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Dermatology (Basel, Switzerland) 2021Increasing availability of panel testing for known high-penetrance familial melanoma genes has made it possible to improve risk awareness in those at greatest risk....
BACKGROUND
Increasing availability of panel testing for known high-penetrance familial melanoma genes has made it possible to improve risk awareness in those at greatest risk. Prior to wider implementation, the role of genetic testing in preventing melanoma, through influencing primary and secondary preventative behaviours, requires clarification.
METHODS
Database searches of PubMed, Embase, CINAHL, PsycINFO and the Cochrane Library were conducted for studies describing preventative behaviour outcomes in response to genetic testing for melanoma risk. Publications describing original research of any study type were screened for eligibility.
RESULTS
Eighteen publications describing 11 unique studies were reviewed. Outcomes assessed are based on health behaviour recommendations for those at increased risk: adherence to sun-protective behaviour (SPB); clinical skin examinations (CSE); skin self-examinations (SSE); and family discussion of risk. Overall, modest increases in adherence to primary prevention strategies of SPB were observed following genetic testing. Importantly, there were no net decreases in SPB found amongst non-carriers. For secondary preventative behaviour outcomes, including CSE and SSE, increases in post-test intentions and long-term adherence were reported across several subgroups in approximately half of the studies. While this increase reached significance in mutation carriers in some studies, one study reported a significant decline in annual CSE adherence of non-mutation carriers.
CONCLUSIONS
Evidence reviewed suggests that genetic testing has a modestly positive impact on preventative behaviour in high-risk individuals. Furthermore, improvements are observed regardless of mutation carrier status, although greater adherence is found in carriers. While additional studies of more diverse cohorts would be needed to inform clinical recommendations, the findings are encouraging and suggest that genetic testing for melanoma has a positive impact on preventative behaviours.
Topics: Genetic Testing; Health Behavior; Humans; Melanoma; Patient Compliance; Primary Prevention; Secondary Prevention; Self-Examination; Skin Neoplasms; Melanoma, Cutaneous Malignant
PubMed: 33588421
DOI: 10.1159/000513919 -
Journal of Medical Genetics Nov 2023While constitutional pathogenic variants in the gene cause familial adenomatous polyposis, c.3920T>A; p.Ile1307Lys (I1307K) has been associated with a moderate... (Meta-Analysis)
Meta-Analysis
While constitutional pathogenic variants in the gene cause familial adenomatous polyposis, c.3920T>A; p.Ile1307Lys (I1307K) has been associated with a moderate increased risk of colorectal cancer (CRC), particularly in individuals of Ashkenazi Jewish descent. However, published data include relatively small sample sizes, generating inconclusive results regarding cancer risk, particularly in non-Ashkenazi populations. This has led to different country/continental-specific guidelines regarding genetic testing, clinical management and surveillance recommendations for I1307K. A multidisciplinary international expert group endorsed by the International Society for Gastrointestinal Hereditary Tumours (InSiGHT), has generated a position statement on the I1307K allele and its association with cancer predisposition. Based on a systematic review and meta-analysis of the evidence published, the aim of this document is to summarise the prevalence of the I1307K allele and analysed the evidence of the associated cancer risk in different populations. Here we provide recommendations on the laboratory classification of the variant, define the role of predictive testing for I1307K, suggest recommendations for cancer screening in I1307K heterozygous and homozygous individuals and identify knowledge gaps to be addressed in future research studies. Briefly, I1307K, classified as pathogenic, low penetrance, is a risk factor for CRC in individuals of Ashkenazi Jewish origin and should be tested in this population, offering carriers specific clinical surveillance. There is not enough evidence to support an increased risk of cancer in other populations/subpopulations. Therefore, until/unless future evidence indicates otherwise, individuals of non-Ashkenazi Jewish descent harbouring I1307K should be enrolled in national CRC screening programmes for average-risk individuals.
