Lone and secondary nonvalvular atrial fibrillation: role of a genetic susceptibility

Background: An involvement of the renin angiotensin system in atrial fibrillation (AF) has been hypothesized, and ACE DD genotype has been suggested to influence the predisposition to AF. The aim of this study was to investigate the role of the ACE I/D polymorphism in relation to the different clinical forms of AF, lone and secondary nonvalvular atrial fibrillation (NVAF). Methods: 510 consecutive patients with documented NVAF (106 patients had lone, and 404 secondary NVAF), and 520 controls with a negative history of cardiovascular disease have been studied. Results: A significant difference in allele frequency between lone and secondary NVAF (p= 0.002) has been found. The ACE D allele was associated with the predisposition to lone NVAF under a dominant, recessive and additive model, both at univariate and multivariate analysis, after adjustment for age and gender (multivariate analysis: dominant OR= 2.87, p= 0.02; recessive OR= 2.01, p= 0.003; additive OR= 4.47, p < 0.0001). ACE D allele was significantly associated with secondary NVAF at both univariate and multivariate analysis under a recessive and additive, but not dominant, model (multivariate analysis: recessive OR= 1.89, p= 0.001; additive OR= 2.50, p < 0.0001). Conclusions: This study highlights the role of ACE gene in predisposing to both lone and secondary NVAF, further contributing to penetrate the genetic mechanisms responsible for this complex disease. The clinical relevance of our results may be related to the possible characterization of subjects predisposed to NVAF in the absence of traditional risk factors, and to the use of ACE-inhibitors therapy able to improve the arrhythmogenic substrate. (C) 2006 Elsevier Ireland Ltd. All rights reserved

Thymidylate synthase expression and genotype have no major impact on the clinical outcome of colorectal cancer patients treated with 5-fluorouracil

BACKGROUND AND OBJECTIVES: Thymidylate synthase (TS) expression levels appear to be related to response to 5-fluorouracil-(5-FU)-based chemotherapy in colorectal cancer (CRC) patients. Three polymorphisms have been proposed as modulators of TS expression: a tandemly repeated sequence (2R/3R) in the 5' UTR, a SNP (G>C) within the 3R allele and a 6bp deletion in the 3' UTR. To evaluate the influence of TS expression and polymorphisms on clinical outcome of 5-FU-treated patients we performed a comprehensive genetic analysis on 63 CRC patients. METHODS: TS expression levels were analyzed in normal and tumor tissues. TS coding sequence and UTR polymorphisms were investigated on DNA from normal tissue. LOH analysis was performed to determine tumor genotype. RESULTS: A difference in disease-free survival (DFS), although not statistically significant, was observed between high and low mRNA expression levels: patients with low levels showed longer DFS. The 2R2R genotype showed significantly lower expression than the 3R3R and 2R3R genotypes in normal tissue. No other TS polymorphism was associated with mRNA expression or clinical outcome. CONCLUSIONS: The results obtained in this pilot study indicate that the number of 5' UTR repeats is the major genetic determinant of TS expression. The lack of association with other polymorphisms might be partially explained by the existence of linkage disequilibrium in the TS gene. Our data support the growing evidence that TS control may require multiple mechanisms acting in close coordination with one another and suggest that TS genotyping alone in tumor samples is not sufficient to accurately predict response to 5-FU

Base-Excision Repair Mutational Signature in Two Sebaceous Carcinomas of the Eyelid

: Personalized medicine aims to develop tailored treatments for individual patients based on specific mutations present in the affected organ. This approach has proven paramount in cancer treatment, as each tumor carries distinct driver mutations that respond to targeted drugs and, in some cases, may confer resistance to other therapies. Particularly for rare conditions, personalized medicine has the potential to revolutionize treatment strategies. Rare cancers often lack extensive datasets of molecular and pathological information, large-scale trials for novel therapies, and established treatment guidelines. Consequently, surgery is frequently the only viable option for many rare tumors, when feasible, as traditional multimodal approaches employed for more common cancers often play a limited role. Sebaceous carcinoma of the eyelid is an exceptionally rare cancer affecting the eye's adnexal tissues, most frequently reported in Asia, but whose prevalence is significantly increasing even in Europe and the US. The sole established curative treatment is surgical excision, which can lead to significant disfigurement. In cases of metastatic sebaceous carcinoma, validated drug options are currently lacking. In this project, we set out to characterize the mutational landscape of two sebaceous carcinomas of the eyelid following surgical excision. Utilizing available bioinformatics tools, we demonstrated our ability to identify common features promptly and accurately in both tumors. These features included a Base-Excision Repair mutational signature, a notably high tumor mutational burden, and key driver mutations in somatic tissues. These findings had not been previously reported in similar studies. This report underscores how, in the case of rare tumors, it is possible to comprehensively characterize the mutational landscape of each individual case, potentially opening doors to targeted therapeutic options

A novel nonsense PTH1R variant shows incomplete penetrance of primary failure of eruption: a case report

Background: Aim of this work was to describe a rare inheritance pattern of Primary Failure of Eruption (PFE) in a small family with incomplete penetrance of PFE and a novel nonsense PTH1R variant. Case presentation: The proband, a 26 year-old man with a significant bilateral open-bite, was diagnosed with PFE using clinical and radiographic characteristics. DNA was extracted from the proband and his immediate family using buccal swabs and the entire PTH1R coding sequence was analyzed, revealing a novel heterozygous nonsense variant in exon 7 of PTH1R (c.505G > T). This variant introduces a premature stop codon in position 169, predicted to result in the production of a truncated and non-functional protein. This variant has never been reported in association with PFE and is not present in the Genome Aggregation Database (gnomAD). Interestingly, the c.505G > T variant has also been identified in the unaffected mother of our proband, suggesting incomplete penetrance of PFE. Conclusions: In this study, we report a new PTH1R variant that segregates in an autosomal dominant pattern and causes PFE with incomplete penetrance. This underlines the diagnostic value of a thorough clinical and genetic analysis of all family members in order to estimate accurate recurrence risks, identify subtle clinical manifestations and provide proper management of PFE patients

A founder MLH1 mutation in families from the districts of Modena and Reggio-Emilia in northern Italy with hereditary non-polyposis colorectal cancer associated with protein elongation and instability.

