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Health Technology Assessment... Sep 2017Inherited mutations in deoxyribonucleic acid (DNA) mismatch repair (MMR) genes lead to an increased risk of colorectal cancer (CRC), gynaecological cancers and other... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Inherited mutations in deoxyribonucleic acid (DNA) mismatch repair (MMR) genes lead to an increased risk of colorectal cancer (CRC), gynaecological cancers and other cancers, known as Lynch syndrome (LS). Risk-reducing interventions can be offered to individuals with known LS-causing mutations. The mutations can be identified by comprehensive testing of the MMR genes, but this would be prohibitively expensive in the general population. Tumour-based tests - microsatellite instability (MSI) and MMR immunohistochemistry (IHC) - are used in CRC patients to identify individuals at high risk of LS for genetic testing. (MutL homologue 1) promoter methylation and V600E testing can be conducted on tumour material to rule out certain sporadic cancers.
OBJECTIVES
To investigate whether testing for LS in CRC patients using MSI or IHC (with or without promoter methylation testing and V600E testing) is clinically effective (in terms of identifying Lynch syndrome and improving outcomes for patients) and represents a cost-effective use of NHS resources.
REVIEW METHODS
Systematic reviews were conducted of the published literature on diagnostic test accuracy studies of MSI and/or IHC testing for LS, end-to-end studies of screening for LS in CRC patients and economic evaluations of screening for LS in CRC patients. A model-based economic evaluation was conducted to extrapolate long-term outcomes from the results of the diagnostic test accuracy review. The model was extended from a model previously developed by the authors.
RESULTS
Ten studies were identified that evaluated the diagnostic test accuracy of MSI and/or IHC testing for identifying LS in CRC patients. For MSI testing, sensitivity ranged from 66.7% to 100.0% and specificity ranged from 61.1% to 92.5%. For IHC, sensitivity ranged from 80.8% to 100.0% and specificity ranged from 80.5% to 91.9%. When tumours showing low levels of MSI were treated as a positive result, the sensitivity of MSI testing increased but specificity fell. No end-to-end studies of screening for LS in CRC patients were identified. Nine economic evaluations of screening for LS in CRC were identified. None of the included studies fully matched the decision problem and hence a new economic evaluation was required. The base-case results in the economic evaluation suggest that screening for LS in CRC patients using IHC, V600E and promoter methylation testing would be cost-effective at a threshold of £20,000 per quality-adjusted life-year (QALY). The incremental cost-effectiveness ratio for this strategy was £11,008 per QALY compared with no screening. Screening without tumour tests is not predicted to be cost-effective.
LIMITATIONS
Most of the diagnostic test accuracy studies identified were rated as having a risk of bias or were conducted in unrepresentative samples. There was no direct evidence that screening improves long-term outcomes. No probabilistic sensitivity analysis was conducted.
CONCLUSIONS
Systematic review evidence suggests that MSI- and IHC-based testing can be used to identify LS in CRC patients, although there was heterogeneity in the methods used in the studies identified and the results of the studies. There was no high-quality empirical evidence that screening improves long-term outcomes and so an evidence linkage approach using modelling was necessary. Key determinants of whether or not screening is cost-effective are the accuracy of tumour-based tests, CRC risk without surveillance, the number of relatives identified for cascade testing, colonoscopic surveillance effectiveness and the acceptance of genetic testing. Future work should investigate screening for more causes of hereditary CRC and screening for LS in endometrial cancer patients.
STUDY REGISTRATION
This study is registered as PROSPERO CRD42016033879.
FUNDING
The National Institute for Health Research Health Technology Assessment programme.
Topics: Colorectal Neoplasms, Hereditary Nonpolyposis; Cost-Benefit Analysis; DNA Mismatch Repair; Endometrial Neoplasms; England; Female; Genetic Testing; Humans; Microsatellite Instability; Quality-Adjusted Life Years
PubMed: 28895526
DOI: 10.3310/hta21510 -
Clinical and Translational... Jul 2017Approximately 35% of colorectal cancer (CRC) risk is attributable to heritable factors known hereditary syndromes, accounting for 6%. The remainder may be due to lower...
