scholarly journals Clinicopathological Features and Management of Cancers in Lynch Syndrome

2012 ◽  
Vol 2012 ◽  
pp. 1-6 ◽  
Author(s):  
Markku Aarnio
Keyword(s):  
Endometrial Cancer ◽  
Lynch Syndrome ◽  
Autosomal Dominant ◽  
Clinicopathological Features ◽  
Genetic Diagnostics ◽  
Dominant Inheritance ◽  
Prophylactic Colectomy ◽  
Dna Mismatch ◽  
Mmr Genes ◽  
Increased Risk

Lynch syndrome (LS) is characterized by an autosomal dominant inheritance of the early onset of colorectal cancer (CRC) and endometrial cancer, as well as increased risk for several other cancers including gastric, urinary tract, ovarian, small bowel, biliary tract, and brain tumors. The syndrome is due to a mutation in one of the four DNA mismatch repair (MMR) genes MLH1, MSH2, MSH6, or PMS2. The majority of LS patients and families can now be identified, and the underlying mutation detected using genetic diagnostics. Regular surveillance for CRC and endometrial cancer has proved beneficial for mutation carriers. However, screening for other tumors is also recommended even though experiences in the screening of these tumors is limited. Prophylactic colectomy, prophylactic hysterectomy, and bilateral salpingo-oophorectomy may be reasonable options for selected patients with LS. This paper describes the features and management of LS.

scholarly journals Novel Mutations inMLH1andMSH2Genes in Mexican Patients with Lynch Syndrome

2016 ◽  
Vol 2016 ◽  
pp. 1-6 ◽  
Author(s):  
Jose Miguel Moreno-Ortiz ◽  
María de la Luz Ayala-Madrigal ◽  
Jorge Román Corona-Rivera ◽  
Manuel Centeno-Flores ◽  
Víctor Maciel-Gutiérrez ◽  
...  
Keyword(s):  
Lynch Syndrome ◽  
High Performance ◽  
Autosomal Dominant ◽  
Immunohistochemical Analysis ◽  
Compound Heterozygous ◽  
Nuclear Staining ◽  
Dna Mismatch ◽  
Two Samples ◽  
Early Onset Colorectal Cancer ◽  
Mexican Patients

Background. Lynch Syndrome (LS) is characterized by germline mutations in the DNA mismatch repair (MMR) genesMLH1,MSH2,MSH6,andPMS2. This syndrome is inherited in an autosomal dominant pattern and is characterized by early onset colorectal cancer (CRC) and extracolonic tumors. The aim of this study was to identify mutations inMMRgenes in three Mexican patients with LS.Methods. Immunohistochemical analysis was performed as a prescreening method to identify absent protein expression. PCR, Denaturing High Performance Liquid Chromatography (dHPLC), and Sanger sequencing complemented the analysis.Results. Two samples showed the absence of nuclear staining for MLH1 and one sample showed loss of nuclear staining for MSH2. The mutations found inMLH1gene were c.2103+1G>C in intron 18 and compound heterozygous mutants c.1852_1854delAAG (p.K618del) and c.1852_1853delinsGC (p.K618A) in exon 16. In theMSH2gene, we identified mutation c.638dupT (p.L213fs) in exon 3.Conclusions. This is the first report of mutations in MMR genes in Mexican patients with LS and these appear to be novel.

Prevalence and molecular characteristics of DNA mismatch repair deficient endometrial cancer in a Japanese hospital-based population

2020 ◽  
Vol 51 (1) ◽  
pp. 60-69 ◽  
Author(s):  
Azusa Yamamoto ◽  
Tatsuro Yamaguchi ◽  
Okihide Suzuki ◽  
Tetsuya Ito ◽  
Noriyasu Chika ◽  
...  
Keyword(s):  
Endometrial Cancer ◽  
Lynch Syndrome ◽  
Mismatch Repair ◽  
Dna Mismatch Repair ◽  
Molecular Characteristics ◽  
Variant Of Uncertain Significance ◽  
Dna Mismatch ◽  
Germline Variant ◽  
Uncertain Significance ◽  
Repair Genes

