RESUMO
Thyroid cancer is the most common endocrine malignancy. However, the cytological diagnosis of follicular thyroid carcinoma (FTC), Hürthle cell carcinoma (HCC), and follicular variant of papillary thyroid carcinoma (FVPTC) and their benign counterparts is a challenge for preoperative diagnosis. Nearly 20-30% of biopsied thyroid nodules are classified as having indeterminate risk of malignancy and incur costs to the health care system. Based on that, 120 patients were screened for the main driver mutations previously described in thyroid cancer. Subsequently, 14 mutation-negative cases that are the main source of diagnostic errors (FTC, HCC, or FVPTC) underwent RNA-Sequencing analysis. Somatic variants in candidate driver genes (ECD, NUP98,LRP1B, NCOR1, ATM, SOS1, and SPOP) and fusions were described. NCOR1 and SPOP variants underwent validation. Moreover, expression profiling of driver-negative samples was compared to 16 BRAF V600E, RAS, or PAX8-PPARg positive samples. Negative samples were separated in two clusters, following the expression pattern of the RAS/PAX8-PPARg or BRAF V600E positive samples. Both negative groups showed distinct BRS, ERK, and TDS scores, tumor mutation burden, signaling pathways and immune cell profile. Altogether, here we report novel gene variants and describe cancer-related pathways that might impact preoperative diagnosis and provide insights into thyroid tumor biology.
RESUMO
Thyroid cancer incidences have been steadily increasing worldwide and are projected to become the fourth leading cancer diagnosis by 2030. Improved diagnosis and prognosis predictions for this type of cancer depend on understanding its genetic bases and disease biology. RAS mutations have been found in a wide range of thyroid tumors, from benign to aggressive thyroid carcinomas. Based on that and in vivo studies, it has been suggested that RAS cooperates with other driver mutations to induce tumorigenesis. This study aims to identify genetic alterations or pathways that cooperate with the RAS mutation in the pathogenesis of thyroid cancer. From a cohort of 120 thyroid carcinomas, 11 RAS-mutated samples were identified. The samples were subjected to RNA-Sequencing analyses. The mutation analysis in our eleven RAS-positive cases uncovered that four genes that belong to the Hippo pathway were mutated. The gene expression analysis revealed that this pathway was dysregulated in the RAS-positive samples. We additionally explored the mutational status and expression profiling of 60 RAS-positive papillary thyroid carcinomas (PTC) from The Cancer Genome Atlas (TCGA) cohort. Altogether, the mutational landscape and pathway enrichment analysis (gene set enrichment analysis (GSEA) and Kyoto Encyclopedia of Genes and Genome (KEGG)) detected the Hippo pathway as dysregulated in RAS-positive thyroid carcinomas. Finally, we suggest a crosstalk between the Hippo and other signaling pathways, such as Wnt and BMP.
RESUMO
PURPOSE: In California, colorectal cancer (CRC) is the second most common cancer in Latinos. Using data from the California Cancer Registry, we investigated demographic and clinical characteristics of 36,133 Latinos with CRC living in California during 1995-2011 taking into account subpopulations defined by country of origin. METHODS: Cases were defined as Latino according to the North American Association of Central Cancer Registries Hispanic Identification Algorithm, which was also used to group cases by country of origin: Mexico (9,678, 27 %), Central or South America (2,636, 7 %), Cuban (558, 2 %), Puerto Rico (295, 1 %), and other or unknown origin (22,966, 64 %; Other/NOS). 174,710 non-Hispanic white (NHW) CRC cases were included for comparison purposes. Annual age-adjusted incidence rates (AAIR) and proportional incidence ratios (PIRs) were calculated. RESULTS: Differences were observed for age at diagnosis, sex distribution, socioeconomic status (SES), nativity (US born vs. foreign born), stage, and tumor localization across Latino subpopulations and compared to NHW. Mexican Latinos had the lowest AAIR and Cuban Latinos had the highest. PIRs adjusted for age, SES, and nativity showed an excess of CRC males and female cases from Cuba, female cases from Puerto Rico and reduced number of female cases from Mexico. CONCLUSIONS: Differences in cancer incidence patterns and tumor characteristics were observed among Latino subpopulations in California. These disparities may reflect differences in cancer determinants among Latinos; therefore, given that country of origin information is unavailable for a large proportion of these patients, greater efforts to collect these data are warranted.