OBJECTIVES
Approximately 35% of colorectal cancer (CRC) risk is attributable to heritable factors known hereditary syndromes, accounting for 6%. The remainder may be due to lower penetrance polymorphisms particularly of DNA repair genes. DNA repair pathways, including base excision repair (BER), nucleotide excision repair (NER), mismatch repair (MMR), direct reversal repair (DRR), and double-strand break repair are complex, evolutionarily conserved, and critical in carcinogenesis. Germline mutations in these genes are associated with high-penetrance CRC syndromes such as Lynch syndrome. However, the association of low-penetrance polymorphisms of DNA repair genes with CRC risk remains unclear.
METHODS
A systematic literature review of PubMed, Embase, and HuGENet databases was conducted. Pre-specified criteria determined study inclusion/exclusion. Per-allele, pooled odds ratios disclosed the risk attributed to each variant. Heterogeneity was investigated by subgroup analyses for ethnicity and tumor location; funnel plots and Egger's test assessed publication bias.
RESULTS
Sixty-one polymorphisms in 26 different DNA repair genes were identified. Meta-analyses for 22 polymorphisms in 17 genes revealed that six polymorphisms were significantly associated with CRC risk within BER (APE1, PARP1), NER (ERCC5, XPC), double-strand break (RAD18), and DRR (MGMT), but none within MMR. Subgroup analyses revealed significant association of OGG1 rs1052133 with rectal cancer risk. Egger's test revealed no publication bias.
CONCLUSIONS
Low-penetrance polymorphisms in DNA repair genes alter susceptibility to CRC. Future studies should therefore analyze whole-genome polymorphisms and any synergistic effects on CRC risk.Translational impact:This knowledge may enhance CRC risk assessment and facilitate a more personalized approach to cancer prevention.
PubMed: 28749454
DOI: 10.1038/ctg.2017.35 -
Familial Cancer Jan 2018Lynch syndrome (LS) is a highly penetrant inherited cancer predisposition syndrome accounting for approximately 1000 cases of colorectal cancer (CRC) in the UK annually.... (Meta-Analysis)
Meta-Analysis
Lynch syndrome (LS) is a highly penetrant inherited cancer predisposition syndrome accounting for approximately 1000 cases of colorectal cancer (CRC) in the UK annually. LS is characterised by autosomal dominant inheritance and germline mutations in DNA mismatch repair genes. The penetrance is highly variable and the reasons for this have not been fully elucidated. This study investigates whether low penetrance genetic risk factors may result in phenotype modification in LS patients. To conduct a systematic literature review and meta-analysis to assess the association between low penetrance genetic risk modifiers and CRC in LS patients. A systematic review was conducted of the PubMed and HuGENet databases. Eligibility of studies was determined by pre-defined criteria. Included studies were analysed via the per-allele model and assessed by pooled odds ratios and establishing 95% confidence intervals. Study heterogeneity was assessed via Cochrane's Q statistic and I2 values. Publication bias was evaluated with funnel plots. Subgroup analysis was conducted on gender. Statistical software used was the Metafor package for the R programme version 3.1.3. Sixty-four polymorphisms were identified and sufficient data was available for analysis of ten polymorphisms, with between 279 and 1768 CRC cases per polymorphism. None demonstrated association with CRC risk in LS patients. However in sub-group analysis the polymorphism rs16892766 (8q23.3) was significant in males (OR 1.53, 95% CI 1.12-2.10). The variable phenotype presentation of the disease still remains largely unexplained, and further investigation is warranted. Other factors may also be influencing the high variability of the disease, such as environmental factors, copy number variants and epigenetic alterations. Investigation into these areas is needed as well as larger and more definitive studies of the polymorphisms analysed in this study.
