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Genetics in Medicine : Official Journal... May 2022Lynch syndrome (LS) is the most common hereditary colorectal cancer (CRC) syndrome, with an estimated prevalence of 2% to 3% of CRC. A prevalence study is needed to... (Meta-Analysis)
Meta-Analysis Review
PURPOSE
Lynch syndrome (LS) is the most common hereditary colorectal cancer (CRC) syndrome, with an estimated prevalence of 2% to 3% of CRC. A prevalence study is needed to provide accurate estimates of the true prevalence of LS.
METHODS
MEDLINE (Ovid), Embase, and Web of Science were searched. Prevalence was calculated by random effects meta-analysis models. I score was used to assess heterogeneity across studies. Meta-regression was performed for between-study variance.
RESULTS
A total of 51 studies were included in this review. The overall pooled yield of LS screening was 2.2% based on all methods of detection. Studies performing germline tests on all participants with CRC reported higher prevalence (5.1%) as opposed to studies only performing germline tests on participants with tumors with mismatch repair deficiency (1.6%) or microsatellite instability (1.1%). Selected cohorts of CRC had a higher prevalence of germline LS diagnoses.
CONCLUSION
LS prevalence across multiple ethnic, geographic, and clinical populations is remarkably similar. Universal germline testing of patients presenting with cancer identifies that most CRCs are attributed to LS. Young patients presenting with CRC and those who fulfill criteria for a familial risk provide the highest returns for LS identification. Our study supports the universal germline CRC screening for LS.
Topics: Colorectal Neoplasms; Colorectal Neoplasms, Hereditary Nonpolyposis; DNA Mismatch Repair; Humans; Microsatellite Instability; Prevalence
PubMed: 35177335
DOI: 10.1016/j.gim.2022.01.014 -
Cancer Science May 2023Advances in molecular diagnostics have led to improved diagnosis and molecular understanding of hereditary cancers in the clinic. Improving the management, treatment,... (Review)
Review
Advances in molecular diagnostics have led to improved diagnosis and molecular understanding of hereditary cancers in the clinic. Improving the management, treatment, and potential prevention of cancers in carriers of predisposing mutations requires preclinical experimental models that reflect the key pathogenic features of the specific syndrome associated with the mutations. Numerous genetically engineered mouse (GEM) models of hereditary cancer have been developed. In this review, we describe the models of Lynch syndrome and hereditary breast and ovarian cancer syndrome, the two most common hereditary cancer predisposition syndromes. We focus on Lynch syndrome models as illustrative of the potential for using mouse models to devise improved approaches to prevention of cancer in a high-risk population. GEM models are an invaluable tool for hereditary cancer models. Here, we review GEM models for some hereditary cancers and their potential use in cancer prevention studies.
Topics: Humans; Female; Animals; Mice; Colorectal Neoplasms, Hereditary Nonpolyposis; Genetic Predisposition to Disease; Neoplastic Syndromes, Hereditary; Hereditary Breast and Ovarian Cancer Syndrome; Mutation
PubMed: 36715493
DOI: 10.1111/cas.15737 -
The Lancet. Oncology Jul 2021Existing clinical practice guidelines for carriers of pathogenic variants of DNA mismatch repair genes (Lynch syndrome) are based on the mean age-specific cumulative...
BACKGROUND
Existing clinical practice guidelines for carriers of pathogenic variants of DNA mismatch repair genes (Lynch syndrome) are based on the mean age-specific cumulative risk (penetrance) of colorectal cancer for all carriers of pathogenic variants in the same gene. We aimed to estimate the variation in the penetrance of colorectal cancer between carriers of pathogenic variants in the same gene by sex and continent of residence.
