High Intra- and Inter-Tumoral Heterogeneity of RAS Mutations in Colorectal Cancer

Approximately 30% of patients with wild type RAS metastatic colorectal cancer are non-responders to anti-epidermal growth factor receptor monoclonal antibodies (anti-EGFR mAbs), possibly due to undetected tumoral subclones harboring RAS mutations. The aim of this study was to analyze the distribution of RAS mutations in different areas of the primary tumor, metastatic lymph nodes and distant metastasis. A retrospective cohort of 18 patients with a colorectal cancer (CRC) was included in the study. Multiregion analysis was performed in 60 spatially separated tumor areas according to the pathological tumor node metastasis (pTNM) staging and KRAS, NRAS and BRAF mutations were tested using pyrosequencing. In primary tumors, intra-tumoral heterogeneity for RAS mutation was found in 33% of cases. Inter-tumoral heterogeneity for RAS mutation between primary tumors and metastatic lymph nodes or distant metastasis was found in 36% of cases. Moreover, 28% of tumors had multiple RAS mutated subclones in the same tumor. A high proportion of CRCs presented intra- and/or inter-tumoral heterogeneity, which has relevant clinical implications for anti-EGFR mAbs prescription. These results suggest the need for multiple RAS testing in different parts of the same tumor and/or more sensitive techniques

ERG expression in prostate cancer: the prognostic paradox.

International audienceTMPRSS2/ERG fusion resulting in ERG overexpression occurs in 30 to 50% of prostate cancer (PCa) in Caucasian patients, but its prognostic relevance remains controversial. In the present study, we investigated ERG expression in all stages of PCa progression, and evaluated the prognostic impact of ERG status in clinically localized PCa (CLC) and in castration resistant disease (CRPC). ERG and AR expressions were evaluated by immunohistochemistry on tissue microarrays containing samples of high grade PIN (n = 57), CLC surgically treated (n = 299, including 185 Caucasians and 114 African-Caribbeans), metastases (n = 17), and CRPC (n = 41). In Caucasians, ERG expression significantly increased from high grade PIN (17.5%) to pT2 (27%) and pT3 CLC (43%), then to metastases (53%). In CLC, stainings for ERG and AR were correlated, and ERG expression was less frequent in African-Caribbeans compared to Caucasians (11.5% vs. 33%). In Caucasians CLC, ERG was associated with longer recurrence free survival, after adjusting for classical prognostic markers. In CRPC, ERG was expressed in 29% of cases, and was associated with a longer overall survival. Our results confirm that ERG expression is less frequent in PCa from patients of African descent. Although ERG expression increases during PCa natural history, positive ERG status is associated with better outcome in both CLC and CRPC. This paradox could be explained in part by the fact that ERG expression is AR dependant, then ERG positive cancers are likely to progress in a rich androgen environment, with a better response to androgen suppression

Lipophagy and prostate cancer: association with disease aggressiveness and proximity to periprostatic adipose tissue

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Innovations and opportunities in processes for concentrated and dried dairy products: can we do better to preserve the bioactivity of the dairy components? An overview

Spray drying is a well-established technique to convert a liquid solution into individual and solid particles. It is widely used in the food industry, especially in the dairy sector. This process allows the production of a wide range of dairy powders and determines their final functionality. The economic, social and environmental impact of each technological stage should be considered in order to optimize existing dairy processes and/or to develop innovative techniques to significantly and simultaneously reduce water and energy consumption in the dairy sector.In this overview, we propose innovative approaches based first on the improvement of performance of dairy powder processing by using several sensors for characterization and optimization of the processing conditions. Several examples of process optimization through improved understanding, including vacuum evaporation, lactose crystallization, homogenization and spray-drying are detailed. We then focus on alternative technologies such as the thin-film, spinning cone evaporator and extrusion-porosification technology. These alternative technologies could replace or supplement falling film vacuum evaporation and spray drying in the future to reduce energy costs and/or to produce dairy powders with improved functionality. The final aim of this overview is to propose an ideal plant to produce dairy powders of high value, quality and energy efficiency with a good environmental impact. Several examples will be set-out to illustrate the dairy powder factory of the future

