time, however, mapping of the DNA mismatch repair (MMR) genes has led to distinguish Lynch syndrome as an independent syndromic unit from a number of Lynch-like syndromes that phenotypically mimic with the most frequent hereditary variant of colon cancer but genetically representing quite a heterogeneous group. This article presents up to date clinical and genetic characteristics of Lynch syndrome and Lynch-like conditions.

scholarly journals Oligonucleotide-directed mutagenesis screen to identify pathogenic Lynch syndrome-associated MSH2 DNA mismatch repair gene variants

2016 ◽  
Vol 113 (15) ◽  
pp. 4128-4133 ◽  
Author(s):  
Hellen Houlleberghs ◽  
Marleen Dekker ◽  
Hildo Lantermans ◽  
Roos Kleinendorst ◽  
Hendrikus Jan Dubbink ◽  
...  
Keyword(s):  
Lynch Syndrome ◽  
Mismatch Repair ◽  
Dna Mismatch Repair ◽  
Embryonic Stem ◽  
Mismatch Repair Gene ◽  
Missense Mutations ◽  
Repair Gene ◽  
Dna Mismatch ◽  
Mmr Genes ◽  
Pathogenic Variants

Single-stranded DNA oligonucleotides can achieve targeted base-pair substitution with modest efficiency but high precision. We show that “oligo targeting” can be used effectively to study missense mutations in DNA mismatch repair (MMR) genes. Inherited inactivating mutations in DNA MMR genes are causative for the cancer predisposition Lynch syndrome (LS). Although overtly deleterious mutations in MMR genes can clearly be ascribed as the cause of LS, the functional implications of missense mutations are often unclear. We developed a genetic screen to determine the pathogenicity of these variants of uncertain significance (VUS), focusing on mutator S homolog 2 (MSH2). VUS were introduced into the endogenous Msh2 gene of mouse embryonic stem cells by oligo targeting. Subsequent selection for MMR-deficient cells using the guanine analog 6-thioguanine allowed the detection of MMR-abrogating VUS. The screen was able to distinguish weak and strong pathogenic variants from polymorphisms and was used to investigate 59 Msh2 VUS. Nineteen of the 59 VUS were identified as pathogenic. Functional assays revealed that 14 of the 19 detected variants fully abrogated MMR activity and that five of the detected variants attenuated MMR activity. Implementation of the screen in clinical practice allows proper counseling of mutation carriers and treatment of their tumors.

scholarly journals High Prevalence of Alterations in DNA Mismatch Repair Genes of Lynch Syndrome in Pediatric Patients with Adrenocortical Tumors Carrying a Germline Mutation on TP53

Cancers ◽  
2020 ◽  
Vol 12 (3) ◽  
pp. 621
Author(s):  
Vania Balderrama Brondani ◽  
Luciana Montenegro ◽  
Amanda Meneses Ferreira Lacombe ◽  
Breno Marchiori Magalhães ◽  
Mirian Yumie Nishi ◽  
...  
Keyword(s):  
Lynch Syndrome ◽  
Mismatch Repair ◽  
Germline Mutation ◽  
Pediatric Patients ◽  
Dna Mismatch Repair ◽  
Malignant Neoplasm ◽  
Adrenocortical Tumors ◽  
Dna Mismatch ◽  
Mmr Genes ◽  
Dismal Prognosis

Adrenocortical cancer is a rare malignant neoplasm associated with a dismal prognosis. Identification of the molecular pathways involved in adrenal tumorigenesis is essential for a better understanding of the disease mechanism and improvement of its treatment. The aim of this study is to define the prevalence of alterations in DNA mismatch repair (MMR) genes in Lynch syndrome among pediatric patients with adrenocortical neoplasia from southern Brazil, where the prevalence of a specific TP53 germline mutation (p.Arg337His) is quite high. Thirty-six pediatric patients were retrospectively evaluated. Immunohistochemistry (IHC) for the MMR enzymes MLH1, MSH2, MSH6, and PMS2, as well as next-generation sequencing (NGS) were performed. For IHC, 36 pediatric tumors were tested. In all of them, the expression of all evaluated MMR proteins was well-preserved. For NGS, 35 patients with pediatric tumor were tested. Three patients (8.57%) with the TP53 p.Arg337His germline mutation presented pathogenic and likely pathogenic variants in the MMR genes (two in MLH1 and one in MSH6). The prevalence of altered MMR genes among pediatric patients was elevated (8.57%) and higher than in colorectal and endometrial cancer cohorts. Pediatric patients with adrenocortical tumors should, thus, be strongly considered as at genetic risk for Lynch syndrome.