METHODS
In this retrospective cohort study, we sourced data from the International Mismatch Repair Consortium, which comprises 273 members from 122 research centres or clinics in 32 countries from six continents who are involved in Lynch syndrome research. Families with at least three members and at least one confirmed carrier of a pathogenic or likely pathogenic variant in a DNA mismatch repair gene (MLH1, MSH2, MSH6, or PMS2) were included. The families of probands with known de-novo pathogenic variants were excluded. Data were collected on the method of ascertainment of the family, sex, carrier status, cancer diagnoses, and ages at the time of pedigree collection and at last contact or death. We used a segregation analysis conditioned on ascertainment to estimate the mean penetrance of colorectal cancer and modelled unmeasured polygenic factors to estimate the variation in penetrance. The existence of unknown familial risk factors modifying colorectal cancer risk for Lynch syndrome carriers was tested by use of a Wald p value for the null hypothesis that the polygenic SD is zero.
FINDINGS
5585 families with Lynch syndrome from 22 countries were eligible for the analysis. Of these, there were insufficient numbers to estimate penetrance for Asia and South America, and for those with EPCAM variants. Therefore, we used data (collected between July 11, 2014, and Dec 31, 2018) from 5255 families (1829 MLH1, 2179 MSH2, 798 MSH6, and 449 PMS2), comprising 79 809 relatives, recruited in 15 countries in North America, Europe, and Australasia. There was strong evidence of the existence of unknown familial risk factors modifying colorectal cancer risk for Lynch syndrome carriers (p<0·0001 for each of the three three continents). These familial risk factors resulted in a wide within-gene variation in the risk of colorectal cancer for men and women from each continent who all carried pathogenic variants in the same gene or the MSH2 c.942+3A>T variant. The variation was especially prominent for MLH1 and MSH2 variant carriers, depending on gene, sex and continent, with 7-56% of carriers having a colorectal cancer penetrance of less than 20%, 9-44% having a penetrance of more than 80%, and only 10-19% having a penetrance of 40-60%.
INTERPRETATION
Our study findings highlight the important role of risk modifiers, which could lead to personalised risk assessments for precision prevention and early detection of colorectal cancer for people with Lynch syndrome.
FUNDING
National Health and Medical Research Council, Australia.
Topics: Adult; Age Factors; Colorectal Neoplasms, Hereditary Nonpolyposis; Female; Gene-Environment Interaction; Genetic Predisposition to Disease; Heredity; Humans; Male; Middle Aged; Pedigree; Phenotype; Residence Characteristics; Retrospective Studies; Risk Assessment; Risk Factors; Sex Factors
PubMed: 34111421
DOI: 10.1016/S1470-2045(21)00189-3 -
Genes Nov 2022Lynch syndrome (LS) is the most common cause of hereditary colorectal cancers (CRC) and is associated with an increased risk for ovarian and endometrial cancers. There...
Lynch syndrome (LS) is the most common cause of hereditary colorectal cancers (CRC) and is associated with an increased risk for ovarian and endometrial cancers. There is lack of knowledge on the epidemiology of LS in the non-Caucasian populations especially in Qatar. The aim of this retrospective study is to explore the prevalence of LS in a selected high-risk cohort in the State of Qatar in addition to investigating the frequency and genotype-phenotype correlation associated with mismatch repair genes pathogenic variants. Retrospective review of medical records of 31 individuals with LS, 20 affected with colorectal cancer and 11 unaffected with family history of cancers, referred from January 2017 until August 2020. The prevalence of LS among affected and unaffected patients is 22% (20/92) and 2.2% respectively. Among affected individuals, and genes were highly frequent while for unaffected individuals, a recurrent pathogenic variant was reported in several related individuals suggesting a tribal effect. This study highlights the epidemiology of LS in high-risk cohort in Qatar which helps to provide recommendations on genetic testing, and personalize surveillance and management programs.