Topics: Humans; Genetic Predisposition to Disease; Adenomatous Polyposis Coli; Colorectal Neoplasms; Genes, APC; Risk Factors; Jews
PubMed: 37076288
DOI: 10.1136/jmg-2022-108984 -
Molecular Biology Reports Jan 2012The association of the two ERCC polymorphisms, Asp312Asn and Lys751Gln, with lung cancer risk remains controversial and inconclusive. To better evaluate the potential... (Meta-Analysis)
Meta-Analysis Review
The association of the two ERCC polymorphisms, Asp312Asn and Lys751Gln, with lung cancer risk remains controversial and inconclusive. To better evaluate the potential role of the two polymorphisms and interaction with tobacco smoking in lung cancer susceptibility presented in diverse populations, we have conducted a meta-analysis based on 26 studies from 24 publications which included analyses of Asp312Asn (7121 cases, 8962 controls) and Lys751Gln (8396 cases, 10510 controls) polymorphisms. Overall, significantly elevated lung cancer risk was associated with ERCC2 312Asn allele(homozygous model: OR=1.20[1.05-1.36], P=0.006; recessive model: OR=1.20[1.06-1.35], P=0.004) and 751Gln allele(homozygous model: OR=1.31[1.17-1.46], P<0.00001; heterozygous model: OR=1.11[1.04-1.19], P=0.003; recessive model: OR=1.23[1.11-1.37], P<0.0001; dominant model: OR=1.15[1.08-1.23], P<0.0001). In ethnic subgroup analyses, significantly increased risk was associated with ERCC2 312Asn allele for both Caucasians and Asians, and 751Gln allele for both Caucasians and Latino-Americans. When stratified by smoking status, significantly elevated risk of both polymorphisms for never-smokers was detected (dominant model, OR=1.46[1.09-1.95] and 1.57[1.19-2.08], P=0.01 and 0.002, respectively). In conclusion, this meta-analysis suggests that the two ERCC2 polymorphisms may contribute to lung cancer susceptibility serving as low-penetrance risk factors. Extremely large-scale evidence would be necessary to confirm the effects on ethnically specific populations and gene-environment interactions.
Topics: Genetic Predisposition to Disease; Humans; Lung Neoplasms; Mutation, Missense; Odds Ratio; Polymorphism, Genetic; Risk Assessment; Smoking; Xeroderma Pigmentosum Group D Protein
PubMed: 21614524
DOI: 10.1007/s11033-011-0710-9 -
PloS One 2012Cyclin D1 (CCND1) plays a vital role in cancer cell cycle progression. Numerous epidemiological studies have evaluated the association between the CCND1 G870A... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Cyclin D1 (CCND1) plays a vital role in cancer cell cycle progression. Numerous epidemiological studies have evaluated the association between the CCND1 G870A polymorphism and the risk of colorectal cancer. However, these studies have yielded conflicting results. To derive a more precise estimation of this association, we conducted a meta-analysis and systematic review.
METHODOLOGY/PRINCIPAL FINDINGS
A comprehensive search was conducted to identify eligible studies of the CCND1 G870A polymorphism and colorectal cancer risk. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were derived from a fixed effect or random effect model. We applied a grading system (Venice criteria) that assessed the epidemiological strength of the association. A total of 22 publications that included 6157 cases and 8198 controls were identified. We found that the CCND1 G870A polymorphism was significantly associated with overall colorectal cancer risk (homozygote genetic model: OR = 1.130, 95% CI = 1.023-1.248, P = 0.016; heterozygote genetic model: OR = 1.124, 95% CI = 1.030-1.226, P = 0.009; dominant genetic model: OR = 1.127, 95% CI = 1.037-1.224, P = 0.005). After further stratified analyses, the increased risk was observed only in the subgroups of hospital-based studies, PCR-RFLP genotyping methods, sporadic colorectal cancer, and Caucasian ethnicity.
CONCLUSIONS
The available evidence demonstrates that the CCND1 870A allele might be a low-penetrant risk factor for colorectal cancer.
