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Cytogenetic and Genome Research 2014Breast cancer is the most common cancer and the second leading cause of death in women worldwide. The disease is caused by a combination of genetic, environmental,... (Review)
Review
Breast cancer is the most common cancer and the second leading cause of death in women worldwide. The disease is caused by a combination of genetic, environmental, lifestyle, and reproductive risk factors. Linkage and family-based studies have identified many pathological germline mutations, which account for around 20% of the genetic risk of familial breast cancer. In recent years, single nucleotide polymorphism-based genetic association studies, especially genome-wide association studies (GWASs), have been very successful in uncovering low-penetrance common variants associated with breast cancer risk. These common variants alone may explain up to an additional 30% of the familial risk of breast cancer. With the advent of available genetic resources and growing collaborations among researchers across the globe, the much needed large sample size to capture variants with small effect sizes and low population frequencies is being addressed, and hence many more common variants are expected to be discovered in the coming days. Here, major GWASs conducted for breast cancer predisposition and prognosis until 2013 are summarized. Few studies investigating other forms of genetic variations contributing to breast cancer predisposition and disease outcomes are also discussed. Finally, the potential utility of the GWAS-identified variants in disease risk models and some future perspectives are presented.
Topics: Breast Neoplasms; Female; Gene-Environment Interaction; Genetic Linkage; Genetic Predisposition to Disease; Genome-Wide Association Study; Genotype; Germ-Line Mutation; Humans; Penetrance; Polymorphism, Single Nucleotide; Prognosis; Risk Factors
PubMed: 25401968
DOI: 10.1159/000369045 -
Pediatric Surgery International Aug 2020Biliary atresia (BA) in twins is extremely rare reported in the literature, but twin studies are useful methods of examining the associated factors of a complex disease.... (Meta-Analysis)
Meta-Analysis
PURPOSE
Biliary atresia (BA) in twins is extremely rare reported in the literature, but twin studies are useful methods of examining the associated factors of a complex disease. The objective of this study was to analyze the characteristics and patterns of biliary atresia in twins from reviewing available articles.
METHODS
PubMed and EMBASE databases were reviewed for related articles using the keywords ''biliary atresia'', ''twins'', ''monozygotic (MZ)'', and ''dizygotic (DZ)'', including relevant papers in the reference lists.
RESULTS
This analysis was extracted from 12 articles, with a total of 35 twin pairs included. BA was found in 36 out of 70 twin subjects (51.4%), of which had an even gender split. 97.1% twins were discordant, among 55.9% of which were monozygotic twin sets, indicating that BA may be related to genetic phenotype or penetrance. Isolated BA was the largest group with 27 (75%) affected twins. Only one pair of dizygotic twins (2.9%) demonstrate concordance for BA, and have one affected family member.
CONCLUSION
BA was found in nearly half of twin subjects with an even gender split. Isolated BA was the largest group, in which the number of monozygotic twins was similar with dizygotic twins, so the onset of the disease may not associate with the zygosity of twins. Most of twin sets had discordant disease presentation, especially monozygotic twins therein, emphasizing the role of epigenetic factor in the pathogenesis of BA. Future studies should take genetic testing among any twin sets in BA, especially the disease-associated mutations, thus be useful to investigate the etiology of disease.
Topics: Adult; Biliary Atresia; Diseases in Twins; Female; Humans; Male; Twins
PubMed: 32504124
DOI: 10.1007/s00383-020-04690-4 -
European Journal of Human Genetics :... May 2020Family-based penetrance is frequently cited as a major challenge for translating penetrance estimates from familial populations to asymptomatic populations. A systematic...
Family-based penetrance is frequently cited as a major challenge for translating penetrance estimates from familial populations to asymptomatic populations. A systematic review was performed to assess the literature evidencing penetrance estimates in patients without a family history of disease, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) framework. Initially 1592 papers were identified, which were filtered to a final nine, through application of inclusion and exclusion criteria. Fundamental differences in the identified papers prevented combination of papers using meta-analysis, so thematic analysis to produce a narrative synthesis was performed. Key themes included disease risk modifiers, evidence, study limitations and bias. A methodological appraisal too was used to assess quality of included studies. It is evident from the findings that the evidence base for penetrance estimates in individuals without a family history of disease is limited. Future work is needed to refine design of penetrance studies and the impact of incorrect estimates.