Topics: Humans; Colorectal Neoplasms, Hereditary Nonpolyposis; Prevalence; Retrospective Studies; Qatar; Genetic Association Studies
PubMed: 36421850
DOI: 10.3390/genes13112176 -
Clinical Genetics Jul 2018DNA repair pathways are essential for cellular survival as our DNA is constantly under assault from both exogenous and endogenous DNA damaging agents. Five major... (Review)
Review
DNA repair pathways are essential for cellular survival as our DNA is constantly under assault from both exogenous and endogenous DNA damaging agents. Five major mammalian DNA repair pathways exist within a cell to maintain genomic integrity. Of these, the DNA mismatch repair (MMR) pathway is highly conserved among species and is well documented in bacteria. In humans, the importance of MMR is underscored by the discovery that a single mutation in any 1 of 4 genes within the MMR pathway (MLH1, MSH2, MSH6 and PMS2) results in Lynch syndrome (LS). LS is a autosomal dominant condition that predisposes individuals to a higher incidence of many malignancies including colorectal, endometrial, ovarian, and gastric cancers. In this review, we discuss the role of PMS2 in the MMR pathway, the evolving testing criteria used to identify variants in the PMS2 gene, the LS phenotype as well as the autosomal recessive condition called constitutional mismatch repair deficiency syndrome, and current methods used to elucidate the clinical impact of PMS2 mutations.
Topics: Alleles; Colorectal Neoplasms, Hereditary Nonpolyposis; DNA Mismatch Repair; Genetic Association Studies; Genetic Predisposition to Disease; Genetic Testing; Humans; Mismatch Repair Endonuclease PMS2; Mutation; Phenotype; Pseudogenes; Structure-Activity Relationship
PubMed: 29286535
DOI: 10.1111/cge.13205 -
Archives of Pathology & Laboratory... Oct 2011About 15% of colorectal cancers are characterized by genomic microsatellite instability, and of these, about 1 in 5 (2%-4% overall) are due to Lynch syndrome, a... (Review)
Review
CONTEXT
About 15% of colorectal cancers are characterized by genomic microsatellite instability, and of these, about 1 in 5 (2%-4% overall) are due to Lynch syndrome, a dominantly inherited condition predisposing the patient to cancers of multiple organ systems, including the gastrointestinal tract. Identification of individuals with Lynch syndrome allows for increased surveillance of the affected individual and of potentially affected family members.
OBJECTIVE
To review the literature on microsatellite instability in colorectal cancer and current laboratory diagnostic testing strategies for the detection of Lynch syndrome.
DATA SOURCES
This review is based on peer-reviewed literature, published guidelines from professional organizations (Evaluation of Genomic Applications in Practice and Prevention Working Group, National Comprehensive Cancer Network), and information from clinical laboratories performing microsatellite instability testing.
CONCLUSIONS
Universal screening for Lynch syndrome in all individuals affected with colorectal cancer has been recommended by the Evaluation of Genomic Applications in Practice and Prevention Working Group. Preliminary screening tests can identify individuals unlikely to be affected by Lynch syndrome, thereby reducing the need for full gene analysis. Immunohistochemistry and polymerase chain reaction-based tests for microsatellite instability have similar clinical sensitivity and specificity, and each method has advantages and limitations. BRAF and MLH1 methylation testing are useful reflex tests for those with a defect in MLH1 identified by immunohistochemistry. Emerging technologies, such as high-throughput sequencing, may substantially affect diagnostic algorithms in the future.
Topics: Adaptor Proteins, Signal Transducing; Algorithms; Colorectal Neoplasms; Colorectal Neoplasms, Hereditary Nonpolyposis; DNA Methylation; DNA Mismatch Repair; Genetic Testing; Germ-Line Mutation; Humans; Immunohistochemistry; Microsatellite Instability; MutL Protein Homolog 1; Nuclear Proteins; Proto-Oncogene Proteins B-raf
PubMed: 21970482
DOI: 10.5858/arpa.2011-0035-RA -
Clinical Cancer Research : An Official... Jan 2022Lynch syndrome is defined by germline pathogenic mutations involving DNA mismatch repair (MMR) genes and linked with the development of MMR-deficient colon and...
