Annals of Human Genetics最新文献

Background

To compare the clinicopathological characteristics of nonmetastatic breast cancer patients with and without BRCA variations and to investigate the impact of BRCA variations on prognosis.

Methods

This retrospective single-center study involved an analysis of 938 patients with localized or locally advanced breast cancer who underwent BRCA variation testing. The patients were divided into three groups: 757 were without BRCA variation, 64 were with BRCA1 variation, and 117 were with BRCA2 variation.

Results

In patients with BRCA1 variation, the Ki67, grade, and frequency of triple-negative breast cancer were significantly higher than in patients without BRCA variation and with BRCA2 variation. The 5-year disease-free survival in patients with BRCA1 variation was significantly worse than the other two groups (without BRCA, BRCA1, and BRCA2; 87.7%, 69.9%, and 95.3%, respectively, p = 0.049). Multivariate analysis detected no significant difference between groups. The pathological complete response rates with neoadjuvant therapy were significantly better in patients with BRCA variations than those without BRCA variations (49.2% vs. 29.6%, p = 0.024).

Conclusion

Patients with BRCA1 variation had more aggressive tumor characteristics, such as higher Ki67 and higher grade. Also, triple-negative breast cancer was more common. The presence of BRCA1 variation may worsen survival outcomes. Neoadjuvant treatment responses of patients with BRCA variations were significantly better, and neoadjuvant treatment may contribute to survival outcomes in nonmetastatic patients with BRCA variations.

Lactase persistence (LP) — the genetic trait that determines the continued expression of the enzyme lactase into adulthood — has undergone recent, rapid positive selection since the advent of animal domestication and dairying in some human populations. While underlying evolutionary explanations have been widely posited and studied, the molecular basis of LP remains less so. This review considers the genetic and epigenetic bases of LP. Multiple single-nucleotide polymorphisms (SNPs) in an LCT enhancer in intron 13 of the neighbouring MCM6 gene are associated with LP. These SNPs alter binding of transcription factors (TFs) and likely prevent age-related increases in methylation in the enhancer, maintaining LCT expression into adulthood to cause LP. However, the complex relationship between the genetics and epigenetics of LP is not fully characterised, and the mode of action of methylation quantitative trait loci (meQTLs) (SNPs affecting methylation) generally remains poorly understood. Here, we examine published LP data to propose a model describing how methylation in the LCT enhancer is prevented in LP adults. We argue that this occurs through altered binding of the TF Oct-1 (encoded by the gene POU2F1) and neighbouring TFs GATA-6 (GATA6), HNF-3A (FOXA1) and c-Ets1 (ETS1) acting in concert. We therefore suggest a plausible new model for LCT downregulation in the context of LP, with wider relevance for future work on the mechanisms of other meQTLs.

The primary etiology of congenital hearing loss is attributed to genetic factors, with GJB2 identified as a pivotal gene across diverse ethnic groups. Additionally, nonsyndromic hearing loss is predominantly inherited in an autosomal recessive manner. We used Sanger sequencing to analyze GJB2 in 17 deaf children from 13 unrelated Ivory Coast families. One family had two children born with severe congenital deafness and exhibited pathogenic compound heterozygous variants. These variants included a nonsense substitution (c.132G > A or p.Trp44Ter) and a newly discovered duplication of 7 base pairs (c.205_211dupTTCCCCA or p.Ser72ProfsTer32). Segregation testing confirmed these variants, marking the first identification of GJB2 in an Ivorian family with congenital hearing loss.

Genome-wide association studies (GWAS) have significantly enhanced our understanding of the genetic basis of complex diseases. Despite the technological advancements, gaps in our understanding remain, partly due to small effect sizes and inadequate coverage of genetic variation. Multiancestry GWAS meta-analysis (MAGMA) addresses these challenges by integrating genetic data from diverse populations, thereby increasing power to detect loci and improving fine-mapping resolution to identify causal variants across different ancestry groups. This review provides an overview of the protocols, statistical methods, and software of MAGMA, as well as highlighting some challenges associated with this approach.