Topics: Genetic Diseases, Inborn; Genetic Testing; Humans; Medical History Taking; Pedigree; Penetrance
PubMed: 31937893
DOI: 10.1038/s41431-019-0556-5 -
The American Journal of Clinical... Aug 2013Hereditary hemochromatosis (HH) leads to iron loading because of a disturbance in the negative-feedback mechanism between dietary iron absorption and iron status. The... (Review)
Review
BACKGROUND
Hereditary hemochromatosis (HH) leads to iron loading because of a disturbance in the negative-feedback mechanism between dietary iron absorption and iron status. The management of HH is achieved by repeated phlebotomies.
OBJECTIVE
We investigated whether HH patients would benefit from a diet with low iron intake and bioavailability.
DESIGN
We performed a systematic review of studies that linked iron bioavailability and status with dietary factors in subjects with diagnosed HH. Studies on heterozygotes for the HFE mutation were excluded.
RESULTS
No prospective, randomized study was reported. Nine studies that directly measured iron bioavailability from test meals in HH patients have been described as well as 3 small, prospective, longitudinal studies in HH patients. Eight cross-sectional studies were identified that investigated the effect of dietary composition on iron status. Calculations of iron bioavailability in HH were made by extrapolating data on hepcidin concentrations and their association with iron bioavailability. The potential reduction in the yearly amount of blood to be phlebotomized when restricting dietary iron absorbed was estimated in the 3 longitudinal studies and ranged between 0.5 and 1.5 L. This amount would be dependent on individual disease penetrance as well as the dietary intervention.
CONCLUSIONS
Despite the limited quantitative evidence and the lack of randomized, prospective trials, dietary interventions that modify iron intake and bioavailability may affect iron accumulation in HH patients. Although this measure may be welcome in patients willing to contribute to their disease management, limited data exist on the clinical and quality-of-life benefit.
Topics: Absorption; Antimicrobial Cationic Peptides; Biological Availability; Diet; Hemochromatosis; Hepcidins; Heterozygote; Humans; Iron, Dietary; Mutation; Penetrance
PubMed: 23803887
DOI: 10.3945/ajcn.112.048264 -
Journal of Hepatology Nov 2010Classical ferroportin disease is characterized by hyperferritinemia, normal transferrin saturation, and iron overload in macrophages. A non-classical form is... (Meta-Analysis)
Meta-Analysis
BACKGROUND & AIMS
Classical ferroportin disease is characterized by hyperferritinemia, normal transferrin saturation, and iron overload in macrophages. A non-classical form is characterized by additional hepatocellular iron deposits and a high transferrin saturation. Both forms demonstrate autosomal dominant transmission and are associated with ferroportin gene (SLC40A1) mutations. SLC40A1 encodes a cellular iron exporter expressed in macrophages, enterocytes, and hepatocytes. The aim of the analysis is to determine the penetrance of SLC40A1 mutations and to evaluate in silico tools to predict the functional impairment of ferroportin mutations as an alternative to in vitro studies.
METHODS
We conducted a systematic review of the literature and meta-analysis of the biochemical presentation, genetics, and pathology of ferroportin disease.
RESULTS
Of the 176 individuals reported with SLC40A1 mutations, 80 were classified as classical phenotype with hyperferritinemia and normal transferrin saturation. The non-classical phenotype with hyperferritinemia and elevated transferrin saturation was present in 53 patients. The remaining patients had normal serum ferritin or the data were reported incompletely. Despite an increased hepatic iron concentration in all biopsied patients, significant fibrosis or cirrhosis was present in only 11%. Hyperferritinemia was present in 86% of individuals with ferroportin mutations. Bio-informatic analysis of ferroportin mutations showed that the PolyPhen score has a sensitivity of 99% and a specificity of 67% for the discrimination between ferroportin mutations and polymorphisms.
