Promoting advanced medical services in the framework of 3PM-a proof-of-concept by the "Centro" Region of Portugal.

Multidisciplinary team from three universities based in the "Centro" Region of Portugal developed diverse approaches as parts of a project dedicated to enhancing and expanding Predictive, Preventive, and Personalized Medicine (3PM) in the Region. In a sense, outcomes acted as a proof-of-concept, in that they demonstrated the feasibility, but also the relevance of the approaches. The accomplishments comprise defining a new regional strategy for implementing 3PM within the Region, training of human resources in genomic sequencing, and generating good practices handbooks dedicated to diagnostic testing via next-generation sequencing, to legal and ethical concerns, and to knowledge transfer and entrepreneurship, aimed at increasing literacy on 3PM approaches. Further approaches also included support for entrepreneurship development and start-ups, and diverse and relevant initiatives aimed at increasing literacy relevant to 3PM. Efforts to enhance literacy encompassed citizens across the board, from patients and high school students to health professionals and health students. This focus on empowerment through literacy involved a variety of initiatives, including the creation of an illustrated book on genomics and the production of two theater plays centered on genetics. Additionally, authors stressed that genomic tools are relevant, but they are not the only resources 3PM is based on. Thus, they defend that other initiatives intended to enable citizens to take 3PM should include multi-omics and, having in mind the socio-economic burden of chronic diseases, suboptimal health status approaches in the 3PM framework should also be considered, in order to anticipate medical intervention in the subclinical phase. Supplementary Information: The online version contains supplementary material available at 10.1007/s13167-024-00353-9.

Influence of clinical factors on the protective or deleterious impact of genetic variants in orthodontically induced external root resorption: an observational study.

BACKGROUND: Prediction of susceptibility to Orthodontically Induced External Apical Root Resorption (OIEARR) has been hampered by the complex architecture of this multifactorial phenotype. The aim of this study was to analyze the impact of the interaction of multiple variables in the susceptibility to OIEARR. METHODS: The study evaluated 195 patients requiring orthodontic treatment. Nine clinical and treatment variables, single nucleotide polymorphisms (SNPs) from five genes and variables interactions were analyzed as risk factors for OIEARR using a multiple linear regression model. RESULTS: The model explained 29% of OIEARR variability (ANOVA: p < 0.01). Duration of treatment was the most important predictor and gender was the second, closely followed by premolar extraction. For genes encoding osteoprotegerin (OPG), the receptor activator of nuclear factor κ B (RANK) and the IL1 receptor antagonist (IL1RN), the effect of analyzed variants changed from protective to deleterious depending on the duration of treatment and the age of the patient. CONCLUSIONS: This work shows that in OIEARR the impact of genetic susceptibility factors is dynamic changing according to clinical variables.

Lack of association of vitamin D receptor gene polymorphisms with susceptibility to type 1 diabetes mellitus in the Portuguese population.

The vitamin D receptor (VDR) gene is a candidate gene for susceptibility to autoimmune disorders. Association studies of VDR polymorphisms and risk of type 1 diabetes often produced conflicting results in different ethnic backgrounds. The aim of this study was to test for association between common VDR polymorphisms and the genetic susceptibility to type 1 diabetes in the Portuguese population. We genotyped 207 patients with type 1 diabetes and 249 controls for the FokI T>C (rs10735810), BsmI A>G (rs1544410), ApaI G>T (rs7975232), and TaqI C>T (rs731236) single nucleotide polymorphisms by polymerase chain reaction and restriction fragment length polymorphism analysis. The distribution of VDR genotype, allele, and haplotype frequencies did not differ significantly between patients and controls. These data suggest that the single nucleotide polymorphisms of the VDR gene are unlikely to contribute significantly to type 1 diabetes susceptibility in the Portuguese population.

Genetic polymorphism of CYP2D6 influences susceptibility to papillary thyroid cancer.

OBJECTIVE: Xenobiotic-metabolizing enzymes are widely polymorphic and confer interindividual variation in the ability to detoxify carcinogens or to activate pro-carcinogens. A common polymorphism of cytochrome P450 2D6 (CYP2D6) results in lack of enzyme activity and has been associated with an altered susceptibility to several cancers. The aim of this study was to investigate the association between the CYP2D6 poor metaboliser genotype and the risk of papillary thyroid cancer (PTC). DESIGN: Retrospective case-control study. PATIENTS: One hundred and eighty-seven patients with PTC and 256 controls. MEASUREMENTS: Genotyping was performed by PCR and restriction enzyme analysis to detect the presence of the common CYP2D6*4 poor metaboliser allele. RESULTS: The frequency of individuals with the homozygous poor metaboliser genotype was lower in the patient group [1.6 vs. 5.5%, P = 0.037, OR = 0.28 (95% CI 0.09-0.93)]. The CYP2D6*4 allele frequency was also lower in the patient group [13.4 vs. 21.7%, P = 0.002, OR = 0.56 (95% CI 0.39-0.80)]. CONCLUSIONS: The results suggest that the poor metaboliser genotype is associated with a protective effect against PTC. This could be explained by a possible role of CYP2D6 on the metabolic activation of putative environmental chemical thyroid carcinogens or by linkage to another cancer-causing gene. Further research may allow the identification of metabolic risk factors and contribute towards understanding the molecular mechanisms involved in thyroid carcinogenesis.

