title: Patients with colorectal tumors with microsatellite instability and large deletions in HSP110 T17 have improved response to 5-fluorouracil–based chemotherapy.
abstract: OBJECTIVE
  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 surface plasmon resonance. By using polymerase chain reaction and fragment analysis, we examined how the size of somatic allelic deletions in HSP110 T(17) affected the HSP110 protein expressed by tumor cells. We screened 329 consecutive patients with stage II–III colorectal tumors with MSI who underwent surgical resection at tertiary medical centers for HSP110 T(17).
  
  
  RESULTS
  HSP110 and HSP110DE9 interacted in a1:1 ratio. Tumor cells with large deletions in T(17) had increased ratios of HSP110DE9:HSP110, owing to the loss of expression of full-length HSP110. Deletions in HSP110 T(17) were mostly biallelic in primary tumor samples with MSI. Patients with stage II–III cancer who received chemotherapy and had large HSP110 T(17) deletions (≥5 bp; 18 of 77 patients, 23.4%) had longer times of relapse-free survival than patients with small or no deletions (≤4 bp; 59 of 77 patients, 76.6%) in multivariate analysis (hazard ratio, 0.16; 95% confidence interval, 0.012–0.8; P = .03). We found a significant interaction between chemotherapy and T17 deletion (P =.009).
  
  
  CONCLUSIONS
  About 25% of patients with stages II–III colorectal tumors with MSI have an excellent response to chemotherapy, due to large, biallelic deletions in the T(17) intron repeat of HSP110 in tumor DNA.
authors: Ada
authors: A
authors: Collura
authors: Anaïs
authors: A
authors: Lagrange
authors: Magali
authors: M
authors: Svrcek
authors: Laetitia
authors: L
authors: Marisa
authors: Olivier
authors: O
authors: Buhard
authors: Agathe
authors: A
authors: Guilloux
authors: Kristell
authors: K
authors: Wanherdrick
authors: Coralie
authors: C
authors: Dorard
authors: Anna
authors: A
authors: Taieb
authors: Arnaud
authors: A
authors: Saget
authors: Marie
authors: M
authors: Loh
authors: Richie
authors: R
authors: Soong
authors: Nikolajs
authors: N
authors: Zeps
authors: Cameron
authors: C
authors: Platell
authors: Andrew
authors: A
authors: Mews
authors: Barry
authors: B
authors: Iacopetta
authors: Aurélie
authors: A
authors: De Thonel
authors: Renaud
authors: R
authors: Seigneuric
authors: Guillaume
authors: G
authors: Marcion
authors: Caroline
authors: C
authors: Chapusot
authors: Come
authors: C
authors: Lepage
authors: Anne-Marie
authors: AM
authors: Bouvier
authors: Marie-Pierre
authors: MP
authors: Gaub
authors: Gérard
authors: G
authors: Milano
authors: Janick
authors: J
authors: Selves
authors: Patrick
authors: P
authors: Senet
authors: Patrice
authors: P
authors: Delarue
authors: Hayat
authors: H
authors: Arzouk
authors: Claire
authors: C
authors: Lacoste
authors: Arnaud
authors: A
authors: Coquelle
authors: Leila
authors: L
authors: Bengrine-Lefèvre
authors: Christophe
authors: C
authors: Tournigand
authors: Jérémie H
authors: JH
authors: Lefèvre
authors: Yann
authors: Y
authors: Parc
authors: Denis S
authors: DS
authors: Biard
authors: Jean-François
authors: JF
authors: Fléjou
authors: Carmen
authors: C
authors: Garrido
authors: Alex
authors: A
authors: Duval
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001483:Base Sequence; D014408:Biomarkers, Tumor / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D015153:Blotting, Western; D045744:Cell Line, Tumor; D017024:Chemotherapy, Adjuvant; D003082:Colectomy; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000601:surgery; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D005500:Follow-Up Studies; D050957:HSP110 Heat-Shock Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007438:Introns; D002955:Leucovorin / Q000008:administration & dosage; D008297:Male; D053842:Microsatellite Instability; D008958:Models, Molecular; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D000077150:Oxaliplatin; D012189:Retrospective Studies; D017384:Sequence Deletion; D020349:Surface Plasmon Resonance; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D050957:HSP110 Heat-Shock Proteins; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D002955:Leucovorin; D005472:Fluorouracil