Percorrer por autor "Pinheiro, Manuela"
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- Combined germline and tumor mutation signature testing identifies new families with NTHL1 tumor syndromePublication . Pinto, Carla; Guerra, Joana; Pinheiro, Manuela; Escudeiro, Carla; Santos, Catarina; Pinto, Pedro; Porto, Miguel; Bartosch, Carla; Silva, João; Peixoto, Ana; Teixeira, Manuel R.NTHL1 tumor syndrome is an autosomal recessive rare disease caused by biallelic inactivating variants in the NTHL1 gene and which presents a broad tumor spectrum. To contribute to the characterization of the phenotype of this syndrome, we studied 467 index patients by KASP assay or next-generation sequencing, including 228 patients with colorectal polyposis and 239 patients with familial/personal history of multiple tumors (excluding multiple breast/ovarian/polyposis). Three NTHL1 tumor syndrome families were identified in the group of patients with polyposis and none in patients with familial/personal history of multiple tumors. Altogether, we identified nine affected patients with polyposis (two of them diagnosed after initiating colorectal cancer surveillance) with biallelic pathogenic or likely pathogenic NTHL1 variants, as well as two index patients with one pathogenic or likely pathogenic NTHL1 variant in concomitance with a missense variant of uncertain significance. Here we identified a novel inframe deletion classified as likely pathogenic using the ACMG criteria, supported also by tumor mutational signature analysis. Our findings indicate that the NTHL1 tumor syndrome is a multi-tumor syndrome strongly associated with polyposis and not with multiple tumors without polyposis.
- Frequency of CDH1, CTNNA1 and CTNND1 germline variants in families with diffuse and mixed gastric cancerPublication . Guerra, Joana; Pinto, Carla; Pinto, Pedro; Pinheiro, Manuela; Santos, Catarina; Peixoto, Ana; Escudeiro, Carla; Barbosa, Ana; Porto, Miguel; Francisco, Inês; Lopes, Paula; Isidoro, Ana Raquel; Cunha, Ana Luísa; Albuquerque, Cristina; Claro, Isabel; Oliveira, Carla; Silva, João; Teixeira, Manuel R.Hereditary diffuse gastric cancer (HDGC) is caused by germline pathogenic variants in the CDH1 and CTNNA1 genes and is characterized by a high prevalence of diffuse gastric cancer and lobular breast cancer. We aimed to evaluate the contribution of CTNNA1 and CTNND1 germline variants to HDGC, as well as to compare the frequencies of CDH1 and CTNNA1 (and eventually CTNND1) germline variants between patients with diffuse and mixed gastric carcinomas. In this study, we report a deleterious CTNNA1 germline variant and four CDH1 pathogenic variants in patients with criteria for genetic testing. None of the cases with mixed gastric cancer carried pathogenic variants in either the CDH1 or the CTNNA1 genes, so there is no evidence to use this tumor type in testing criteria.
- A novel deleterious variant and a founder effect in four new families of MBD4-Associated Neoplasia Syndrome recruited over a period of 20 YearsPublication . Querido, Inês; Pinto, Carla; Arinto, Patrícia; Brandão, Andreia; Santos, Catarina; Pinheiro, Manuela; Guerra, Joana; Silva, João; Peixoto, Ana; Teixeira, Manuel R.; Pinto, CarlaDNA glycosylases play a crucial role in DNA repair mediated by the base excision repair (BER) pathway, and alterations in these enzymes have been associated with hereditary cancer predisposition. Recently, germline biallelic loss-of-function variants in MBD4 were shown to be responsible for a novel autosomal recessive multi-tumor predisposition syndrome, provisionally denominated as MBD4-associated neoplasia syndrome and characterized by the association of adenomatous polyposis, colorectal cancer, and acute myeloid leukemia (AML). Here, we studied the MBD4 gene in five individuals from four families affected by adenomatous polyposis and AML, who had been referred for genetic counselling at a single institution over a period of approximately 20 years. All patients with this phenotype presented homozygous deleterious germline variants in MBD4, of which one is a founder variant recurrent in three of the families, and another variant has not been previously described in the literature. Our work allowed a molecular diagnosis for these families and significantly contributes to expanding the knowledge about this emerging syndrome caused by MBD4 constitutional deficiency.