Tumour-based mutational profiles predict visceral metastasis outcome and early death in prostate cancers

International audienceBackground: Visceral metastases are known to occur in advanced prostate cancer, usually when the tumour is resistant to androgen deprivation and, have worse outcomes regardless of therapies. Objective: To analyse genomic alterations in tumour samples according to their lymphatic, bone and visceral metastatic stages and overall survival. Design, Setting, and Participants: We selected 200 patients with metastatic prostate cancer. Genomic profiling of 111 genes and molecular signatures (Homologous recombination deficiency: HRD; Microsatellite instability: MSI and Tumour burden mutation: TMB) was performed with the MyChoice™ test (Myriads Genetics, Inc). Outcome Measurements and Statistical Analysis: Association between genomic profiles and visceral metastatic evolution was evaluated using logistic regression. Kaplan-Meier and Cox proportional hazards analyses were used for analyses of early death.Results and limitations: 173 (87%) genomic profiles were obtained. Eighty-four (49%) patients died during the follow-up period (median duration = 76 months). TP53 was the most frequently mutated gene, followed by FANC genes, including BRCA2, and those of the Wnt-pathway (APC/CTNNB1). TP53 gene mutations were more frequent in patients of European (42%) than African (16%) ancestry. An HRD score >25 was predictive of FANC genes mutations. The mutational status of TP53 (p<0.001) and APC (p=0.002) genes were significantly associated with the risk of visceral metastases. The mutational status of CTNNB1 (p=0.001), TP53 (p=0.015), BRCA2 (p=0.027), and FANC (p=0.005) genes were significantly associated with an earlier age at death. The limitations are the retrospective study design based on a selection of genes and, the low frequency of certain molecular events. Conclusion: Mutations in the TP53 gene and genes (APC/CTNNB1) related to the Wnt-pathway are associated with metastatic visceral dissemination and early death. These genomic alterations could be considered as markers to identify prostate cancer patients at high risk of life-threatening disease who might benefit from more intensified treatment or new targeted therapies.Patient summary: In this report, we evaluated relationships between genomic profiles (gene mutations and molecular signatures) of tumour samples from patients with metastatic prostate cancer and early death. We found that mutations of specific genes, notably TP53 and APC/CTNNB1 related to the Wnt-pathway, are associated with visceral metastatic progression and an earlier age at death

HSP110 as a Diagnostic but Not a Prognostic Biomarker in Colorectal Cancer With Microsatellite Instability

Determination of microsatellite instability (MSI) using molecular test and deficient mismatch repair (dMMR) using immunohistochemistry (IHC) has major implications on colorectal cancer (CRC) management. The HSP110 T 17 microsatellite has been reported to be more monomorphic than the common markers used for MSI determination. Large deletion of HSP110 T 17 has been associated with efficacy of adjuvant chemotherapy in dMMR/MSI CRCs. The aim of this study was to evaluate the interest of HSP110 deletion/expression as a diagnostic tool of dMMR/MSI CRCs and a predictive tool of adjuvant chemotherapy efficacy. All patients with MSI CRC classified by molecular testing were included in this multicenter prospective cohort ( n = 381). IHC of the 4 MMR proteins was carried out. HSP110 expression was carried out by IHC ( n = 343), and the size of HSP110 T 17 deletion was determined by PCR (n = 327). In the 293 MSI CRCs with both tests, a strong correlation was found between the expression of HSP110 protein and the size of HSP110 T 17 deletion. Only 5.8% of MSI CRCs had no HSP110 T 17 deletion ( n = 19/327). HSP110 T 17 deletion helped to re-classify 4 of the 9 pMMR/MSI discordance cases as pMMR/MSS cases. We did not observe any correlation between HSP110 expression or HSP110 T 17 deletion size with time to recurrence in patients with stage II and III CRC, treated with or without adjuvant chemotherapy. HSP110 is neither a robust prognosis marker nor a predictor tool of adjuvant chemotherapy efficacy in dMMR/MSI CRC. However, HSP110 T 17 is an interesting marker, which may be combined with the other pentaplex markers to identify discordant cases between MMR IHC and MSI