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Advances in Experimental Medicine and... 2021Genetic susceptibility explains 5-10% of all breast cancer cases. High-penetrance breast cancer susceptibility genes deliberate a greater than tenfold relative risk of... (Review)
Review
Genetic susceptibility explains 5-10% of all breast cancer cases. High-penetrance breast cancer susceptibility genes deliberate a greater than tenfold relative risk of breast cancer. BRCA1 and BRCA2 genes are the most common cause of hereditary breast cancer, and TP53, PTEN, and SKT11 (LKB1) are rarely present. The prevalence of BRCA1 and BRCA2 genetic alterations differ in various ethnic groups. The Korean Hereditary Breast Cancer (KOHBRA) Study, nationwide-scale study, was established to acquire evidence for the accurate risk assessment and management of hereditary breast and ovarian cancer (HBOC) in Korea prospectively since 2007. In this chapter, we review previous research related to hereditary breast cancer and summarize the present concepts and research results centered on the Korean Hereditary Breast Cancer Research at this time.
Topics: Breast Neoplasms; Female; Genes, BRCA2; Genetic Predisposition to Disease; Humans; Mutation; Ovarian Neoplasms; Penetrance; Republic of Korea
PubMed: 33983595
DOI: 10.1007/978-981-32-9620-6_25 -
Advances in Experimental Medicine and... 2021Susceptibility genes involved in disease etiology and prognosis are categorized into two groups: high penetrance genes (i.e., BRCA1, CHEK2, ATM, etc.) and low penetrance...
Susceptibility genes involved in disease etiology and prognosis are categorized into two groups: high penetrance genes (i.e., BRCA1, CHEK2, ATM, etc.) and low penetrance genes (i.e., NATs, GSTs, CYPs, etc., and variants identified by genome-wide association studies). Since low penetrance genes have high population attributable risk, the usefulness of those genes to research on breast cancer prevention is not small. In this chapter, the previous studies on low-penetrance genetic susceptibility through a candidate gene approach and genome-wide association of breast cancer were summarized. The contribution of low-penetrance susceptibility genes to the breast cancer risk prediction models will also be discussed on the utility in clinical or public health application.
Topics: Breast Neoplasms; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Penetrance
PubMed: 33983592
DOI: 10.1007/978-981-32-9620-6_22 -
Cold Spring Harbor Perspectives in... Jun 2015Despite remarkable progress in the identification of mutations that drive genetic disorders, progress in understanding the effect of genetic background on the penetrance... (Review)
Review
Despite remarkable progress in the identification of mutations that drive genetic disorders, progress in understanding the effect of genetic background on the penetrance and expressivity of causal alleles has been modest, in part because of the methodological challenges in identifying genetic modifiers. Nonetheless, the progressive discovery of modifier alleles has improved both our interpretative ability and our analytical tools to dissect such phenomena. In this review, we analyze the genetic properties and behaviors of modifiers as derived from studies in patient populations and model organisms and we highlight conceptual and technological tools used to overcome some of the challenges inherent in modifier mapping and cloning. Finally, we discuss how the identification of these modifiers has facilitated the elucidation of biological pathways and holds the potential to improve the clinical predictive value of primary causal mutations and to develop novel drug targets.
Topics: Alleles; Animals; Cloning, Molecular; Forecasting; Genes, Modifier; Humans; Mice; Mice, Inbred Strains; Models, Genetic; Multifactorial Inheritance; Mutation; Penetrance; Phenotype; Retinal Degeneration
PubMed: 26033081
DOI: 10.1101/cshperspect.a017145 -
Trends in Cancer Nov 2018Inherited diseases are not always expressed in the same way in every individual that carries the same variant in a disease-causing gene. This phenomenon is known as... (Review)
Review
Inherited diseases are not always expressed in the same way in every individual that carries the same variant in a disease-causing gene. This phenomenon is known as reduced or incomplete penetrance. Variable and incomplete penetrance may explain why inherited diseases are occasionally transmitted through unaffected parents, but also why clinically healthy individuals can carry potentially pathogenic variants without expressing features of the disease. Here, we will provide an overview of factors that play a fundamental role in the concept of penetrance and expressivity of cancer predisposing genes in children with malignancies. These findings are important to understand the complexity of inherited diseases and cancer development and to improve genetic counselling for the affected families.
Topics: Genetic Predisposition to Disease; Genetic Variation; Humans; Neoplasms; Penetrance; Risk Factors; Syndrome
PubMed: 30352675
DOI: 10.1016/j.trecan.2018.09.002 -
Disease Models & Mechanisms Dec 2022Meckel syndrome, nephronophthisis, Joubert syndrome and Bardet-Biedl syndrome are caused by mutations in proteins that localize to the ciliary transition zone (TZ). The...