PURPOSE
Lynch syndrome is defined by germline pathogenic mutations involving DNA mismatch repair (MMR) genes and linked with the development of MMR-deficient colon and endometrial cancers. Whether breast cancers developing in the context of Lynch syndrome are causally related to MMR deficiency (MMRd), remains controversial. Thus, we explored the morphologic and genomic characteristics of breast cancers occurring in Lynch syndrome individuals.
EXPERIMENTAL DESIGN
A retrospective analysis of 20,110 patients with cancer who underwent multigene panel genetic testing was performed to identify individuals with a likely pathogenic/pathogenic germline variant in , , , or who developed breast cancers. The histologic characteristics and IHC assessment of breast cancers for MMR proteins and programmed death-ligand 1 (PD-L1) expression were assessed on cases with available materials. DNA samples from paired tumors and blood were sequenced with Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (≥468 key cancer genes). Microsatellite instability (MSI) status was assessed utilizing MSISensor. Mutational signatures were defined using SigMA.
RESULTS
A total of 272 individuals with Lynch syndrome were identified, 13 (5%) of whom had primary breast cancers. The majority of breast cancers (92%) were hormone receptor-positive tumors. Five (42%) of 12 breast cancers displayed loss of MMR proteins by IHC. Four (36%) of 11 breast cancers subjected to tumor-normal sequencing showed dominant MSI mutational signatures, high tumor mutational burden, and indeterminate (27%) or high MSISensor scores (9%). One patient with metastatic MMRd breast cancer received anti-PD1 therapy and achieved a robust and durable response.
CONCLUSIONS
A subset of breast cancers developing in individuals with Lynch syndrome are etiologically linked to MMRd and may benefit from anti-PD1/PD-L1 immunotherapy.
Topics: Breast Neoplasms; Colorectal Neoplasms, Hereditary Nonpolyposis; DNA Mismatch Repair; Female; Germ-Line Mutation; Humans; Microsatellite Instability; MutL Protein Homolog 1; Retrospective Studies
PubMed: 34667028
DOI: 10.1158/1078-0432.CCR-21-2027 -
Gynecologic Oncology Jul 2009Lynch syndrome is a heritable, cancer susceptibility syndrome. This study aims to review current and emerging trends in the identification of Lynch syndrome in the... (Review)
Review
OBJECTIVE
Lynch syndrome is a heritable, cancer susceptibility syndrome. This study aims to review current and emerging trends in the identification of Lynch syndrome in the endometrial cancer patient population.
METHODS
We performed a comprehensive review of past and present screening algorithms for Lynch syndrome, including a review of the utility of both the Amsterdam criteria and Bethesda guidelines. Because non-colon cancers have historically not been the focus of Lynch syndrome research, current literature is ripe with questions regarding screening among this patient population. Low BMI, age less than 50, positive family history and pathologic features have all been identified as risk factors in endometrial cancer patients who might benefit from Lynch screening. Additionally, based on experience at our own institution we offer a feasible screening algorithm for these patients.
RESULTS
A comprehensive review of the data demonstrated that immunohistochemistry is becoming an efficient, inexpensive way to screen tumors at risk for mismatch repair deficiency. The sensitivity and specificity of immunohistochemistry for predicting Lynch syndrome approaches 100%. Ideally, prospective screening of all endometrial cancer patients with IHC is a feasible, cost-efficient way to detect Lynch in this patient population given the limitations of using personal/family history of malignancy as well as pathologic risk factors.
CONCLUSION
It is imperative that clinicians be mindful of the risk of Lynch syndrome in women with endometrial cancer. Given the opportunity for colon cancer screening and prevention strategies to be initiated, the identification of probands with endometrial cancer as a result of Lynch syndrome will lead to a reduction in morbidity and mortality for these patients and their families.