scholarly journals Contribution of Large Genomic Rearrangements in Italian Lynch Syndrome Patients: Characterization of a Novel Alu-Mediated Deletion

2013 ◽  
Vol 2013 ◽  
pp. 1-7 ◽  
Author(s):  
Francesca Duraturo ◽  
Angela Cavallo ◽  
Raffaella Liccardo ◽  
Bianca Cudia ◽  
Marina De Rosa ◽  
...  
Keyword(s):  
Lynch Syndrome ◽  
Germ Line ◽  
Point Mutations ◽  
Low Frequency ◽  
Genomic Rearrangements ◽  
Dna Mismatch ◽  
Mmr Genes ◽  
Large Genomic Rearrangements ◽  
Large Deletions ◽  
Long Range Pcr

Lynch syndrome is associated with germ-line mutations in the DNA mismatch repair (MMR) genes, mainlyMLH1andMSH2. Most of the mutations reported in these genes to date are point mutations, small deletions, and insertions. Large genomic rearrangements in the MMR genes predisposing to Lynch syndrome also occur, but the frequency varies depending on the population studied on average from 5 to 20%. The aim of this study was to examine the contribution of large rearrangements in theMLH1andMSH2genes in a well-characterised series of 63 unrelated Southern Italian Lynch syndrome patients who were negative for pathogenic point mutations in theMLH1,MSH2, andMSH6genes. We identified a large novel deletion in theMSH2gene, including exon 6 in one of the patients analysed (1.6% frequency). This deletion was confirmed and localised by long-range PCR. The breakpoints of this rearrangement were characterised by sequencing. Further analysis of the breakpoints revealed that this rearrangement was a product of Alu-mediated recombination. Our findings identified a novel Alu-mediated rearrangement withinMSH2gene and showed that large deletions or duplications inMLH1andMSH2genes are low-frequency mutational events in Southern Italian patients with an inherited predisposition to colon cancer.

scholarly journals From Genetics to Histomolecular Characterization: An Insight into Colorectal Carcinogenesis in Lynch Syndrome

2021 ◽  
Vol 22 (13) ◽  
pp. 6767
Author(s):  
Martina Lepore Signorile ◽  
Vittoria Disciglio ◽  
Gabriella Di Carlo ◽  
Antonio Pisani ◽  
Cristiano Simone ◽  
...  
Keyword(s):  
Lynch Syndrome ◽  
Colorectal Carcinogenesis ◽  
Early Event ◽  
Molecular Models ◽  
Typically Develop ◽  
Dna Mismatch ◽  
Screening Interval ◽  
Mmr Genes ◽  
Insight Into

Lynch syndrome is a hereditary cancer-predisposing syndrome caused by germline defects in DNA mismatch repair (MMR) genes such as MLH1, MSH2, MSH6, and PMS2. Carriers of pathogenic mutations in these genes have an increased lifetime risk of developing colorectal cancer (CRC) and other malignancies. Despite intensive surveillance, Lynch patients typically develop CRC after 10 years of follow-up, regardless of the screening interval. Recently, three different molecular models of colorectal carcinogenesis were identified in Lynch patients based on when MMR deficiency is acquired. In the first pathway, adenoma formation occurs in an MMR-proficient background, and carcinogenesis is characterized by APC and/or KRAS mutation and IGF2, NEUROG1, CDK2A, and/or CRABP1 hypermethylation. In the second pathway, deficiency in the MMR pathway is an early event arising in macroscopically normal gut surface before adenoma formation. In the third pathway, which is associated with mutations in CTNNB1 and/or TP53, the adenoma step is skipped, with fast and invasive tumor growth occurring in an MMR-deficient context. Here, we describe the association between molecular and histological features in these three routes of colorectal carcinogenesis in Lynch patients. The findings summarized in this review may guide the use of individualized surveillance guidelines based on a patient’s carcinogenesis subtype.

