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Journal of Thoracic Oncology : Official... Dec 2023Brain metastases (BMs) in patients with advanced and metastatic NSCLC are linked to poor prognosis. Identifying genomic alterations associated with BM development could... (Meta-Analysis)
Meta-Analysis Review
INTRODUCTION
Brain metastases (BMs) in patients with advanced and metastatic NSCLC are linked to poor prognosis. Identifying genomic alterations associated with BM development could influence screening and determine targeted treatment. We aimed to establish prevalence and incidence in these groups, stratified by genomic alterations.
METHODS
A systematic review and meta-analysis compliant with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses were conducted (PROSPERO identification CRD42022315915). Articles published in MEDLINE, EMBASE, and Cochrane Library between January 2000 and May 2022 were included. Prevalence at diagnosis and incidence of new BM per year were obtained, including patients with EGFR, ALK, KRAS, and other alterations. Pooled incidence rates were calculated using random effects models.
RESULTS
A total of 64 unique articles were included (24,784 patients with NSCLC with prevalence data from 45 studies and 9058 patients with NSCLC having incidence data from 40 studies). Pooled BM prevalence at diagnosis was 28.6% (45 studies, 95% confidence interval [CI]: 26.1-31.0), and highest in patients that are ALK-positive (34.9%) or with RET-translocations (32.2%). With a median follow-up of 24 months, the per-year incidence of new BM was 0.13 in the wild-type group (14 studies, 95% CI: 0.11-0.16). Incidence was 0.16 in the EGFR group (16 studies, 95% CI: 0.11-0.21), 0.17 in the ALK group (five studies, 95% CI: 0.10-0.27), 0.10 in the KRAS group (four studies, 95% CI: 0.06-0.17), 0.13 in the ROS1 group (three studies, 95% CI: 0.06-0.28), and 0.12 in the RET group (two studies, 95% CI: 0.08-0.17).
CONCLUSIONS
Comprehensive meta-analysis indicates a higher prevalence and incidence of BM in patients with certain targetable genomic alterations. This supports brain imaging at staging and follow-up, and the need for targeted therapies with brain penetrance.
Topics: Humans; Lung Neoplasms; Incidence; Protein-Tyrosine Kinases; Proto-Oncogene Proteins p21(ras); Proto-Oncogene Proteins; Carcinoma, Non-Small-Cell Lung; Genomics; Brain Neoplasms; Receptor Protein-Tyrosine Kinases; ErbB Receptors
PubMed: 37392903
DOI: 10.1016/j.jtho.2023.06.017 -
Journal of Clinical Oncology : Official... Feb 2024To develop recommendations for germline mutation testing for patients with breast cancer.
PURPOSE
To develop recommendations for germline mutation testing for patients with breast cancer.
METHODS
An ASCO-Society of Surgical Oncology (SSO) panel convened to develop recommendations based on a systematic review and formal consensus process.
RESULTS
Forty-seven articles met eligibility criteria for the germline mutation testing recommendations; 18 for the genetic counseling recommendations.
RECOMMENDATIONS
/ mutation testing should be offered to all newly diagnosed patients with breast cancer ≤65 years and select patients >65 years based on personal history, family history, ancestry, or eligibility for poly(ADP-ribose) polymerase (PARP) inhibitor therapy. All patients with recurrent breast cancer who are candidates for PARP inhibitor therapy should be offered / testing, regardless of family history. / testing should be offered to women who develop a second primary cancer in the ipsilateral or contralateral breast. For patients with prior history of breast cancer and without active disease, testing should be offered to patients diagnosed ≤65 years and selectively in patients diagnosed after 65 years, if it will inform personal and family risk. Testing for high-penetrance cancer susceptibility genes beyond / should be offered to those with supportive family histories; testing for moderate-penetrance genes may be offered if necessary to inform personal and family cancer risk. Patients should be provided enough pretest information for informed consent; those with pathogenic variants should receive individualized post-test counseling. Variants of uncertain significance should not impact management, and patients with such variants should be followed for reclassification. Referral to providers experienced in clinical cancer genetics may help facilitate patient selection and interpretation of expanded testing, and provide counseling of individuals without pathogenic germline variants but with significant family history.Additional information is available at www.asco.org/breast-cancer-guidelines.
Topics: Humans; Female; Breast Neoplasms; Genetic Testing; BRCA1 Protein; Surgical Oncology; BRCA2 Protein; Neoplasm Recurrence, Local; Germ-Line Mutation; Risk Assessment; Germ Cells; Genetic Predisposition to Disease
PubMed: 38175972
DOI: 10.1200/JCO.23.02225 -
Circulation Jan 2024Hypertrophic cardiomyopathy (HCM) is characterized by unexplained left ventricular hypertrophy and is classically caused by pathogenic or likely pathogenic variants... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Hypertrophic cardiomyopathy (HCM) is characterized by unexplained left ventricular hypertrophy and is classically caused by pathogenic or likely pathogenic variants (P/LP) in genes encoding sarcomere proteins. Not all subclinical variant carriers will manifest clinically overt disease because penetrance (proportion of sarcomere or sarcomere-related P/LP variant carriers who develop disease) is variable, age dependent, and not reliably predicted.