Abstract Background The prevalence and molecular characteristics of defective DNA mismatch repair endometrial cancers in the Japanese population have been underexplored. Data supporting clinical management of patients with Lynch-like syndrome and germline variant of uncertain significance of mismatch repair genes are still lacking. Methods Immunohistochemistry of mismatch repair proteins (MLH1, MSH2, MSH6 and PMS2) was performed on formalin-fixed paraffin-embedded sections prepared from resected primary endometrial cancers in 395 women with a median age of 59 years. Genetic and/or epigenetic alterations of the mismatch repair genes were also investigated. Results Loss of expression of one or more mismatch repair proteins was observed in 68 patients (17.2%). A total of 17 out of 68 patients (25%, 4.3% of all cases) were identified as candidates for genetic testing for Lynch syndrome after excluding 51 patients with MLH1 hypermethylated cancer. Fourteen of these 17 patients subjected to genetic testing were found to have Lynch syndrome (n = 5), germline variant of uncertain significance (n = 2) or Lynch-like syndrome (n = 7). Compared with patients with Lynch syndrome, those with germline variant of uncertain significance and Lynch-like syndrome tended to demonstrate an older age at the time of endometrial cancer diagnosis (P = 0.07), less fulfillment of the revised Bethesda guidelines (P = 0.09) and lower prevalence of Lynch syndrome-associated tumors in their first-degree relatives (P = 0.01). Conclusions This study provides useful information for management in patients with DNA mismatch repair endometrial cancer. Specifically, cancer surveillance as recommended in patients with Lynch syndrome might not be necessary in patients with germline variant of uncertain significance and Lynch-like syndrome and their relatives.

scholarly journals Differential diagnosis of small bowel occlusions

2009 ◽  
Vol 3 (2) ◽  
pp. 81-87
Author(s):  
Paolo Ghiringhelli
Keyword(s):  
Colorectal Cancer ◽  
Differential Diagnosis ◽  
Lynch Syndrome ◽  
Hereditary Nonpolyposis Colorectal Cancer ◽  
Autosomal Dominant ◽  
Age At Onset ◽  
Clinical Manifestations ◽  
Early Age ◽  
Increased Risk ◽  
Hereditary Nonpolyposis

Hereditary nonpolyposis colorectal cancer (HNPCC), also known as Lynch syndrome, is a common autosomal dominant syndrome characterized by early age at onset, and microsatellite instability (MSI). Patients with Lynch syndrome have a markedly increased risk of colorectal cancer. We report a case of a 28-year-old male with Lynch syndrome; the case allows to describe clinical manifestations and diagnostic criteria of this syndrome, and to underline the importance of genetics in the diagnosis of this disease.

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 A tumor association to be aware: endometrial cancer and colon cancer in relation to lynch syndrome

2022 ◽  
Author(s):  
Behyamet Onka ◽  
Daoud ali Mohamed ◽  
Romeo Thierry Tessi Yehouenou ◽  
Boris Adeyemi ◽  
Wend-Yam Mohammed Traore ◽  
...  
Keyword(s):  
Endometrial Cancer ◽  
Molecular Biology ◽  
Lynch Syndrome ◽  
Genetic Disorder ◽  
Repair System ◽  
Dna Mismatch ◽  
Dna Mismatch Repair System ◽  
Mismatch Repair System ◽  
Mutl Homolog 1 ◽  
Tumor Association

lynch syndrome (LS) is an autosomal dominant genetic disorder with incomplete penetration caused by a germline mutation in one of the genes of the deoxyribonucleic acid (DNA) mismatch repair system (MMR) namely: mutL homolog 1 (MLH1), mutS homolog 2 (MSH2), mutS homolog 6 (MHS6), post-meiotic segregation increased 1 homolog 2 (PMS2) or the EpCAM (Epithelial CellAdhesionMolecule) gene, which causes the inactivation of MSH2. Patients with this syndrome have a high relative risk of developing cancers at a young age, led by colorectal cancer (CRC) and endometrial cancer in females. The diagnosis is suspected when the patient’s personal and family history meets the Amsterdam or Bethesda criteria. It is guided by immunohistochemistry (IHC) and/or molecular biology that show loss of expression of one or more proteins of the MMR system and microsatellite instability on tumor DNA. In case of positive IHC and/or molecular biology, the patient should be referred to an oncogenetic consultation for a definitive diagnosis. We present the case of a 49-year-old patient who presented an anaemic syndrome in metrorrhagia. After a clinical, imaging, biological and anatomopathological examination, the diagnosis of LS was made.