Topics: Case-Control Studies; Colorectal Neoplasms; Cyclin D1; Female; Genes, bcl-1; Genetic Predisposition to Disease; Humans; Male; Polymorphism, Single Nucleotide; Risk Factors; White People
PubMed: 22606291
DOI: 10.1371/journal.pone.0036813 -
Human Reproduction (Oxford, England) Jan 2012Numerous studies have reported CFTR mutations in CBAVD (congenital bilateral absence of the vas deferens) patients, but their results are not completely consistent.... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Numerous studies have reported CFTR mutations in CBAVD (congenital bilateral absence of the vas deferens) patients, but their results are not completely consistent. Here, we present a systemic review and meta-analysis with emphasis on clarifying further the genetic association of CFTR mutations with CBAVD.
METHODS
We searched the MEDLINE database until March, 2011 for eligible articles reporting CFTR mutations in CBAVD. Relevant data from each included study were abstracted by two independent reviewers. The overall frequency of CFTR mutations in CBAVD and the odds ratio (OR) for common specific alleles were pooled under random-effect or fixed-effect model as appropriate. Subgroup analysis was performed by ethnicity, and potential heterogeneity and bias were both assessed.
RESULTS
Among CBAVD patients, 78% had at least one CFTR mutation, 46% having two and 28% only one. Moreover, the common heterozygous F508del/5T and F508del/R117H were observed in 17 and 4% of CBAVD cases respectively, and the allele frequency in CBAVD was 17% for F508del, 25% for 5T and 3% for R117H. Subgroup analysis indicated an increased frequency of cases with two mutations in Caucasian patients than in Non-Caucasian (68 versus 50%, P= 0.012), but no differences for cases with at least one mutation (88 versus 77%, P= 0.163) or with only one mutation (17 versus 25%, P= 0.115). Caucasian patients had higher F508del frequency, but lower 5T frequency, than Non-Caucasian (22 versus 8%, P= 0.001; 20 versus 31%, P= 0.009). Summary OR was 9.25 for 5T [95% confidence interval (CI) 7.07-12.11, P= 0.000], with moderate heterogeneity (I(2)= 49.20%, P= 0.019) and evident bias (Egger's test, P= 0.005), and it was 19.43 for 5T/(TG)12_13 (95% CI 10.48-30.03, P= 0.000) without any evidence of heterogeneity (I(2)= 0.1%, P= 0.391) and bias (Egger's test, P= 0.160). The OR for 5T/(TG)12_13 was significantly higher than that for 5T allele (P= 0.000).
CONCLUSIONS
In summary, our results demonstrate a high frequency of CFTR mutations in CBAVD patients, and these exhibit evident ethnic differences. In addition, 5T allele and 5T/(TG)12_13 may contribute to the increased risk for CBAVD, with the 5T penetrance probably being modulated by adjacent (TG)12_13.
Topics: Alleles; Cystic Fibrosis Transmembrane Conductance Regulator; Genetic Predisposition to Disease; Genotype; Heterozygote; Homozygote; Humans; Male; Male Urogenital Diseases; Mutation; Odds Ratio; Risk; Vas Deferens
PubMed: 22081250
DOI: 10.1093/humrep/der377 -
International Journal of Molecular... Feb 2024Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a genetic disorder characterized by the progressive fibro-fatty replacement of the right ventricular... (Review)
Review
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a genetic disorder characterized by the progressive fibro-fatty replacement of the right ventricular myocardium, leading to myocardial atrophy. Although the structural changes usually affect the right ventricle, the pathology may also manifest with either isolated left ventricular myocardium or biventricular involvement. As ARVC shows an autosomal dominant pattern of inheritance with variable penetrance, the clinical presentation of the disease is highly heterogeneous, with different degrees of severity and patterns of myocardial involvement even in patients of the same familiar group with the same gene mutation: the pathology spectrum ranges from the absence of symptoms to sudden cardiac death (SCD) sustained by ventricular arrhythmias, which may, in some cases, be the first manifestation of an otherwise silent pathology. An evidence-based systematic review of the literature was conducted to evaluate the state of the art of the diagnostic techniques for the correct post-mortem identification of ARVC. The research was performed using the electronic databases PubMed and Scopus. A methodological approach to reach a correct post-mortem diagnosis of ARVC was described, analyzing the main post-mortem peculiar macroscopic, microscopic and radiological alterations. In addition, the importance of performing post-mortem genetic tests has been underlined, which may lead to the correct identification and characterization of the disease, especially in those ARVC forms where anatomopathological investigation does not show evident morphostructural damage. Furthermore, the usefulness of genetic testing is not exclusively limited to the correct diagnosis of the pathology, but is essential for promoting targeted screening programs to the deceased's family members. Nowadays, the post-mortem diagnosis of ARVC performed by forensic pathologist remains very challenging: therefore, the identification of a clear methodological approach may lead to both a reduction in under-diagnoses and to the improvement of knowledge on the disease.