CONCLUSIONS
In contrast to HFE hemochromatosis, ferroportin disease has a high penetrance, is genetically heterogeneous and is rarely associated with fibrosis. Non-classical ferroportin disease is associated with a higher risk of fibrosis and a more severe overload of hepatic iron.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Amino Acid Sequence; Cation Transport Proteins; Child; Child, Preschool; Female; Ferritins; Hemochromatosis; Humans; Iron Overload; Male; Middle Aged; Molecular Sequence Data; Mutation; Polymorphism, Genetic; Transferrin
PubMed: 20691492
DOI: 10.1016/j.jhep.2010.05.016 -
Clinical Otolaryngology : Official... Feb 2018A cholesteatoma is a mass of keratinising epithelium in the middle ear. It is a rare disorder that is associated with significant morbidity, and its causative risk... (Review)
Review
OBJECTIVE
A cholesteatoma is a mass of keratinising epithelium in the middle ear. It is a rare disorder that is associated with significant morbidity, and its causative risk factors are poorly understood; on a global scale, up to a million people are affected by this each year. We have conducted a systematic literature review to identify reports about the heritability of cholesteatoma or any constitutional genetic factors that may be associated with its aetiology.
DATA SOURCES
A systematic search of MEDLINE (EBSCO) and two databases of curated genetic research (OMIM and Phenopedia) was conducted.
STUDY SELECTION
The participants and populations of interest for this review were people treated for cholesteatoma and their family members. The studies of interest reported evidence of heritability for the trait, or any association with congenital syndromes and particular genetic variants.
DATA EXTRACTION
The searches identified 449 unique studies, of which 35 were included in the final narrative synthesis.
DATA SYNTHESIS
A narrative synthesis was conducted, and data were tabulated to record characteristics, including study design, genetic data and author conclusions. Most of the studies identified in the literature search, and described here, are case reports and so represent the lowest level of evidence. In a few case reports, congenital and acquired cholesteatomas have been shown to segregate within families in the pattern typical of a monogenic or oligogenic disorder with incomplete penetrance. Evidence from syndromic cases could suggest that genes controlling ear morphology may be risk factors for cholesteatoma formation.
CONCLUSIONS
This is the first systematic review about the genetics of cholesteatoma, and we have identified a small body of relevant literature that provides evidence of a heritable component for its aetiology. Cholesteatoma is a complex and heterogeneous clinical phenotype, and it is often associated with chronic otitis media and with some rare congenital syndromes known to affect ear morphology and related pathologies.
Topics: Cholesteatoma, Middle Ear; Genetic Research; Humans
PubMed: 28485112
DOI: 10.1111/coa.12900 -
The Journal of Clinical Endocrinology... Apr 2024Carriers of germline pathogenic variants (PV) in succinate dehydrogenase type B (SDHB) are at increased risk of developing pheochromocytomas and paragangliomas (PPGL)....
CONTEXT
Carriers of germline pathogenic variants (PV) in succinate dehydrogenase type B (SDHB) are at increased risk of developing pheochromocytomas and paragangliomas (PPGL). Understanding their outcomes can guide recommendations for risk assessment and early detection.
OBJECTIVE
We performed a systematic review and meta-analysis of the following outcomes in SDHB PV carriers: age-specific risk of developing tumors, metastatic progression, second primary tumor development, and mortality.
MATERIALS AND METHODS
Pubmed, MEDLINE and EMBASE were searched. Sixteen studies met the inclusion criteria and were sorted into four outcome categories: age-specific penetrance, metastatic disease, risk of second tumour and mortality. We assessed heterogeneity and performed a meta-analysis across studies using a random effects model with the DerSimonian and Laird method.