Outcomes of Lynch syndrome (LS) patients treated with immune checkpoint inhibitors (ICI).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 1548-1548
Author(s):  
Shahla Bari ◽  
Richard D. Kim ◽  
Xia Wang ◽  
Marco Matejcic ◽  
Jameel Muzaffar
Keyword(s):  
Lynch Syndrome ◽  
Median Overall Survival ◽  
Progressive Disease ◽  
Checkpoint Inhibitors ◽  
Complete Response ◽  
Dna Mismatch ◽  
Mmr Genes ◽  
The Mean ◽  
The One

1548 Background: LS is caused by a germline mutation in one of several DNA mismatch repair (MMR) genes: MLH1, MSH2, MSH6 or PMS2 (d-MMR). A minority of LS patients have MMR proficient tumors (p-MMR). ICI therapy has dramatically changed outcome of d-MMR (majority of LS patients. However, data about response to ICI in LS patients, irrespective of their tumor MMR status is scarce. The aim of this study was to evaluate outcomes of ICI therapy in all LS associated Cancer. Methods: This was a retrospective analysis of LS associated cancers treated with one of the 6 ICIs at our center. We also looked at age, sex, microsatellite status, response and survival. Results: Out of 262 LS patients analyzed, 194 had cancer and 22 received ICIs. Among the patients analyzed, the mean age at diagnosis of 1st cancer was 51 yrs. There were 10 females (47%). 10 patients had colorectal (45%), 3 urothelial (14%), 2 renal cell, 2 cholangiocarcinoma and one each of esophageal, ovarian, uterine, glioblastoma multiforme and pancreatic cancer. One patient died from progressive disease after receiving a single dose and was not included in the analysis. 17 patients (80%) received Pembrolizumab, 11 patients were microsatellite unstable (MSI), 3 were microsatellite stable (MSS) while 7 were unknown. 2 patients achieved complete response (CR) (10%), 1 patient had partial response (PR) (5%), 13 had stable disease (62%) while 5 had progressive disease (23%) leading to a disease control rate (DCR) of 76%. Of the 3 known MSS Lynch syndrome patients, 2 did not respond while the 3rd continues to respond at 9 months of therapy. Of the 5 patients who had PD, 2 were MSS, 2 unknown and 1 MSI. Among the 16 patients who responded, 15 of 16 (94%) had sustained response and have not experienced disease progression or relapse. 3 of these patients have been off therapy (1 due to immune related adverse evet) and have had no relapse. One responder progressed after 18 cycles of therapy. The DCR was 71% at 12 months as well as 48 months of follow up. Median progression survival has not been reached. Similarly, median overall survival has not been reached. Conclusions: Our study is the one of the largest reported analysis of LS associated cancer patients treated with ICIs and included LS patients with both MSI and MSS tumors. Though small, our data suggests robust DCR and prolonged responses in Lynch associated MSS tumors treated with ICI. This encouraging response in MSS tumors along with higher response rates in LS associated cancers as compared to non-LS MSI tumors, suggests that there may be additional drivers of response to ICI in LS patients leading to superior responses.

scholarly journals Functional assay-based classification of PMS2 variants in Lynch Syndrome

2021 ◽  
Author(s):  
Emily Rayner ◽  
Yvonne Tiersma ◽  
Cristina Fortuno ◽  
Sandrine van Hees-Stuivenberg ◽  
Mark Drost ◽  
...  
Keyword(s):  
Lynch Syndrome ◽  
Functional Assay ◽  
Sequence Information ◽  
Predictive Values ◽  
Personalized Healthcare ◽  
Dna Mismatch ◽  
Variants Of Unknown Significance ◽  
Pathogenic Variants

The large majority of germline alterations identified in the DNA mismatch repair (MMR) gene PMS2, a low-penetrance gene for the cancer predisposition Lynch Syndrome (LS, OMIM 120435), represent variants of unknown significance (VUS). The inability to assess pathogenicity of such VUS interferes with personalized healthcare. The complete in vitro MMR activity (CIMRA) assay, that only requires sequence information on the VUS, provides a functional analysis-based tool suited for VUS classification. To derive a formula that translates CIMRA assay results for PMS2 VUS into the odds of pathogenicity (OddsPath), we used a set of clinically classified PMS2 variants, supplemented by inactivating variants generated by an in cellulo genetic screen, as proxies for pathogenic variants. Validation of this OddsPath revealed very high predictive values for PMS2 VUS. We conclude that this OddsPath provides an integral metric that, similar to the other, higher penetrance, MMR proteins MSH2, MLH1 and MSH6, can be incorporated into the upcoming criteria for MMR gene VUS classification of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP). This will represent a seminal step forward in enabling personalized healthcare for individuals suspected of LS and their relatives.

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