Background

Observational studies have shown that cholelithiasis and cholecystectomy are associated with the risk of breast cancer (BC) and gynecological cancers, but whether these relationships are causal has not been established and remains controversial.

Methods

Our study began with a meta-analysis that synthesized data from prior observational studies to examine the association between cholelithiasis, cholecystectomy, and the risk of BC and gynecological cancers. Subsequently, a two-sample Mendelian randomization (MR) analysis was conducted utilizing genetic variant data to investigate the potential causal relationship between cholelithiasis, cholecystectomy, and the aforementioned cancers.

Results

The results of the meta-analysis demonstrated a significant association between cholecystectomy and the risk of BC (risk ratio [RR] = 1.04, 95% confidence interval [CI]: 1.01–1.06, p = 0.002) and endometrial cancer (EC) (RR = 1.26, 95% CI: 1.02–1.56, p = 0.031). Conversely, no significant association was observed between cholelithiasis and the risk of BC, EC, and ovarian cancer. The MR analysis revealed no discernible causal connection between cholelithiasis and overall BC (p = 0.053), as well as BC subtypes (including estrogen receptor-positive/negative). Similarly, there was no causal effect of cholecystectomy on BC risk (p = 0.399) and its subtypes. Furthermore, no causal associations were identified between cholelithiasis, cholecystectomy, and the risk of gynecological cancers (ovarian, endometrial, and cervical cancer [CC]) (all p > 0.05).

Conclusion

This study does not support a causal link between cholelithiasis and cholecystectomy and an increased risk of female cancers such as breast, endometrial, ovarian, and CC.

Introduction

The phenotypic consequences of the p.Arg577Ter variant in the α-actinin-3 (ACTN3) gene are suggestive of a trade-off between performance traits for speed and endurance sports. Although there is a consistent association of the c.1729C allele (aka R allele) with strength/power traits, there is still a debate on whether the null allele (c.1729T allele; aka X allele) influences endurance performance. The present study aimed to test the association of the ACTN3 p.Arg577Ter variant with long-distance endurance athlete status, using previously published data with the Brazilian population.

Methods

Genotypic data from 203 long-distance athletes and 1724 controls were analysed in a case–control approach.

Results

The frequency of the X allele was significantly higher in long-distance athletes than in the control group (51.5% vs. 41.4%; p = 0.000095). The R/X and X/X genotypes were overrepresented in the athlete group. Individuals with the R/X genotype instead of the R/R genotype had a 1.6 increase in the odds of being a long-distance athlete (p = 0.012), whereas individuals with the X/X genotype instead of the R/R genotype had a 2.2 increase in the odds of being a long-distance athlete (p = 0.00017).

Conclusion

The X allele, mainly the X/X genotype, was associated with long-distance athlete status in Brazilians.

Introduction

Iran, a country in the Middle East, has several ethnic and ethno-religious groups and needs its own ethnic-specific databases for the forensic statistical parameters and allele frequency of STR markers.

Methods

We have investigated 600 unrelated Turk individuals from four northwestern provinces of Iran using the Identifiler™ system (TPOX, FGA, vWA, TH01, CSF1PO, D2S1338, D3S1358, D5S818, D7S820, D8S1179, D13S317, D16S539, D18S51, D19S433, and D21S11). Furthermore, STR allelic frequencies were compared to previously population-based data.

Results and conclusion

After Bonferroni correction, deviation from Hardy-Weinberg equilibrium (HWE) was observed in the FGA, TPOX, VWA, and D19S433 loci (P value < 0.05). The combined power of discrimination (CPD) and exclusion (CPE) values for all 15 STR loci were 0.9999999999999999999984 and 0.9999999, respectively. In comparison with Azerbaijani and Turkish populations, there were no significant differences on all STR markers. However, in the Chinese Han population, differences at 13 STR loci were detected. Additionally, comparisons of Fischer genetic distance indices (FST) P-values did not reveal any statistically significant difference between Northwestern Iran, Azerbaijan and Iran (Fars) populations. PCA and PCoA analyses showed that our population was grouped with different populations in different quarters, showing a positive and negative correlation, respectively. In the NJ and UPGMA phylogenetic trees, Iranian populations were grouped together. These results demonstrated that the given set of STR markers can be confidently used for all identification tests in Northwestern Iran.