RESULTS
Penetrance of PPGL for non-proband/non-index SDHB PV carriers by age 20 was 4% (95% CI, 3%-6%), 11% (95% CI, 8%-15%) by age 40, 24% (95% CI, 19%-31%) by age 60 and 35% (95% CI, 25%-47%) by age 80. The overall risk of metastatic disease for non-proband/non-index carriers with PPGL was 9% (95% CI, 5-16%) per lifetime. In all affected cases (combining both proband/index and non-proband/non-index carriers with tumors), the risk of a second tumor was 24% (95% CI, 18-31%) and all cause 5-year mortality was 18% (95% CI 6-40%).
CONCLUSION
Penetrance for PPGL in SDHB PV carriers increases linearly with age. Affected carriers are at risk of developing and dying from metastatic disease, or of developing second tumors. Lifelong surveillance is appropriate.
PubMed: 38605204
DOI: 10.1210/clinem/dgae233 -
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 -
Journal of Community Genetics Feb 2022Preimplantation genetic testing (PGT) involves testing embryos created through in vitro fertilization for the presence of hereditary genetic disorders and chromosome... (Review)
Review
Preimplantation genetic testing (PGT) involves testing embryos created through in vitro fertilization for the presence of hereditary genetic disorders and chromosome abnormalities. PGT for monogenic conditions (PGT-M) is generally performed for childhood-onset, lethal disorders, but is increasingly accepted for certain adult-onset conditions, conditions with available treatment options or conditions with lower penetrance. Furthermore, the development of PGT for polygenic conditions (PGT-P) makes ethical questions regarding PGT indications imperative. A systematic review was therefore performed to gather and analyse studies on the perspectives of healthcare professionals on the appropriate scope of PGT, with the aim of getting insights into the concerns about the scope of PGT now and in the near future. PRISMA guidelines were followed. Twelve qualitative articles were included. The main themes extracted were the scope of PGT and decision-making about PGT. Defining 'a serious genetic condition' was seen as complex, but severity, high penetrance and absence of treatability and patients' experience were seen as relevant indications to determine the appropriateness of PGT. In navigating the decision-making processes with patients, professionals experienced friction between setting limits and respecting patients' autonomy. Such friction and ethical dilemmas around seriousness, informed decision-making and preventative medicine show that while expanding the list of possible PGT indications and the development of PGT-P could augment patients' reproductive autonomy, it could also lead to an increased reproductive 'burden' for patients. These insights are crucial for establishing guidelines that help healthcare professionals navigate ethical tensions associated with PGT.
PubMed: 35028914
DOI: 10.1007/s12687-021-00573-w -
Cancers Mar 2024Neurofibromatosis Type 1 is an autosomal dominant tumour-predisposition condition commonly diagnosed in childhood and fully penetrant by adulthood. Long-term monitoring... (Review)
Review
BACKGROUND
Neurofibromatosis Type 1 is an autosomal dominant tumour-predisposition condition commonly diagnosed in childhood and fully penetrant by adulthood. Long-term monitoring through imaging is inconsistent and varies between high- and low-income countries. Implementation of a clinical practice guideline through a multidisciplinary clinic is instrumental to the care of adult Neurofibromatosis Type 1 patients. We aim to systematically review international diagnostic modalities and strategies to evaluate any association between a country's socioeconomic status and diagnostic modalities or strategies used for Neurofibromatosis Type 1 patients.
METHODS
We searched PubMed, Embase, Web of Science, and Cochrane. Relevant clinical information on the surveillance of adult Neurofibromatosis Type 1 patients worldwide was reviewed, extracted, and synthesised.
RESULTS
We identified 51 papers reporting on 7724 individuals. Multiple imaging modalities are actively employed in high-income and upper-middle-income countries for surveying adult Neurofibromatosis Type 1 patients. We did not find any relevant papers from low- and middle-income countries.
CONCLUSIONS
This systematic review suggests that there is robust data on diagnostic modalities for adult Neurofibromatosis Type 1 patients in high-income countries, but not for low- and middle-income countries. There is a lack of data on consolidated diagnostic strategies from both high- and low-income countries. Efforts should be made to publish data on usual clinical practice in low- and middle-income countries to develop clinical practice guidelines describing best medical practice to fit a local context.
PubMed: 38539455
DOI: 10.3390/cancers16061119