Topics: Chromosomes, Human, Pair 8; Colorectal Neoplasms, Hereditary Nonpolyposis; DNA Copy Number Variations; DNA Mismatch Repair; Female; Genetic Predisposition to Disease; Germ-Line Mutation; Humans; Male; Penetrance; Polymorphism, Single Nucleotide; Sex Factors
PubMed: 28508326
DOI: 10.1007/s10689-017-9995-8 -
Pharmacogenomics and Personalized... 2017The emerging dual imperatives of personalized medicine and technologic advances make population screening for preventable conditions resulting from genetic alterations a... (Review)
Review
BACKGROUND
The emerging dual imperatives of personalized medicine and technologic advances make population screening for preventable conditions resulting from genetic alterations a realistic possibility. Lynch syndrome is a potential screening target due to its prevalence, penetrance, and the availability of well-established, preventive interventions. However, while population screening may lower incidence of preventable conditions, implementation without evidence may lead to unintentional harms. We examined the literature to determine whether evidence exists that screening for Lynch-associated mismatch repair (MMR) gene mutations leads to improved overall survival, cancer-specific survival, or quality of life. Documenting evidence and gaps is critical to implementing genomic approaches in public health and guiding future research.
MATERIALS AND METHODS
Our 2014-2015 systematic review identified studies comparing screening with no screening in the general population, and controlled studies assessing analytic validity of targeted next-generation sequencing, and benefits or harms of interventions or screening. We conducted meta-analyses for the association between early or more frequent colonoscopies and health outcomes.
RESULTS
Twelve studies met our eligibility criteria. No adequate evidence directly addressed the main question or the harms of screening in the general population. Meta-analyses found relative reductions of 68% for colorectal cancer incidence (relative risk: 0.32, 95% confidence interval: 0.23-0.43, three cohort studies, 590 participants) and 78% for all-cause mortality (relative risk: 0.22, 95% confidence interval: 0.09-0.56, three cohort studies, 590 participants) for early or more frequent colonoscopies among family members of people with cancer who also had an associated MMR gene mutation.
CONCLUSION
Inadequate evidence exists examining harms and benefits of population-based screening for Lynch syndrome. Lack of evidence highlights the need for data that directly compare benefits and harms.
PubMed: 28260941
DOI: 10.2147/PGPM.S123808 -
Health Technology Assessment... Sep 2014Lynch syndrome (LS) is an inherited autosomal dominant disorder characterised by an increased risk of colorectal cancer (CRC) and other cancers, and caused by mutations... (Review)
Review
BACKGROUND
Lynch syndrome (LS) is an inherited autosomal dominant disorder characterised by an increased risk of colorectal cancer (CRC) and other cancers, and caused by mutations in the deoxyribonucleic acid (DNA) mismatch repair genes.
OBJECTIVE
To evaluate the accuracy and cost-effectiveness of strategies to identify LS in newly diagnosed early-onset CRC patients (aged < 50 years). Cascade testing of relatives is employed in all strategies for individuals in whom LS is identified.
DATA SOURCES AND METHODS
Systematic reviews were conducted of the test accuracy of microsatellite instability (MSI) testing or immunohistochemistry (IHC) in individuals with CRC at risk of LS, and of economic evidence relating to diagnostic strategies for LS. Reviews were carried out in April 2012 (test accuracy); and in February 2012, repeated in February 2013 (economic evaluations). Databases searched included MEDLINE (1946 to April week 3, 2012), EMBASE (1980 to week 17, 2012) and Web of Science (inception to 30 April 2012), and risk of bias for test accuracy was assessed using the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) quality appraisal tool. A de novo economic model of diagnostic strategies for LS was developed.
RESULTS
Inconsistencies in study designs precluded pooling of diagnostic test accuracy results from a previous systematic review and nine subsequent primary studies. These were of mixed quality, with significant methodological concerns identified for most. IHC and MSI can both play a part in diagnosing LS but neither is gold standard. No UK studies evaluated the cost-effectiveness of diagnosing and managing LS, although studies from other countries generally found some strategies to be cost-effective compared with no testing. The de novo model demonstrated that all strategies were cost-effective compared with no testing at a threshold of £20,000 per quality-adjusted life-year (QALY), with the most cost-effective strategy utilising MSI and BRAF testing [incremental cost-effectiveness ratio (ICER) = £5491 per QALY]. The maximum health benefit to the population of interest would be obtained using universal germline testing, but this would not be a cost-effective use of NHS resources compared with the next best strategy. When the age limit was raised from 50 to 60 and 70 years, the ICERs compared with no testing increased but remained below £20,000 per QALY (except for universal germline testing with an age limit of 70 years). The total net health benefit increased with the age limit as more individuals with LS were identified. Uncertainty was evaluated through univariate sensitivity analyses, which suggested that the parameters substantially affecting cost-effectiveness: were the risk of CRC for individuals with LS; the average number of relatives identified per index patient; the effectiveness of colonoscopy in preventing metachronous CRC; the cost of colonoscopy; the duration of the psychological impact of genetic testing on health-related quality of life (HRQoL); and the impact of prophylactic hysterectomy and bilateral salpingo-oophorectomy on HRQoL (this had the potential to make all testing strategies more expensive and less effective than no testing).