Topics: Humans; Arrhythmogenic Right Ventricular Dysplasia; Autopsy; Myocardium; Databases, Factual; Death, Sudden, Cardiac
PubMed: 38473714
DOI: 10.3390/ijms25052467 -
Pancreatology : Official Journal of the... Oct 2020Since the description of the SPINK1 gene encoding the serine protease inhibitor Kazal type 1 and the CTRC gene encoding the Chymotrypsin C as being involved in chronic...
Since the description of the SPINK1 gene encoding the serine protease inhibitor Kazal type 1 and the CTRC gene encoding the Chymotrypsin C as being involved in chronic pancreatitis, more than 56 SPINK1 and 87 CTRC variants have been reported. Assessing the clinical relevance of SPINK1 and CTRC variants is often complicated in the absence of functional evidence and interpretation of rare variants is not very easy in clinical practice. The aim of this study was to review the different variants identified in these two genes and to classify them according to their degree of damaging effect. This classification was based on the results of in vitro experiments, in silico analysis using different prediction tools, and on population data, in comparing the allelic frequency of each variant in patients with pancreatitis and in unaffected control individuals. This review should help geneticists and clinicians in charge of patient's care and genetic counseling to interpret the results of genetic studies.
Topics: Chymotrypsin; Computer Simulation; Gene Frequency; Genetic Variation; Humans; Pancreatitis; Predictive Value of Tests; Trypsin Inhibitor, Kazal Pancreatic
PubMed: 32948427
DOI: 10.1016/j.pan.2020.09.001 -
Frontiers in Pediatrics 2021Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiomyopathy characterized by fibrofatty infiltration of predominantly the right ventricular...
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiomyopathy characterized by fibrofatty infiltration of predominantly the right ventricular (RV) myocardium. Affected patients typically present as young adults with hemodynamically stable ventricular tachycardia, although pediatric cases are increasingly recognized. These young subjects often have a more severe phenotype with a high risk of sudden cardiac death (SCD) and progression toward heart failure. Diagnosis of ARVC is made by combining multiple sources of information as prescribed by the consensus-based Task Force Criteria. The description of Naxos disease, a fully penetrant autosomal recessive disorder that is associated with ARVC and a cutaneous phenotype of palmoplantar keratoderma and wooly hair facilitated the identification of the genetic cause of ARVC. At present, approximately 60% of patients are found to carry a pathogenic variant in one of five genes associated with the cardiac desmosome. The incomplete penetrance and variable expressivity of these variants however implies an important role for environmental factors, of which participation in endurance exercise is a strong risk factor. Since there currently is no definite cure for ARVC, disease management is directed toward symptom reduction, delay of disease progression, and prevention of SCD. This clinically focused review describes the spectrum of ARVC among children and adolescents, the genetic architecture underlying this disease, the cardio-cutaneous syndromes that led to its identification, and current diagnostic and therapeutic strategies in pediatric ARVC subjects.
PubMed: 34926342
DOI: 10.3389/fped.2021.750916 -
Clinical Journal of the American... May 2024Liddle syndrome was initially characterized by hypertension, hypokalemia, metabolic alkalosis, and suppressed plasma renin and aldosterone, resulting from...
BACKGROUND
Liddle syndrome was initially characterized by hypertension, hypokalemia, metabolic alkalosis, and suppressed plasma renin and aldosterone, resulting from gain-of-function variants in the epithelial Na + channel (ENaC). Efficient treatment with ENaC inhibitors is available, but the phenotypic spectrum of genetically confirmed Liddle syndrome is unknown, and some patients may remain undiagnosed and at risk of inefficient treatment. In this study, we used a reverse phenotyping approach to investigate the Liddle syndrome phenotypic spectrum and genotype-phenotype correlations.