Meckel syndrome, nephronophthisis, Joubert syndrome and Bardet-Biedl syndrome are caused by mutations in proteins that localize to the ciliary transition zone (TZ). The phenotypically distinct syndromes suggest that these TZ proteins have differing functions. However, mutations in a single TZ gene can result in multiple syndromes, suggesting that the phenotype is influenced by modifier genes. We performed a comprehensive analysis of ten zebrafish TZ mutants, including mks1, tmem216, tmem67, rpgrip1l, cc2d2a, b9d2, cep290, tctn1, nphp1 and nphp4, as well as mutants in ift88 and ift172. Our data indicate that variations in phenotypes exist between different TZ mutants, supporting different tissue-specific functions of these TZ genes. Further, we observed phenotypic variations within progeny of a single TZ mutant, reminiscent of multiple disease syndromes being associated with mutations in one gene. In some mutants, the dynamics of the phenotype became complex with transitory phenotypes that are corrected over time. We also demonstrated that multiple-guide-derived CRISPR/Cas9 F0 'crispant' embryos recapitulate zygotic null phenotypes, and rapidly identified ciliary phenotypes in 11 cilia-associated gene candidates (ankfn1, ccdc65, cfap57, fhad1, nme7, pacrg, saxo2, c1orf194, ttc26, zmynd12 and cfap52).
Topics: Animals; Cilia; Zebrafish; Penetrance; Syndrome; Polycystic Kidney Diseases; Biological Variation, Population; Zebrafish Proteins; Vesicular Transport Proteins
PubMed: 36533556
DOI: 10.1242/dmm.049568 -
Endocrine Jun 2020Familial nonmedullary thyroid cancer (FNMTC) constitutes 3-9% of all thyroid cancer cases. FNMTC is divided into two groups: syndromic and nonsyndromic. Nonsyndromic... (Review)
Review
Familial nonmedullary thyroid cancer (FNMTC) constitutes 3-9% of all thyroid cancer cases. FNMTC is divided into two groups: syndromic and nonsyndromic. Nonsyndromic FNMTC is more common as compared with syndromic FNMTC. In syndromic FNMTC, patients are at risk of nonmedullary thyroid cancer (NMTC) and other tumors, and the susceptibility genes are known. In nonsyndromic FNMTC, NMTC is the major feature of the disease and occurs in isolation with an autosomal dominant pattern of inheritance and variable penetrance. New data have emerged on the genetics, clinical characteristics, and outcomes of patients with FNMTC that may have clinical relevance in the management of patients. In this review, we focus on newly characterized syndromic FNMTC entities, criteria for screening and surveillance of nonsyndromic FNMTC, and the classification of nonsyndromic FNMTC as well as the genetic background and heterogeneity of nonsyndromic FNMTC.
Topics: Carcinoma, Papillary; Genetic Predisposition to Disease; Humans; Penetrance; Thyroid Cancer, Papillary; Thyroid Neoplasms
PubMed: 32162184
DOI: 10.1007/s12020-020-02250-3 -
British Journal of Clinical Pharmacology Jun 2019Metabolic bone diseases comprise a diverse group of disorders characterized by alterations in skeletal homeostasis, and are often associated with abnormal circulating... (Review)
Review
Metabolic bone diseases comprise a diverse group of disorders characterized by alterations in skeletal homeostasis, and are often associated with abnormal circulating concentrations of calcium, phosphate or vitamin D metabolites. These diseases commonly have a genetic basis and represent either a monogenic disorder due to a germline or somatic single gene mutation, or an oligogenic or polygenic disorder that involves variants in more than one gene. Germline single gene mutations causing Mendelian diseases typically have a high penetrance, whereas the genetic variations causing oligogenic or polygenic disorders are each associated with smaller effects with additional contributions from environmental factors. Recognition of familial monogenic disorders is of clinical importance to facilitate timely investigations and management of the patient and any affected relatives. The diagnosis of monogenic metabolic bone disease requires careful clinical evaluation of the large diversity of symptoms and signs associated with these disorders. Thus, the clinician must pursue a systematic approach beginning with a detailed history and physical examination, followed by appropriate laboratory and skeletal imaging evaluations. Finally, the clinician must understand the increasing number and complexity of molecular genetic tests available to ensure their appropriate use and interpretation.
Topics: Animals; Bone Diseases, Metabolic; Bone Remodeling; Genetic Predisposition to Disease; Genetic Therapy; Germ-Line Mutation; Heredity; Humans; Medical History Taking; Molecular Diagnostic Techniques; Pedigree; Penetrance; Phenotype; Physical Examination; Predictive Value of Tests; Prognosis; Risk Factors
PubMed: 30357886
DOI: 10.1111/bcp.13803 -
Annals of Neurology Nov 2022Parkinson's disease (PD) is a complex neurodegenerative condition in which genetic and environmental factors interact to contribute to its etiology. Remarkable progress... (Review)
Review
Parkinson's disease (PD) is a complex neurodegenerative condition in which genetic and environmental factors interact to contribute to its etiology. Remarkable progress has been made in deciphering disease etiology through genetic approaches, but there is limited data about how environmental and genetic factors interact to modify penetrance, risk, and disease severity. Here, we provide insights into environmental modifiers of PD, discussing precedents from other neurological and non-neurological conditions. Based on these examples, we outline genetic and environmental factors contributing to PD and review potential environmental modifiers of penetrance and clinical variability in monogenic and idiopathic PD. We also highlight the potential challenges and propose how future studies might tackle these important questions. ANN NEUROL 2022;92:715-724.
