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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.
- Hands-on and remote lab in an engineering statistics coursePublication . Zannin, Marcelo; Lima, Natércia; Pinto, Carla M.A.
- The role of multi-organ cancer predisposition genes in the risk of inherited and histologically diverse gastric cancerPublication . Carvajal-Carmona, Luis G.; Pinto, Carla; Pinto, CarlaApproximately 10% of cases with gastric cancer (GC) exhibit familial clustering, however, only 1–3% of cases can be explained by two known hereditary syndromes: Hereditary Diffuse Gastric Cancer (HDGC) caused by CDH1 and CTNNA1 pathogenic germline variants; and Gastric Adenocarcinoma and Proximal Polyposis of the Stomach (GAPPS), caused by germline variants in APC 1B promoter. Familial intestinal gastric cancer (FIGC) has been defined clinically, but it remains mostly genetically unexplained. Likewise, the heritability of mixed histology GC remains to be known. We aimed to estimate the frequency of known cancer predisposition gene variants in GC cases with and without a cancer family history, diverse histological subtypes, and varied age of onset. We evaluated the contribution of pathogenic or likely pathogenic (P/LP) variants in well-established moderate-to-high penetrance multi-organ cancer predisposition genes for GC risk in a large international multi-centre retrospective cohort study involving 750 patients with GC of early-onset or family history of cancer, either by panel sequencing or whole exome sequencing (WES). Panel sequencing was conducted on 328 cases, while WES was performed on the remaining 422. Tumour sequence analyses were performed on samples from 15 patients with P/LP variants. Mutations identified in five index cases were also tested in their relatives. We identified 45 patients (6%) with P/LP variants in: ATM (17 cases), BRCA2 (10 cases), MLH1 (five cases), TP53 (three cases), BRCA1, PALB2, RAD51D, and CHEK2 (two patients each), and RAD51C and PMS2 (one case each), all of which were mutually exclusive. The P/LP variant prevalence was higher in intestinal (9.8%) than in diffuse (4.3%) or mixed GC (4.5%) (p-value = 0.023), without difference per mutated gene by histological subtypes. Only 16 of the 45 patients who carried P/LP variants fulfilled the National Comprehensive Cancer Network genetic testing criteria of at least one cancer predisposition syndrome. Our findings indicate that a broader panel of cancer predisposition genes, beyond CDH1 and CTNNA1, should be included in gene panels to investigate germline variants in patients with GC. This would be especially beneficial when there is a family history of cancer, irrespective of histology subtype, as it would increase the chance of identifying patients who could benefit from risk reduction, targeted treatment, and surveillance of other cancer types.
- 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.