Genetic identification and characterization of Lynch syndrome in a multi-ethnic biobank.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 1520-1520
Author(s):  
Rachel Rosenblum ◽  
Sabrina A. Suckiel ◽  
Gillian M. Belbin ◽  
Sinead Cullina ◽  
Judy H. Cho ◽  
...  
Keyword(s):  
Lynch Syndrome ◽  
Diagnostic Criteria ◽  
Sequence Data ◽  
Genetic Identification ◽  
European Ancestry ◽  
Gene Variants ◽  
Loss Of Function ◽  
Mmr Genes ◽  
Pathogenic Variants ◽  
Increased Risk

1520 Background: Lynch syndrome (LS), caused by germline pathogenic variants in mismatch repair (MMR) genes, results in increased risk of colorectal, endometrial, and other cancers. LS has a prevalence of ~1 in 440 in European ancestry populations; prevalence data in other populations are limited. We identified and characterized carriers of pathogenic MMR gene variants in the multi-ethnic Bio Me Biobank in New York City. Methods: Exome sequence data from ~31,000 Bio Me participants were evaluated for known (per ClinVar) and predicted (loss-of-function) pathogenic variants in MMR genes. Population groups were defined by genetic ancestry. Participant questionnaires and electronic health records (EHRs) of carriers were reviewed for personal or family history of malignancy. Results: We identified 48 carriers of 33 distinct pathogenic variants in PMS2 (48%), MLH1 (27%), MSH6 (15%), and MSH2 (10%), for an estimated prevalence of ~1/640 in the Bio Me Biobank. Prevalence was higher among individuals of Non-Jewish European (N = 14; 1/400) and African (N = 14; 1/490) ancestries, compared to Puerto Rican (N = 8; 1/640), Ashkenazi Jewish (N = 6; 1/690), and other/mixed (N = 6) ancestries. Carriers had a median age of 56 (range 27 to 77) years and were 50% female. Overall rate of malignancy among carriers was 38%, with the lowest rate in PMS2 (26%) and the highest rate in MSH6 (57%) variant carriers. We found a high prevalence of endometrial cancer (21% of female carriers) and a lower prevalence of colorectal cancer (4% of all carriers). Only 2 carriers (4%) had a diagnosis of LS in their EHRs, and only 1 carrier met Amsterdam diagnostic criteria for LS. Conclusions: These data show that ~0.15% of participants in a multi-ethnic biobank are carriers of pathogenic MMR gene variants and suggest that the prevalence is higher in European and lower in non-European ancestry populations. Notably, most carriers do not have a clinical diagnosis of LS and do not meet diagnostic criteria for LS. Carriers demonstrate variable rates of cancer, which may contribute to under-diagnosis of LS. Genomic screening for pathogenic MMR variants may lead to earlier diagnosis of LS and improved outcomes.

scholarly journals Cancer Risks for PMS2-Associated Lynch Syndrome

2018 ◽  
Vol 36 (29) ◽  
pp. 2961-2968 ◽  
Author(s):  
Sanne W. ten Broeke ◽  
Heleen M. van der Klift ◽  
Carli M.J. Tops ◽  
Stefan Aretz ◽  
Inge Bernstein ◽  
...  
Keyword(s):  
Endometrial Cancer ◽  
General Population ◽  
Lynch Syndrome ◽  
Cumulative Risk ◽  
Large Data ◽  
Cancer Site ◽  
Data Set ◽  
Pathogenic Variants ◽  
Mutation Carriers ◽  
Increased Risk