PROP1 gene analysis in Portuguese patients with combined pituitary hormone deficiency.

OBJECTIVE: Mutations of the PROP1 gene lead to combined pituitary hormone deficiency (CPHD), which is characterized by a deficiency of GH, TSH, LH/FSH, PRL and, less frequently, ACTH. This study was undertaken to investigate the molecular defect in a cohort of patients with CPHD. DESIGN, PATIENTS AND MEASUREMENTS: A multicentric study involving 46 cases of CPHD (17 familial cases belonging to seven kindreds and 29 sporadic cases) selected on the basis of clinical and hormonal evidence of GH deficiency, central hypothyroidism and hypogonadotrophic hypogonadism, in the absence of an identified cause of hypopituitarism. Mutations of PROP1 were investigated by DNA sequencing. Clinical, hormonal and neuroradiological data were collected at each centre. RESULTS: PROP1 mutations were identified in all familial cases: five kindreds presented a c. 301-302delAG mutation, one kindred presented a c. 358C --> T (R120C) mutation and one presented a previously unreported initiation codon mutation, c. 2T --> C. Of the 29 sporadic cases, only two (6.9%) presented PROP1 germline mutations (c. 301-302delAG, in both). Phenotypic variability was observed among patients with the same mutations, particularly the presence and age of onset of hypocortisolism, the levels of PRL and the results of pituitary imaging. One patient presented a sellar mass that persisted into adulthood. CONCLUSIONS: This is the first report of a mutation in the initiation codon of the PROP1 gene and this further expands the spectrum of known mutations responsible for CPHD. The low mutation frequency observed in sporadic cases may be due to the involvement of other unidentified acquired or genetic causes.

Molecular detection of EGFRvIII-positive cells in the peripheral blood of breast cancer patients.

The aim of this study is to evaluate epidermal growth factor receptor variant III, EGFRvIII, a cancer specific mutant, as a possible marker for the diagnosis of breast cancer occult systemic disease. EGFRvIII mRNA was identified by an RT-nested PCR with a high sensitivity. In 102 women studied, the mutant was detected in the peripheral blood of 30% of 33 low risk, early stage patients, in 56% of 18 patients selected for neoadjuvant chemotherapy, in 63.6% of 11 patients with disseminated disease and 0% of 40 control women. In low risk, early stage patients, the presence of one or more tumour characteristics predicting recurrence such as the absence of oestrogen receptors and the presence of ERBB2 or histologic grades G2/G3 was significantly associated with EFGRvIII detection (p<0.05). EGFRvIII mRNA has characteristics to be a useful marker for the diagnosis of occult systemic disease in breast cancer. Follow-up studies will evaluate its clinical value as a decision criterion for systemic therapy.

CYP2D6 genetic polymorphisms are associated with susceptibility to pituitary tumors.

Several polymorphisms of drug-metabolizing enzymes have been implicated in the susceptibility to tumor development. The role of the CYP2D6, GSTM1 and GSTT1 genes has been extensively studied, with alleles conferring different metabolic efficiencies and tumor risk. We studied the relationship between the main polymorphisms of these genes and the susceptibility to develop pituitary tumors, by performing a case-control study comprising 235 patients and 256 controls which were genotyped by means of PCR-RFLP based assays. Frequencies of the CYP2D6*1 and of the poor metabolizer allele CYP2D6*4, were determined along with the frequencies of the GSTM1 and GSTT1 null genotypes. CYP2D6 genotype frequencies were similar in patients and controls (p=0.087). CYP2D6*1 and CYP2D6*4 allele frequencies were 83.8%, 16.2% in cases and 78.3%, 21.7% in controls, showing a significant difference between the two groups (p=0.012). There were no significant differences between the frequencies of the GSTM1 and GSTT1 null genotypes in both groups. No association was found between histological type and any of the studied polymorphisms. Our data suggest an association of the CYP2D6*1 allele and the susceptibility to pituitary adenomas, which could be due to an increased metabolism of unidentified procarcinogens or to linkage disequilibrium with another gene involved in pituitary tumorigenesis.

Early onset of medullary thyroid carcinoma in a kindred with multiple endocrine neoplasia type iia associated with cutaneous lichen amyloidosis.

OBJECTIVE: To describe the molecular characterization of a kindred affected by the rare variant of multiple endocrine neoplasia type IIA (MEN IIA) associated with cutaneous lichen amyloidosis and to discuss the clinical implications in the management of this syndrome. METHODS: A kindred with four affected family members was identified, and DNA analysis was performed by sequencing exon 11 of the RET proto-oncogene. Presymptomatic genetic screening was offered to all first-degree relatives. RESULTS: Sequencing analysis of the RET proto-oncogene revealed a Cys634Trp (TGC->TGG) mutation in all clinically affected family members and in an asymptomatic 5-year-old child who, after thyroidectomy, was found to have multicentric medullary thyroid carcinoma and C-cell hyperplasia. A Gly691Ser (GGT->AGT) polymorphism was also detected in this family but did not segregate with the disease. CONCLUSION: To our knowledge, this is the earliest detection of medullary thyroid carcinoma reported thus far in a kindred with MEN IIA associated with cutaneous lichen amyloidosis, and this finding suggests that prophylactic thyroidectomy, in kindreds with this variant, should be performed before the age of 5 years.