Introduction

Multiple insertion-deletion (multi-InDel) has greater potential in forensic genetics than InDel, and its efficacy in kinship testing, individual identification, DNA mixture detection and ancestry inference remains to be explored.

Methods

Consequently, we designed an efficient and robust system consisting of 41 multi-InDels to evaluate its efficacy in forensic applications in Chinese Hezhou Han (HZH) and Southern Shaanxi Han (SNH) populations and explore the genetic relationships between the SNH, HZH, and 26 reference populations.

Results and conclusion

The obtained results showed that 38 out of the 41 multi-InDels had fairly high genetic variations. The the cumulative probability of discrimination and exclusion values of the multi-InDels (except MI38) in HZH and SNH populations both exceeded 1-e⁻²⁵ and 1-e⁻⁶, correspondingly. The genetic compositions of HZH and SNH individuals were similar to that of East Asians and the Naive Bayes model could well distinguish East Asians, Africans and Americans. These results indicated that the multi-InDel systerm can serve as an effective tool to provide important evidence for the development of multi-InDels in forensic practice and better analyse the genetic background of the Han Chinese populations.

Introduction

Long-read whole genome sequencing like Oxford Nanopore Technology, is increasingly being introduced in clinical settings. With its ability to simultaneously call sequence variation and DNA modifications including 5-methylcytosine, nanopore is a promising technology to improve diagnostics of imprinting disorders.

Methods

Currently, no tools to analyze DNA methylation patterns at known clinically relevant imprinted regions are available. Here we present NanoImprint, which generates an easily interpretable report, based on long-read nanopore sequencing, to use for identifying clinical relevant abnormalities in methylation levels at 14 imprinted regions and diagnosis of common imprinting disorders.

Results and conclusion

NanoImprint outputs a summarizing table and visualization plots displays methylation frequency (%) and chromosomal positions for all regions, with phased data color-coded for the two alleles. We demonstrate the utility of NanoImprint using three imprinting disorder samples from patients with Beckwith-Wiedemann syndrome (BWS), Angelman syndrome (AS) and Prader-Willi syndrome (PWS). NanoImprint script is available from https://github.com/carolinehey/NanoImprint.

Introduction

The progression of prostate cancer (PCa) has been linked worldwide, including in African populations, to the dysregulation of the epithelial–mesenchymal transition (EMT).

Methods

To clarify the connection among EMT markers, clinicopathological parameters, and epidemiological factors, we analyzed 35 PCa specimens from patients in Tunisia, a country in North Africa, arranged by stages. We also carried out extensive molecular and epidemiological analyses.

Results

Significant dysregulation of EMT genes was found, with an overexpression of ZEB-1, Twist, Snail-1, and Vimentin (p < 0.05) and underexpression of E-cadherin and β-catenin (p < 0.05). Positive correlations were observed between transcription factors and the mesenchymal marker Vimentin (p < 0.001, r = 0.574; p = 0.029, r = 0.411; and p < 0.001; r = 0.506) according to Spearman correlation analyses, whereas negative correlations were found between epithelial markers (E-cadherin, β-catenin) and Vimentin (p < 0.05; r < 0). Higher PSA, Gleason scores, and metastasis were all correlated with the dysregulation of EMT (p < 0.05). Notably, there was a positive correlation between higher consumption of tobacco (≥20 Packets per year) and Vimentin expression (p < 0.001, r = 0.854), suggesting a relationship between smoking and EMT activation in the Tunisian population. Moreover, Twist showed a positive correlation with diabetes (p < 0.001, r = 0.385), whereas no significant correlations were found between EMT markers and comorbidities such as hypertension and coronary insufficiency. These results demonstrate the intricate connection between molecular changes, epidemiological factors, and disease progression, and they emphasize the crucial role that EMT plays in promoting PCa aggressiveness in African populations, particularly in Tunisia.

Conclusion

In summary, understanding these correlations could help develop focused treatment plans and enhance patient outcomes for PCa management in African settings.