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Disease expression in juvenile polyposis syndrome : a retrospective survey on a cohort of 221 European patients and comparison with a literature-derived cohort of 473 SMAD4/BMPR1A pathogenic variant carriers

Purpose Juvenile polyposis syndrome (JPS) is a rare, autosomal-dominantly inherited cancer predisposition caused in approximately 50% of cases by pathogenic germline variants in SMAD4 and BMPR1A. We aimed to gather detailed clinical and molecular genetic information on JPS disease expression to provide a basis for management guidelines and establish open access variant databases. Methods We performed a retrospective, questionnaire-based European multicenter survey on and established a cohort of SMAD4/BMPR1A pathogenic variant carriers from the medical literature. Results We analyzed questionnaire-based data on 221 JPS patients (126 kindreds) from ten European centers and retrieved literature-based information on 473 patients. Compared with BMPR1A carriers, SMAD4 carriers displayed anemia twice as often (58% vs. 26%), and exclusively showed overlap symptoms with hemorrhagic telangiectasia (32%) and an increased prevalence (39% vs. 13%) of gastric juvenile polyps. Cancer, reported in 15% of JPS patients (median age 41 years), mainly occurred in the colorectum (overall: 62%, SMAD4: 58%, BMPR1A: 88%) and the stomach (overall: 21%; SMAD4: 27%, BMPR1A: 0%). Conclusion This comprehensive retrospective study on genotype-phenotype correlations in 694 JPS patients corroborates previous observations on JPS in general and SMAD4 carriers in particular, facilitates recommendations for clinical management, and provides the basis for open access variant SMAD4 and BMPR1A databases.Peer reviewe

Constitutional mismatch repair deficiency–associated brain tumors: report from the European C4CMMRD consortium

Abstract Background Malignant brain tumors (BT) are among the cancers most frequently associated with constitutional mismatch repair deficiency (CMMRD), a rare childhood cancer predisposition syndrome resulting from biallelic germline mutations in mismatch repair genes. This study analyzed data from the European "Care for CMMRD" (C4CMMRD) database to describe their clinical characteristics, treatments, and outcome with the aim of improving its diagnosis/treatment. Methods Retrospective analysis of data on patients with CMMRD and malignant BT from the C4CMMRD database up to July 2017. Results Among the 87 registered patients, 49 developed 56 malignant BTs: 50 high-grade gliomas (HGG) (with giant multinucleated cells in 16/21 histologically reviewed tumors) and 6 embryonal tumors. The median age at first BT was 9.2 years [1.1–40.6], with nine patients older than 18. Twenty-seven patients developed multiple malignancies (including16 before the BT). Most patients received standard treatment, and eight patients immunotherapy for relapsed HGG. The 3- and 5-year overall survival (OS) rates were 30% (95% CI: 19–45) and 22% (95% CI: 12–37) after the first BT, with worse prognosis for HGG (3-year OS = 20.5%). Six patients were alive (median follow-up 2.5 years) and 43 dead (38 deaths, 88%, were BT-related). Other CMMRD-specific features were café-au-lait macules (40/41), multiple BTs (5/15), developmental brain anomalies (11/15), and consanguinity (20/38 families). Conclusions Several characteristics could help suspecting CMMRD in pediatric malignant BTs: giant cells on histology, previous malignancies, parental consanguinity, café-au-lait macules, multiple BTs, and developmental brain anomalies. The prognosis of CMMRD-associated BT treated with standard therapies is poor requiring new therapeutic up-front approaches

The chromosome analysis of the miscarriage tissue. Miscarried embryo/fetal crown rump length (CRL) measurement: A practical use

Objective To investigate whether miscarried embryo/fetal crown rump length (CRL) measurement may yield a practical application for predicting a conclusive result at the cytogenetic analysis of miscarriage tissue. Our study might help in improving the cytogenetic method, the results of which may be affected by maternal cell contamination (MCC). In particular, we aimed at establishing whether the miscarried embryo/fetal CRL measurement shows accuracy in predicting the possibility of MCC and the scan cut-off value useful to this purpose and, as a result, suggest a multi-step procedure for the genetic ascertainment. Methods Women experiencing at least two miscarriages of less than 20 weeks size at the Pregnancy Loss Unit at Fondazione Policlinico A. Gemelli underwent a scan before surgery. The CRL value was recorded. After the dilatation and courettage (D&C) procedure, miscarriage tissue was processed through the proposed multi-step procedure before performing oligo-nucleotide- based and SNP (single nucleotide polymorphisms)-based comparative genomic hybridization (CGH+SNP) microarray analysis. Results 63 women and 63 miscarriages met the criteria. By using the Receiving Operator Characteristic (ROC) curves, CRL showed an AUC of 0.816 (95%CI:0.703\ub10.928,p<0.001). A CRL24.5 mm cut-off value showed a higher positive likelihood ratio (5.27) but, conversely, a higher negative likelihood ratio (0.64) in predicting the possibility of MCC. Microarray analysis was successful in the totality of cases in which the embryo/fetal origin of miscarriage tissues was proven