METHODS
A systematic search of the literature was performed. We used random-effects generalized linear mixed model meta-analyses to contrast the cross-sectional prevalence and penetrance of sarcomere or sarcomere-related genes in 2 different contexts: clinically-based studies on patients and families with HCM versus population or community-based studies. Longitudinal family/clinical studies were additionally analyzed to investigate the rate of phenotypic conversion from subclinical to overt HCM during follow-up.
RESULTS
In total, 455 full-text manuscripts and articles were assessed. In family/clinical studies, the prevalence of sarcomere variants in patients diagnosed with HCM was 34%. The penetrance across all genes in nonproband relatives carrying P/LP variants identified during cascade screening was 57% (95% CI, 52%-63%), and the mean age at HCM diagnosis was 38 years (95% CI, 36%-40%). Penetrance varied from ≈32% for (myosin light chain 3) to ≈55% for (myosin-binding protein C3), ≈60% for (troponin T2) and (troponin I3), and ≈65% for (myosin heavy chain 7). Population-based genetic studies demonstrate that P/LP sarcomere variants are present in the background population but at a low prevalence of <1%. The penetrance of HCM in incidentally identified P/LP variant carriers was also substantially lower at ≈11%, ranging from 0% in Atherosclerosis Risk in Communities to 18% in UK Biobank. In longitudinal family studies, the pooled phenotypic conversion across all genes was 15% over an average of ≈8 years of follow-up, starting from a mean of ≈16 years of age. However, short-term gene-specific phenotypic conversion varied between ≈12% for and ≈23% for .
CONCLUSIONS
The penetrance of P/LP variants is highly variable and influenced by currently undefined and context-dependent genetic and environmental factors. Additional longitudinal studies are needed to improve our understanding of true lifetime penetrance in families and in the community and to identify drivers of the transition from subclinical to overt HCM.
Topics: Humans; Adult; Penetrance; Mutation; Cross-Sectional Studies; Pedigree; Cardiomyopathy, Hypertrophic; Troponin T
PubMed: 37929589
DOI: 10.1161/CIRCULATIONAHA.123.065987 -
Obesity Reviews : An Official Journal... May 2024The recent development of next-generation sequencing (NGS) technologies has led to an increase of mutation screening reports of monogenic obesity genes in diverse... (Review)
Review
Sequencing methods, functional characterization, prevalence, and penetrance of rare coding mutations in panels of monogenic obesity genes from the leptin-melanocortin pathway: A systematic review.
The recent development of next-generation sequencing (NGS) technologies has led to an increase of mutation screening reports of monogenic obesity genes in diverse experimental designs. However, no study to date has summarized their findings. Two reviewers independently conducted a systematic review of MEDLINE, Embase, and Web of Science Core Collection databases from inception to September 2022 to identify monogenic non-syndromic obesity gene screening studies. Of 1051 identified references, 31 were eligible after title and abstract screening and 28 after full-text reading and risk of bias and quality assessment. Most studies (82%) used NGS methods. The number of genes screened varied from 2 to 12 genes from the leptin-melanocortin pathway. While all the included studies used in silico tools to assess the functional status of mutations, only 2 performed in vitro tests. The prevalence of carriers of pathogenic/likely pathogenic monogenic mutations is 13.24% on average (heterozygous: 12.31%; homozygous/heterozygous composite: 0.93%). As no study reported the penetrance of pathogenic mutations on obesity, we estimated that homozygous carriers exhibited a complete penetrance (100%) and heterozygous carriers a variable penetrance (3-100%). The review provides an exhaustive description of sequencing methods, functional characterization, prevalence, and penetrance of rare coding mutations in monogenic non-syndromic obesity genes.
PubMed: 38779716
DOI: 10.1111/obr.13754 -
Journal of Neurosurgery. Spine Apr 2024Chiari malformations (CMs) are a group of congenital or acquired disorders characterized by hindbrain overcrowding into an underdeveloped posterior cranial fossa. CM is... (Review)
Review
OBJECTIVE
Chiari malformations (CMs) are a group of congenital or acquired disorders characterized by hindbrain overcrowding into an underdeveloped posterior cranial fossa. CM is considered largely sporadic-however, there exists growing evidence of transmissible genetic underpinnings. The purpose of this systematic review of all familial studies of CM was to investigate the existence of an inherited component and provide recommendations to manage and monitor at-risk family members.