Topics: Humans; Parkinson Disease; Penetrance
PubMed: 35913124
DOI: 10.1002/ana.26467 -
Genetics in Medicine : Official Journal... Jan 2016Germ-line mutations in MLH1, MSH2, MSH6, and PMS2 have been shown to cause Lynch syndrome. The penetrance of the cancer and tumor spectrum has been repeatedly studied,... (Review)
Review
Germ-line mutations in MLH1, MSH2, MSH6, and PMS2 have been shown to cause Lynch syndrome. The penetrance of the cancer and tumor spectrum has been repeatedly studied, and multiple professional societies have proposed clinical management guidelines for affected individuals. Several studies have demonstrated a reduced penetrance for monoallelic carriers of PMS2 mutations compared with the other mismatch repair (MMR) genes, but clinical management guidelines have largely proposed the same screening recommendations for all MMR gene carriers. The authors considered whether enough evidence existed to propose new screening guidelines specific to PMS2 mutation carriers with regard to age at onset and frequency of colonic screening. Published reports of PMS2 germ-line mutations were combined with unpublished cases from the authors' research registries and clinical practices, and a discussion of potential modification of cancer screening guidelines was pursued. A total of 234 monoallelic PMS2 mutation carriers from 170 families were included. Approximately 8% of those with colorectal cancer (CRC) were diagnosed before age 30, and each of these tumors presented on the left side of the colon. As it is currently unknown what causes the early onset of CRC in some families with monoallelic PMS2 germline mutations, the authors recommend against reducing cancer surveillance guidelines in families found having monoallelic PMS2 mutations in spite of the reduced penetrance.Genet Med 18 1, 13-19.
Topics: Adenosine Triphosphatases; Colorectal Neoplasms, Hereditary Nonpolyposis; DNA Repair Enzymes; DNA-Binding Proteins; Early Detection of Cancer; Germ-Line Mutation; Heterozygote; Humans; Mismatch Repair Endonuclease PMS2; Penetrance
PubMed: 25856668
DOI: 10.1038/gim.2015.27 -
Gastric Cancer : Official Journal of... Sep 2023Germline CDH1 pathogenic or likely pathogenic variants cause hereditary diffuse gastric cancer (HDGC). Once a genetic cause is identified, stomachs' and breasts'...
BACKGROUND
Germline CDH1 pathogenic or likely pathogenic variants cause hereditary diffuse gastric cancer (HDGC). Once a genetic cause is identified, stomachs' and breasts' surveillance and/or prophylactic surgery is offered to asymptomatic CDH1 carriers, which is life-saving. Herein, we characterized an inherited mechanism responsible for extremely early-onset gastric cancer and atypical HDGC high penetrance.
METHODS
Whole-exome sequencing (WES) re-analysis was performed in an unsolved HDGC family. Accessible chromatin and CDH1 promoter interactors were evaluated in normal stomach by ATAC-seq and 4C-seq, and functional analysis was performed using CRISPR-Cas9, RNA-seq and pathway analysis.
RESULTS
We identified a germline heterozygous 23 Kb CDH1-TANGO6 deletion in a family with eight diffuse gastric cancers, six before age 30. Atypical HDGC high penetrance and young cancer-onset argued towards a role for the deleted region downstream of CDH1, which we proved to present accessible chromatin, and CDH1 promoter interactors in normal stomach. CRISPR-Cas9 edited cells mimicking the CDH1-TANGO6 deletion display the strongest CDH1 mRNA downregulation, more impacted adhesion-associated, type-I interferon immune-associated and oncogenic signalling pathways, compared to wild-type or CDH1-deleted cells. This finding solved an 18-year family odyssey and engaged carrier family members in a cancer prevention pathway of care.
CONCLUSION
In this work, we demonstrated that regulatory elements lying down-stream of CDH1 are part of a chromatin network that control CDH1 expression and influence cell transcriptome and associated signalling pathways, likely explaining high disease penetrance and very young cancer-onset. This study highlights the importance of incorporating scientific-technological updates and clinical guidelines in routine diagnosis, given their impact in timely genetic diagnosis and disease prevention.
Topics: Humans; Adult; Stomach Neoplasms; Penetrance; Genetic Predisposition to Disease; Adenocarcinoma; Cadherins; Chromatin; Germ-Line Mutation; Antigens, CD
PubMed: 37249750
DOI: 10.1007/s10120-023-01395-0