Purpose Lynch syndrome due to pathogenic variants in the DNA mismatch repair genes MLH1, MSH2, and MSH6 is predominantly associated with colorectal and endometrial cancer, although extracolonic cancers have been described within the Lynch tumor spectrum. However, the age-specific cumulative risk (penetrance) of these cancers is still poorly defined for PMS2-associated Lynch syndrome. Using a large data set from a worldwide collaboration, our aim was to determine accurate penetrance measures of cancers for carriers of heterozygous pathogenic PMS2 variants. Methods A modified segregation analysis was conducted that incorporated both genotyped and nongenotyped relatives, with conditioning for ascertainment to estimates corrected for bias. Hazard ratios (HRs) and corresponding 95% CIs were estimated for each cancer site for mutation carriers compared with the general population, followed by estimation of penetrance. Results In total, 284 families consisting of 4,878 first- and second-degree family members were included in the analysis. PMS2 mutation carriers were at increased risk for colorectal cancer (cumulative risk to age 80 years of 13% [95% CI, 7.9% to 22%] for males and 12% [95% CI, 6.7% to 21%] for females) and endometrial cancer (13% [95% CI, 7.0%–24%]), compared with the general population (6.6%, 4.7%, and 2.4%, respectively). There was no clear evidence of an increased risk of ovarian, gastric, hepatobiliary, bladder, renal, brain, breast, prostate, or small bowel cancer. Conclusion Heterozygous PMS2 mutation carriers were at small increased risk for colorectal and endometrial cancer but not for any other Lynch syndrome–associated cancer. This finding justifies that PMS2-specific screening protocols could be restricted to colonoscopies. The role of risk-reducing hysterectomy and bilateral salpingo-oophorectomy for PMS2 mutation carriers needs further discussion.

scholarly journals DNA Mismatch Repair Protein Immunohistochemistry and MLH1 Promotor Methylation Testing for Practical Molecular Classification and the Prediction of Prognosis in Endometrial Cancer

Cancers ◽  
2018 ◽  
Vol 10 (9) ◽  
pp. 279 ◽  
Author(s):  
Jisup Kim ◽  
Jin Kong ◽  
Wookyeom Yang ◽  
Hanbyoul Cho ◽  
Doo Chay ◽  
...  
Keyword(s):  
Endometrial Cancer ◽  
Lynch Syndrome ◽  
Mismatch Repair ◽  
Promoter Methylation ◽  
Molecular Classification ◽  
Clinicopathologic Features ◽  
Immune Markers ◽  
Dna Mismatch ◽  
Sporadic Cancer ◽  
Mmr Deficiency

The incidence of endometrial cancer is rapidly increasing worldwide, and its molecular classification has gained importance for new therapeutic approaches. This study sought to examine the clinicopathologic features and immune markers associated with the DNA mismatch repair (MMR) status and MLH1 promoter methylation status of endometrial cancer patients. A total of 173 patients with primary endometrial cancer who had received a hysterectomy were evaluated for four MMR proteins (MLH1, MSH2, MSH6, and PMS2), immune markers (CD8, programmed cell death protein 1 (PD-1), and programmed death-ligand 1 (PD-L1)) and p53 by immunohistochemistry (IHC), followed by an MLH1 methylation test. Patients were classified into MMR deficiency or proficiency, sporadic cancer, or probable Lynch syndrome (PLS), and the clinicopathologic features (including the expression of peritumoral immune markers) and prognosis of each group were compared. Patients with MMR deficiency or PLS showed an increase in immune markers compared those with MMR proficiency or sporadic cancer, respectively, and PLS demonstrated higher immune marker expression than MLH1 promoter methylation. Regarding prognosis, patients with MMR deficiency showed significant adverse overall survival (OS) when in stages I and II. Practical molecular classifications based on p53 staining results, in addition to MMR or PLS status, revealed an increased predictive ability for OS compared with the European Society of Medical Oncologists (ESMO) risk groups. The results of this study suggest that PLS may be a better candidate for an immune checkpoint inhibitor than MMR deficiency. The practical molecular classification contributes not only to the screening of Lynch syndrome, but also assists in predicting the prognosis in endometrial cancer.

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 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.

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