METHODS
This paper includes the following: 1) a unique case report of dizygotic twins who presented at the Toronto Western Hospital Spinal Cord Clinic with symptomatic CM type 1 (CM-1) and syringomyelia; and 2) a systematic review of familial CM. The EMBASE and MEDLINE databases were searched on June 27, 2023, in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Only articles in the English language concerning the diagnosis of CM in > 1 human family member presented as a case study, case series, or literature review were included.
RESULTS
Among the 29 articles included in the final analysis, a total of 34 families with CM were analyzed. An average of 3 cases of CM were found per family among all generations. Eighty-one cases (88%) reported CM-1, whereas the other 11 (12%) cases reported either CM-0, CM-1.5, or tonsillar ectopia. A syrinx was present in 37 (54%) cases, with 14 (38%) of these patients also reporting a skeletal abnormality, the most common comorbidity. Most family members diagnosed with CM were siblings (18; 35%), followed by monozygotic twins/triplets (12; 23%).
CONCLUSIONS
Patients most often presented with headaches, sensory disturbances, or generalized symptoms. Overall, there exists mounting evidence for a hereditary component of CM. It is unlikely to be explained by a classic mendelian inheritance pattern, but is rather a polygenic architecture influenced by variable penetrance, cosegregation, and entirely nongenetic factors. For first-degree relatives of those affected by CM, the authors' findings may influence clinicians to conduct closer clinical and radiographic monitoring, promote patient education, and consider earlier genetic testing.
PubMed: 38608294
DOI: 10.3171/2024.1.SPINE231277 -
Molecular Genetics and Metabolism Jul 2023Sengers syndrome (OMIM# 212350) is a rare autosomal recessive mitochondrial disease caused by biallelic pathogenic variants in the AGK gene, which encodes the... (Review)
Review
Sengers syndrome (OMIM# 212350) is a rare autosomal recessive mitochondrial disease caused by biallelic pathogenic variants in the AGK gene, which encodes the acylglycerol kinase enzyme. The syndrome was originally defined as a "triad" of hypertrophic cardiomyopathy, cataracts, and lactic acidosis, with or without skeletal myopathy. The clinical manifestation of Sengers Syndrome exhibits substantial heterogeneity, with mild and severe/infantile forms reported. Further, biallelic AGK pathogenic variants have also been identified in a familial case of non-syndromic isolated cataract (OMIM# 614691), expanding our understanding of the gene's influence beyond the originally defined syndrome. In this study, we provide a systematic review of molecularly confirmed cases with biallelic AGK pathogenic variants (Supplementary Table 1). Our analysis demonstrates the variable expressivity and penetrance of the central features of Sengers syndrome, as follows: cataracts (98%), cardiomyopathy (88%), lactic acidosis (adjusted 88%), and skeletal myopathy (adjusted 74%) (Table 1). Furthermore, we investigate the associations between genotype, biochemical profiles, and clinical outcomes, with a particular focus on infantile mortality. Our findings reveal that patients carrying homozygous nonsense variants have a higher incidence of infant mortality and a lower median age of death (p = 0.005 and p = 0.02, Table 2a). However, the location of pathogenic variants within the AGK domains was not significantly associated with infantile death (p = 0.62, Table 2b). Additionally, we observe a borderline association between the absence of lactic acidosis and longer survival (p = 0.053, Table 2c). Overall, our systematic review sheds light on the diverse clinical manifestations of AGK-related disorders and highlights potential factors that influence its prognosis. These provide important implications for the diagnosis, treatment, and counseling of affected individuals and families.
Topics: Infant; Humans; Acidosis, Lactic; Cardiomyopathies; Cataract; Muscular Diseases; Biological Variation, Population; Phosphotransferases (Alcohol Group Acceptor)
PubMed: 37354892
DOI: 10.1016/j.ymgme.2023.107626 -
Frontiers in Genetics 2023To analyze the phenotypes, genotypes, and the relationship of phenotypes and genotypes for Chinese patients with Bardet-Biedl syndrome (BBS). The Chinese Wanfang and...
