Patients with colorectal tumors with microsatellite instability and large deletions in HSP110 T17 have improved response to 5-fluorouracil–based chemotherapy.

Background & Aims Patients with colorectal tumors with microsatellite instability (MSI) have better prognoses than patients with tumors without MSI, but have a poor response to 5-fluorouracil–based chemotherapy. A dominant-negative form of heat shock protein (HSP)110 (HSP110DE9) expressed by cancer cells with MSI, via exon skipping caused by somatic deletions in the T 17 intron repeat, sensitizes the cells to 5-fluorouracil and oxaliplatin. We investigated whether HSP110 T 17 could be used to identify patients with colorectal cancer who would benefit from adjuvant chemotherapy with 5-fluorouracil and oxaliplatin. Methods We characterized the interaction between HSP110 and HSP110DE9 using su…

HSP110 T17 simplifies and improves the microsatellite instability testing in patients with colorectal cancer

IF 5.65; International audience; Background Every colorectal cancer (CRC) patient should be tested for microsatellite instability (MSI, a marker for defective DNA mismatch repair) as a first screen for Lynch syndrome (LS). In this study, we investigated whether it may be possible to improve the detection of MSI in CRC. We examined whether the HT17 DNA repeat (critical for correct splicing of the chaperone HSP110) might constitute a superior marker for diagnosis of the MSI phenotype in patients with CRC compared with the standard panel of markers (pentaplex).Methods The HT17 polymorphism was analysed in germline DNA from 1037 multi-ethnic individuals. We assessed its sensitivity and specific…

HSP110 promotes colorectal cancer growth through STAT3 activation.

IF 7.932; International audience; Heat shock protein 110 (HSP110) is induced by different stresses and, through its anti-apoptotic and chaperoning properties, helps cells survive these adverse situations. In colon cancers, HSP110 is abnormally abundant. We have recently shown that colorectal cancer patients with microsatellite instability (MSI) had an improved response to chemotherapy because they harbor an HSP110-inactivating mutation (HSP110DE9). In this work, we used patient biopsies, human colorectal cancer cells grown in vitro and in vivo (xenografts), and intestinal crypts to demonstrate that HSP110 is also involved in colon cancer growth. We showed that HSP110 induces colon cancer ce…

Intratumor CMS Heterogeneity Impacts Patient Prognosis in Localized Colon Cancer

Abstract Purpose: The consensus molecular subtypes (CMS) represent a significant advance in the understanding of intertumor heterogeneity in colon cancer. Intratumor heterogeneity (ITH) is the new frontier for refining prognostication and understanding treatment resistance. This study aims at deciphering the transcriptomic ITH of colon cancer and understanding its potential prognostic implications. Experimental Design: We deconvoluted the transcriptomic profiles of 1,779 tumors from the PETACC8 trial and 155 colon cancer cell lines as weighted sums of the four CMSs, using the Weighted In Silico Pathology (WISP) algorithm. We assigned to each tumor and cell line a combination of up to three …

Colon cancer molecular subtype intratumoral heterogeneity and its prognostic impact: An extensive molecular analysis of the PETACC-8

Effect of adding oxaliplatin to adjuvant 5-fluorouracil/leucovorin (5FU/LV) in patients with defective mismatch repair (dMMR) colon cancer stage II and III included in the MOSIAC study.

3524 Background: The MOSAIC study (André T, N Engl J Med, 2004) demonstrated that adding oxaliplatin to adjuvant 5FU and LV improved three-year disease-free survival (DFS) in stage II and III resected CC. Efficacy of FOLFOX4 in pts with dMMR stage III was suggested in a retrospective study (Zaanan A, Ann Oncol 2010). Methods: Of the 2,246 pts included in MOSAIC study, formalin-fixed, paraffin-embedded (FFPE) tissue blocks or slides from 1,019 pts were obtained. Thirty-three samples with insufficient tumor tissue were excluded from this translational study. MMR status was determined by immunohistochemistry (IHC) analysis of the protein products of MLH1, MSH2, PMS2, and MSH6 genes. Results: …

Mutation d’HSP110 dans les cancers colorectaux

Expression of a mutant HSP110 sensitizes colorectal cancer cells to chemotherapy and improves disease prognosis

Heat shock proteins (HSPs) are necessary for cancer cell survival. We identified a mutant of HSP110 (HSP110ΔE9) in colorectal cancer showing microsatellite instability (MSI CRC), generated from an aberrantly spliced mRNA and lacking the HSP110 substrate-binding domain. This mutant was expressed at variable levels in almost all MSI CRC cell lines and primary tumors tested. HSP110ΔE9 impaired both the normal cellular localization of HSP110 and its interaction with other HSPs, thus abrogating the chaperone activity and antiapoptotic function of HSP110 in a dominant-negative manner. HSP110ΔE9 overexpression caused the sensitization of cells to anticancer agents such as oxaliplatin and 5-fluorou…

Adjuvant Fluorouracil, Leucovorin, and Oxaliplatin in Stage II to III Colon Cancer: Updated 10-Year Survival and Outcomes According to BRAF Mutation and Mismatch Repair Status of the MOSAIC Study

Purpose The MOSAIC (Multicenter International Study of Oxaliplatin/Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer) study has demonstrated 3-year disease-free survival (DFS) and 6-year overall survival (OS) benefit of adjuvant oxaliplatin in stage II to III resected colon cancer. This update presents 10-year OS and OS and DFS by mismatch repair (MMR) status and BRAF mutation. Methods Survival actualization after 10-year follow-up was performed in 2,246 patients with resected stage II to III colon cancer. We assessed MMR status and BRAF mutation in 1,008 formalin-fixed paraffin-embedded specimens. Results After a median follow-up of 9.5 years, 10-year OS rates in the bolus/…

Microsatellite Instability in Colorectal Cancer: Time to Stop Hiding!

Colorectal cancer (CRC) is the second cause of cancer-related death worldwide. Surgery constitutes the primary therapy for these tumors, together with chemotherapy that is usually recommended in patients with metastatic primary CRC. Although molecularly distinct entities arising from different physiopathogenic mechanisms - microsatellite (MSI) and chromosomal instability (also called microsatellite stable, MSS) - have been characterized in CRC, there is still no specific therapeutic approach that takes into account disease’s molecular heterogeneity [1]. MSI is observed in 1015% of sporadic CRCs. MSI CRCs displayed particular morphologic features, with greater predilection for the right colo…