LIMITATIONS
The absence of high-quality data for the impact of prophylactic gynaecological surgery and the psychological impact of genetic testing on HRQoL is an acknowledged limitation.
CONCLUSIONS
Results suggest that reflex testing for LS in newly diagnosed CRC patients aged < 50 years is cost-effective. Such testing may also be cost-effective in newly diagnosed CRC patients aged < 60 or < 70 years. Results are subject to uncertainty due to a number of parameters, for some of which good estimates were not identified. We recommend future research to estimate the cost-effectiveness of testing for LS in individuals with newly diagnosed endometrial or ovarian cancer, and the inclusion of aspirin chemoprevention. Further research is required to accurately estimate the impact of interventions on HRQoL.
STUDY REGISTRATION
This study is registered as PROSPERO CRD42012002436.
FUNDING
The National Institute for Health Research Health Technology Assessment programme.
Topics: Aged; Colorectal Neoplasms, Hereditary Nonpolyposis; Cost-Benefit Analysis; Genetic Testing; Humans; Middle Aged
PubMed: 25244061
DOI: 10.3310/hta18580 -
Breast Cancer Research : BCR Mar 2013Lynch syndrome is an autosomal dominantly inherited disorder of cancer susceptibility caused by germline mutations in the DNA mismatch repair (MMR) genes. Mutation... (Review)
Review
INTRODUCTION
Lynch syndrome is an autosomal dominantly inherited disorder of cancer susceptibility caused by germline mutations in the DNA mismatch repair (MMR) genes. Mutation carriers have a substantial burden of increased risks of cancers of the colon, rectum, endometrium and several other organs which generally occur at younger ages than for the general population. The issue of whether breast cancer risk is increased for MMR gene mutation carriers has been debated with evidence for and against this association.
METHODS
Using the PUBMED, we identified all relevant studies of breast cancer associated with Lynch syndrome that were published by 15 December 2012. In the review, we included: (i) molecular studies that reported microsatellite instability and/or immunohistochemistry in breast cancer tumors of MMR gene mutation carriers; and (ii) risk studies that investigated risk of breast cancer for confirmed MMR gene mutation carriers or families or clinically and/or pathologically defined Lynch syndrome families.
RESULTS
We identified 15 molecular studies and, when combined, observed 62 of 122 (51%; 95% CI 42 to 60%) breast cancers in MMR gene mutation carriers were MMR-deficient. Of the 21 risk studies identified, 13 did not observe statistical evidence for an association of breast cancer risk with Lynch syndrome while 8 studies found an increased risk of breast cancer ranging from 2- to 18-fold compared with the general population (or non-carriers). There is only one prospective study demonstrating an elevated risk of breast cancer for MMR gene mutation carriers compared with the general population (standardized incidence ratio 3.95; 95% CI 1.59, 8.13).
CONCLUSIONS
Since breast cancer is a relatively common disease in the general population, more precise estimates of risk and gene-specific risks will need to utilize large prospective cohort studies with a long follow-up. While current data are inconclusive at a population level, individual tumor testing results suggest that MMR deficiency is involved with breast cancers in some individuals with Lynch syndrome.
Topics: Breast Neoplasms; Colorectal Neoplasms, Hereditary Nonpolyposis; Female; Humans; Risk Factors
PubMed: 23510156
DOI: 10.1186/bcr3405 -
International Journal of Cancer Oct 2011Loss of mismatch repair (MMR) capacity may represent an important tumor initiating mechanism in ovarian cancer. We conducted a systematic review to analyze the frequency... (Review)
Review
Frequency of mismatch repair deficiency in ovarian cancer: a systematic review This article is a US Government work and, as such, is in the public domain of the United States of America.