To analyze the phenotypes, genotypes, and the relationship of phenotypes and genotypes for Chinese patients with Bardet-Biedl syndrome (BBS). The Chinese Wanfang and Weipu data, and PubMed were searched up to December 2022. Patients with detailed clinical feature data were involved in the analysis. A total of 153 Chinese patients, including 87 males, 53 females, and 12 unknown, were enrolled. Their ages ranged from 1.2 to 44 years old with a mean of 16.70 ± 9.90 years old. Among these patients, 80 (52.29%) were reported by ophthalmologists, and only 24 (15.68%) reported by pediatricians. Most patients (132/137, 96.35%) had visual problems; 131/153 (85.62%) had polydactyly; 124/132 (93.93%) were overweight or obese; 63/114 (55.26%) had renal abnormalities; kidney dysfunction was found in 33 (21.57%); 83/104 (79.81%) had hypogonadism and/or genital hypoplasia; and 111/136 (81.62%) had mental retardation. In this series, genetic analysis was performed in 90 (58.82%) patients, including 22 (24.71%), 20 (22.73%), and 10 (11.24%) patients. Moreover, 11 fetuses were diagnosed prenatally in the last 4 years except for one patient in 2004 year. It was noted that had higher penetrance. had higher hearing impairment and lower renal abnormality penetrance. also had lower renal abnormality penetrance as well. Misdiagnosis or miss diagnosis of BBS may be common in China. In patients with polydactyly, visual impairment, obesity, renal abnormalities, hypogonadism, and mental retardation, or in fetuses with polydactyly and/or renal abnormalities, BBS should be considered in the differential diagnosis. Other deformities should be evaluated carefully and genetic analysis should be performed as early as possible.
PubMed: 38034494
DOI: 10.3389/fgene.2023.1247557 -
The Journal of Antimicrobial... Apr 2024Aminoglycosides (AGs) are important antibiotics in the treatment of Gram-negative sepsis. However, they are associated with the risk of irreversible sensorineural...
BACKGROUND
Aminoglycosides (AGs) are important antibiotics in the treatment of Gram-negative sepsis. However, they are associated with the risk of irreversible sensorineural hearing loss (SNHL). Several genetic variants have been implicated in the development of ototoxicity.
OBJECTIVES
To evaluate the pharmacogenetic determinants of AG-related ototoxicity.
METHODS
This study followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses and was registered on Prospero (CRD42022337769). In Dec 2022, PubMed, Cochrane Library, Embase and MEDLINE were searched. Included studies were those reporting original data on the effect of the AG-exposed patient's genome on the development of ototoxicity.
RESULTS
Of 10 202 studies, 31 met the inclusion criteria. Twenty-nine studies focused on the mitochondrial genome, while two studied the nuclear genome. One study of neonates found that 30% of those with the m.1555A > G variant failed hearing screening after AG exposure (level 2 evidence). Seventeen additional studies found the m.1555A > G variant was associated with high penetrance (up to 100%) of SNHL after AG exposure (level 3-4 evidence). Nine studies of m.1494C > T found the penetrance of AG-related SNHL to be up to 40%; however, this variant was also identified in those with SNHL without AG exposure (level 3-4 evidence). The variants m.1005T > C and m.1095T > C may be associated with AG-related SNHL; however, further studies are needed.
CONCLUSIONS
This review found that the m.1555A > G and m.1494C > T variants in the MT-RNR1 gene have the strongest evidence in the development of AG-related SNHL, although study quality was limited (level 2-4). These variants were associated with high penetrance of a SNHL phenotype following AG exposure.
PubMed: 38629462
DOI: 10.1093/jac/dkae106 -
Clinical Kidney Journal Jan 2024Several studies have examined the frequency of sleep apnoea (SA) in patients with chronic kidney disease (CKD), reporting different prevalence rates. Our systematic...
BACKGROUND
Several studies have examined the frequency of sleep apnoea (SA) in patients with chronic kidney disease (CKD), reporting different prevalence rates. Our systematic review and meta-analysis aimed to define the clinical penetrance of SA in CKD and end-stage kidney disease (ESKD) patients.
METHODS
Ovid-MEDLINE and PubMed databases were explored up to 5 June 2023 to identify studies providing SA prevalence in CKD and ESKD patients assessed by different diagnostic methods, either sleep questionnaires or respiration monitoring equipment [such as polysomnography (PSG), type III portable monitors or other diagnostic tools]. Single-study data were pooled using the random-effects model. The Chi and Cochrane-I tests were used to assess the presence of heterogeneity, which was explored performing sensitivity and/or subgroup analyses.
RESULTS
A cumulative analysis from 32 single-study data revealed a prevalence of SA of 57% [95% confidence interval (CI) 42%-71%] in the CKD population, whereas a prevalence of 49% (95% CI 47%-52%) was found pooling data from 91 studies in ESKD individuals. The prevalence of SA using instrumental sleep monitoring devices, including classical PSG and type III portable sleep monitors, was 62% (95% CI 52%-72%) and 56% (95% CI 42%-69%) in CKD and ESKD populations, respectively. Sleep questionnaires revealed a prevalence of 33% (95% CI 16%-49%) and 39% (95% CI 30%-49%).
CONCLUSIONS
SA is commonly seen in both non-dialysis CKD and ESKD patients. Sleep-related questionnaires underestimated the presence of SA in this population. This emphasizes the need to use objective diagnostic tools to identify such a syndrome in kidney disease.
PubMed: 38186876
DOI: 10.1093/ckj/sfad179 -
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