METHODS
Pubmed, Embase, Scopus, and the Human Gene Mutation Database were searched for articles reporting Liddle syndrome variants. The genetic variants were systematically classified to identify patients with genetically confirmed Liddle syndrome. We identified 62 articles describing 45 unique variants within 86 Liddle syndrome families, and phenotypic data were pooled for 268 patients with confirmed Liddle syndrome.
RESULTS
The Liddle syndrome variants localized to exon 13 of SCNN1B and SCNN1G , disrupting the PPPxY motif critical for downregulating ENaC activity. Hypertension sensitive to ENaC inhibition was present in 97% of adults carrying Liddle syndrome variants while hypokalemia, metabolic alkalosis, and plasma renin and aldosterone suppression showed incomplete penetrance. In addition, 95% and 55% of patients had a family history of hypertension or cerebrovascular events, respectively. The genotype had minor phenotypic effects; however, probands compared with relatives showed significant phenotypic discrepancies consistent with selection bias for initial genetic screening.
CONCLUSIONS
Patients with genetically confirmed Liddle syndrome displayed a phenotypic spectrum, with ENaC-sensitive hypertension and family history of hypertension being the most common features. The phenotype seemed independent of the specific gene or variant type involved.
Topics: Humans; Liddle Syndrome; Epithelial Sodium Channels; Phenotype; Adult; Genetic Association Studies; Female; Male; Hypertension; Renin; Hypokalemia; Adolescent; Young Adult; Genetic Predisposition to Disease; Child; Mutation
PubMed: 38265765
DOI: 10.2215/CJN.0000000000000430 -
Gastroenterology Aug 2001Increasingly, studies of the relationship between common genetic variants and colorectal tumor risk are being proposed. To assess the evidence that any of these confers... (Meta-Analysis)
Meta-Analysis
BACKGROUND & AIMS
Increasingly, studies of the relationship between common genetic variants and colorectal tumor risk are being proposed. To assess the evidence that any of these confers a risk, a systematic review and meta-analysis of published studies was undertaken.
METHODS
Fifty studies of the effect of common alleles of 13 genes on risk were identified. To clarify the impact of individual polymorphisms on risk, pooled analyses were performed.
RESULTS
Of the 50 studies identified, significant associations were seen in 16, but only 3 were reported in more than one study. Pooling studies, significant associations were only seen for 3 of the polymorphisms: adenomatosis polyposis coli (APC)-I1307K (odds ratio [OR] = 1.58, 95% confidence interval [CI]: 1.21-2.07); Harvey ras-1 variable number tandem repeat polymorphism (HRAS1-VNTR; OR = 2.50, 95% CI: 1.54-4.05); and methylenetetrahydrofolate reductase (MTHFR)(Val/Val) (OR = 0.76, 95% CI: 0.62-0.92). For tumor protein 53 (TP53), N-acetyl transferase 1 (NAT1), NAT2, glutathione-S transferase Mu (GSTM1), glutathione-S transferase Theta (GSTT1), and glutathione-S transferase Pi (GSTP1) polymorphisms, the best estimates are sufficient to exclude a 1.7-fold increase in risk of colorectal cancer.
CONCLUSIONS
APC-I1307K, HRAS1-VNTR, and MTHFR variants represent the strongest candidates for low penetrance susceptibility alleles identified to date. Although their genotypic risks are modest, their high frequency in the population implies that they may well have considerable impact on colorectal cancer incidence. Determining precise risk estimates associated with other variants and gene-gene and gene-environment interactions will be contingent on further studies with sample sizes larger than typically used to date.
Topics: Colorectal Neoplasms; DNA Methylation; Genes, Tumor Suppressor; Genetic Predisposition to Disease; Humans; Oncogenes; Polymorphism, Genetic; Risk Factors
PubMed: 11487538
DOI: 10.1053/gast.2001.26265