Immunohistochemical molecular phenotypes of gastric cancer based on SOX2 and CDX2 predict patient outcome

Background Gastric cancer remains a serious health concern worldwide. Patients would greatly benefit from the discovery of new biomarkers that predict outcome more accurately and allow better treatment and follow-up decisions. Here, we used a retrospective, observational study to assess the expression and prognostic value of the transcription factors SOX2 and CDX2 in gastric cancer. Methods SOX2, CDX2, MUC5AC and MUC2 expression were assessed in 201 gastric tumors by immunohistochemistry. SOX2 and CDX2 expression were crossed with clinicopathological and follow-up data to determine their impact on tumor behavior and outcome. Moreover, SOX2 locus copy number status was assessed by FISH (N = 21) and Copy Number Variation Assay (N = 62). Results SOX2 was expressed in 52% of the gastric tumors and was significantly associated with male gender, T stage and N stage. Moreover, SOX2 expression predicted poorer patient survival, and the combination with CDX2 defined two molecular phenotypes, SOX2+CDX2- versus SOX2-CDX2+, that predict the worst and the best long-term patients’ outcome. These profiles combined with clinicopathological parameters stratify the prognosis of patients with intestinal and expanding tumors and in those without signs of venous invasion. Finally, SOX2 locus copy number gains were found in 93% of the samples reaching the amplification threshold in 14% and significantly associating with protein expression. Conclusions We showed, for the first time, that SOX2 combined with CDX2 expression profile in gastric cancer segregate patients into different prognostic groups, complementing the clinicopathological information. We further demonstrate a molecular mechanism for SOX2 expression in a subset of gastric cancer cases.

TERT Promoter Mutations Are a Major Indicator of Poor Outcome in Differentiated Thyroid Carcinomas

Context: Telomerase promoter mutations (TERT) were recently described in follicular cell-derived thyroid carcinomas (FCDTC) and seem to be more prevalent in aggressive cancers. Objectives: We aimed to evaluate the frequency of TERT promoter mutations in thyroid lesions and to investigate the prognostic significance of such mutations in a large cohort of patients with differentiated thyroid carcinomas (DTCs). Design: This was a retrospective observational study. Setting and Patients: We studied 647 tumors and tumor-like lesions. A total of 469 patients with FCDTC treated and followed in five university hospitals were included. Mean follow-up (±SD) was 7.8 ± 5.8 years. Main Outcome Measures: Predictive value of TERT promoter mutations for distant metastasization, disease persistence at the end of follow-up, and disease-specific mortality. Results: TERT promoter mutations were found in 7.5% of papillary carcinomas (PTCs), 17.1% of follicular carcinomas, 29.0% of poorly differentiated carcinomas, and 33.3% of anaplastic thyroid carcinomas. Patients with TERT-mutated tumors were older (P < .001) and had larger tumors (P = .002). In DTCs, TERT promoter mutations were significantly associated with distant metastases (P < .001) and higher stage (P < .001). Patients with DTC harboring TERT promoter mutations were submitted to more radioiodine treatments (P = .009) with higher cumulative dose (P = .004) and to more treatment modalities (P = .001). At the end of follow-up, patients with TERT-mutated DTCs were more prone to have persistent disease (P = .001). TERT promoter mutations were significantly associated with disease-specific mortality [in the whole FCDTC (P < .001)] in DTCs (P < .001), PTCs (P = .001), and follicular carcinomas (P < .001). After adjusting for age at diagnosis and gender, the hazard ratio was 10.35 (95% confidence interval 2.01–53.24; P = .005) in DTC and 23.81 (95% confidence interval 1.36–415.76; P = .03) in PTCs. Conclusions: TERT promoter mutations are an indicator of clinically aggressive tumors, being correlated with worse outcome and disease-specific mortality in DTC. TERT promoter mutations have an independent prognostic value in DTC and, notably, in PTC.

The role of functional polymorphisms in immune response genes as biomarkers of BCG Immunotherapy outcome in bladder cancer: Establishment of a predictive profile in a Southern Europe population

OBJECTIVE: To evaluate the predictive value of genetic polymorphisms in the context of BCG immunotherapy outcome and create a predictive profile that may allow discriminating the risk of recurrence. MATERIAL AND METHODS: In a dataset of 204 patients treated with BCG, we evaluate 42 genetic polymorphisms in 38 genes involved in the BCG mechanism of action, using Sequenom MassARRAY technology. Stepwise multivariate Cox Regression was used for data mining. RESULTS: In agreement with previous studies we observed that gender, age, tumor multiplicity and treatment scheme were associated with BCG failure. Using stepwise multivariate Cox Regression analysis we propose the first predictive profile of BCG immunotherapy outcome and a risk score based on polymorphisms in immune system molecules (SNPs in TNFA-1031T/C (rs1799964), IL2RA rs2104286 T/C, IL17A-197G/A (rs2275913), IL17RA-809A/G (rs4819554), IL18R1 rs3771171 T/C, ICAM1 K469E (rs5498), FASL-844T/C (rs763110) and TRAILR1-397T/G (rs79037040) in association with clinicopathological variables. This risk score allows the categorization of patients into risk groups: patients within the Low Risk group have a 90% chance of successful treatment, whereas patients in the High Risk group present 75% chance of recurrence after BCG treatment. CONCLUSION: We have established the first predictive score of BCG immunotherapy outcome combining clinicopathological characteristics and a panel of genetic polymorphisms. Further studies using an independent cohort are warranted. Moreover, the inclusion of other biomarkers may help to improve the proposed model.