Loss of mismatch repair (MMR) capacity may represent an important tumor initiating mechanism in ovarian cancer. We conducted a systematic review to analyze the frequency of microsatellite instability (MSI), immunohistochemical (IHC) staining for MMR proteins, and hypermethylation of the MLH1 promoter region in ovarian cancers. Studies examining MSI, loss of MMR gene expression by IHC staining and MLH1 promoter hypermethylation in ovarian cancer were identified by a systematic literature search of the PubMed electronic database through August 31, 2009. Pertinent data was extracted from eligible studies and estimates for pooled proportions were computed using random effects models. The pooled proportion of MSI detection was 0.10 (95% CI, 0.06-0.14) among 1,234 cases in 22 studies. Dinonucleotide markers had a higher frequency of instability than mononucleotide markers. The pooled proportion of MLH1 or MSH2 staining loss was 0.06 (95% CI, 0.01-0.17) among 474 cases in three studies, with a higher frequency of loss in MLH1. The pooled proportion of MLH1 methylation was 0.10 (95% CI, 0.06-0.15) among 672 cases in seven studies. Data reporting MSI and loss of MMR staining in the same cases was limited. Although MMR deficiency was found in all histologic subtypes, endometrioid cancers had the highest proportion. Approximately 10% of unselected ovarian cancers are related to MMR deficiency. While MMR deficiency is associated with improved survival in other MMR-deficiency related cancer sites, epidemiological and clinical factors related to the MMR-deficient phenotype have not been adequately studied in ovarian cancer to date.
Topics: Adaptor Proteins, Signal Transducing; DNA Methylation; DNA Mismatch Repair; Female; Humans; Microsatellite Instability; MutL Protein Homolog 1; MutS Homolog 2 Protein; Nuclear Proteins; Ovarian Neoplasms
PubMed: 21140452
DOI: 10.1002/ijc.25835 -
Clinical Cancer Research : An Official... Nov 2008A meta-analytic approach was used to estimate the frequency of: (a) microsatellite instability-high (MSI-H) phenotype in unselected ovarian cancers and (b) various... (Meta-Analysis)
Meta-Analysis Review
PURPOSE
A meta-analytic approach was used to estimate the frequency of: (a) microsatellite instability-high (MSI-H) phenotype in unselected ovarian cancers and (b) various histologic subtypes of mismatch repair (MMR)-deficient epithelial ovarian cancers.
METHODS
A systematic search of the Medline electronic database was conducted to identify articles published between January 1, 1966, and December 31, 2007, that examined MMR deficiency in ovarian cancers. Data were extracted on the study population, sample size, MSI-H frequency, and histology of MMR-deficient ovarian tumors.
RESULTS
The pooled proportion of MSI-H ovarian cancers was 0.12 [95% confidence interval (CI), 0.08-0.17] from 18 studies with 977 cases. The proportion of histologic subtypes in the pooled analysis from 15 studies with 159 cases was serous at 0.32 (95% CI, 0.20-0.44), mucinous at 0.19 (95% CI, 0.12-0.27), endometrioid at 0.29 (95% CI, 0.22-0.36), clear cell at 0.18 (95% CI, 0.09-0.28), and mixed at 0.24 (95% CI, 0.07-0.47). There was significant heterogeneity between studies.
CONCLUSIONS
The frequency of the MSI-H phenotype in unselected ovarian cancers approximates 12%. MMR-deficient ovarian cancers also seem to be characterized by an overrepresentation of nonserous histologic subtypes. Knowledge of histologic subtype may aid clinicians in identifying the relatively large proportion of ovarian cancers due to MMR defects; such knowledge has potential implications for medical management.
Topics: DNA Mismatch Repair; Female; Humans; Microsatellite Instability; Ovarian Neoplasms; Phenotype
PubMed: 18980979
DOI: 10.1158/1078-0432.CCR-08-1387