Topics: Algorithms; Colorectal Neoplasms, Hereditary Nonpolyposis; Endometrial Neoplasms; Female; Genetic Predisposition to Disease; Humans; Immunohistochemistry; Mass Screening; Predictive Value of Tests; Public Health; Sensitivity and Specificity
PubMed: 19375789
DOI: 10.1016/j.ygyno.2009.03.003 -
European Journal of Oncology Nursing :... Jun 2022Lynch Syndrome is one of the most common hereditary cancer syndromes, arising from DNA mismatch repair. Lynch Syndrome carriers are at increased lifetime risk of...
PURPOSE
Lynch Syndrome is one of the most common hereditary cancer syndromes, arising from DNA mismatch repair. Lynch Syndrome carriers are at increased lifetime risk of developing certain cancers, such as colorectal and endometrial. This increased risk can result in adverse psychological outcomes. The present qualitative study explores the experiences of individuals with Lynch Syndrome when accessing and managing healthcare in the period after learning of their Lynch Syndrome status.
METHODS
Twelve interviews were conducted with Lynch Syndrome carriers in Ireland, with recruitment occurring predominantly online through closed social media platforms. This was coordinated by Lynch Syndrome Ireland, a patient representative group. Reflexive thematic analysis was used to analyse the data. There was significant Public and Patient Involvement in this study, with the committee members (N = 2) of Lynch Syndrome Ireland acting on the panel. The involvement of the PPI panel began from initial project idea conception and continued throughout the study.
RESULTS
Lynch Syndrome carriers highlighted the lack of adequate information from medical professionals regarding their diagnosis. Furthermore, participants spoke of the significant lack of knowledge amongst medical professionals about Lynch Syndrome. A theme depicting guilt was also noted regarding passing Lynch Syndrome to their children, and the worry experienced when children underwent genetic testing.
CONCLUSIONS
This study highlighted the experiences of having a Lynch Syndrome diagnosis and demonstrates a need for further psychological and medical support for the Lynch Syndrome community, including a clear need for improvements in genetic cancer services in this field.
Topics: Child; Colorectal Neoplasms, Hereditary Nonpolyposis; DNA Mismatch Repair; Humans; Ireland
PubMed: 35306248
DOI: 10.1016/j.ejon.2022.102117 -
BMJ Open Dec 2021To assess clinicopathological predictors and prognosis in early-onset colorectal cancer (CRC) in Lynch syndrome with comparison to patients diagnosed from age 40 and up.
OBJECTIVE
To assess clinicopathological predictors and prognosis in early-onset colorectal cancer (CRC) in Lynch syndrome with comparison to patients diagnosed from age 40 and up.
DESIGN
National, retrospective register-based case-control study.
SETTING
Danish national hereditary CRC register.
PARTICIPANTS
Individuals with Lynch syndrome diagnosed with CRC from January 1950 to June 2020. The analysis was based on 215 early-onset CRCs diagnosed between 15 and 39 years of age and 574 CRCs diagnosed at age 40-88 years.
MAIN OUTCOME MEASURES
Clinical and histopathological characteristics and survival. Confounding variables were analysed by Cox analysis.
RESULTS
27.2% of the tumours in the Danish Lynch syndrome cohort were diagnosed under age 40. Disease-predisposing alterations in and were overrepresented in the age 15-39 cohort compared with patients diagnosed over age 40. CRCs diagnosed under age 40 showed an adverse stage distribution with 36.2% stage III-IV tumours compared with 25.8% in the over age 40 group. However, young patients diagnosed with early-stage tumours did have a significantly better prognosis compared with early-stage tumours in the older age group.
CONCLUSIONS
Early-onset CRC in Lynch syndrome is primarily linked to alterations in and and displays an adverse stage distribution. These observations serve as a reminder of surveillance, symptom awareness and rapid diagnostic handling of CRC in young adults with Lynch syndrome.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Case-Control Studies; Colorectal Neoplasms; Colorectal Neoplasms, Hereditary Nonpolyposis; DNA Mismatch Repair; Denmark; Humans; Middle Aged; MutL Protein Homolog 1; Retrospective Studies; Young Adult
PubMed: 34911717
DOI: 10.1136/bmjopen-2021-053538