Identification of Germline Mutations in Genes Involved in Classic FAP in Patients from Northern Brazil.

BACKGROUND: Colorectal cancer is a common cancer worldwide, with 5-10% of cases being hereditary. Familial adenomatous polyposis syndrome (FAP) is caused by germline mutations in the APC gene or rarely in the MUTYH gene. PATIENTS AND METHODS: This work did not identify germline mutations in the MUTYH, NTHL1, POLD1 and POLE genes in 15 individuals belonging to five families with classic FAP, who had the mutation in the APC gene confirmed in a previous study. Our results support mutations in the APC gene as the main genetic contribution of classical FAP with severe phenotype. In the family that had the most aggressive form of the disease, we performed an array-based Comparative Genomic Hybridization analysis and identified the germinal loss of an allele of the NOTCH2 and BMPR2 genes in the mother (proband) and daughter. In order to validate the involvement of these genes in the other four families of this study, we analyzed the DNA copy number variation in the peripheral blood of the 15 participants. RESULTS: FAP is a syndrome with considerable genetic and phenotypic heterogeneity and this phenomenon may explain the presence of secondary genetic alterations, such as the allelic loss of NOTCH2 and BMPR2 genes, found only in one family in this study. The CNV analysis confirmed that only the two members of the FAP2 family (patient 02H and 02F) had a deletion of these two genes, as the aCGH methodology had found. The other study participants did not show allelic loss for these two genes. CONCLUSION: Validation in a larger number of families could confirm the presence of these new genetic alterations in classic FAP and improve understanding of the different types of aggressiveness of the disease.

Expression of hsa-miR-9 and MYC Copy Number Variation in Hereditary Diffuse Gastric Cancer.

BACKGROUND/AIM: Approximately, 15-50% of families affected by hereditary diffuse gastric cancer (HDGC) exhibit CDH1 germline mutations. CDH1 gene encodes E-cadherin, protein essential to the cell-cell contact of gastric epithelium. Studies have shown that hsa-miR-9 participates in this protein downregulation. Moreover, MYC is responsible for the transcription of hsa-miR-9-3. In the present study, hsa-miR-9 expression and MYC copy number variation were investigated to elucidate the hsa-miR-9 role in HDGC. PATIENTS AND METHODS: Tumor samples were obtained from nine individuals with HDGC history belonging to four Brazilian families. Then, relative quantification of hsa-miR-9 expression and MYC gene copy number variation analysis were performed by real-time PCR. RESULTS: In all the samples, an overexpression of hsa-miR-9 and an increased MYC copy number (≥3 copies) were observed. CONCLUSION: hsa-miR-9 acts as an oncomiR in HDGC. In addition, we suggest that hsa-miR-9 acts as second event in individuals with HDGC carrying CDH1 gene germinline mutations.

High-density array comparative genomic hybridization detects novel copy number alterations in gastric adenocarcinoma.

AIM: To investigate frequent quantitative alterations of intestinal-type gastric adenocarcinoma. MATERIALS AND METHODS: We analyzed genome-wide DNA copy numbers of 22 samples and using CytoScan® HD Array. RESULTS: We identified 22 gene alterations that to the best of our knowledge have not been described for gastric cancer, including of v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 4 (ERBB4), SRY (sex determining region Y)-box 6 (SOX6), regulator of telomere elongation helicase 1 (RTEL1) and UDP-Gal:betaGlcNAc beta 1,4- galactosyltransferase, polypeptide 5 (B4GALT5). The most significant alterations related to peritoneal invasion involved the regions 13q21.1 (gain) and 15q15.1, 17q23.1, 19q13.2 and 20q11.22 (loss of heterozygozity; LOH), where we found LOH of erythrocyte membrane protein band 4.1-like 1 (EPB41L1) gene. In relation to early age of onset, the most significant alterations were gains in the regions Xq26 and Xp22.31 and a loss in the region 11p15.4. CONCLUSION: These quantitative changes may play a role in the development of this type of neoplasia and may be used as markers in evaluating poor prognosis, as well as act as potential therapeutic targets for gastric cancer.