title: Molecular patterns in deficient mismatch repair colorectal tumours: results from a French prospective multicentric biological and genetic study.
abstract: BACKGROUND
  To test the prognostic value of tumour protein and genetic markers in colorectal cancer (CRC) and examine whether deficient mismatch repair (dMMR) tumours had a distinct profile relative to proficient mismatch repair (pMMR) tumours.
  
  
  METHODS
  This prospective multicentric study involved 251 stage I-III CRC patients. Analysed biomarkers were EGFR (binding assay), VEGFA, thymidylate synthase (TS), thymidine phosphorylase (TP) and dihydropyrimidine dehydrogenase (DPD) expressions, MMR status, mutations of KRAS (codons 12-13), BRAF (V600E), PIK3CA (exons 9 and 20), APC (exon 15) and P53 (exons 4-9), CpG island methylation phenotype status, ploidy, S-phase, LOH.
  
  
  RESULTS
  The only significant predictor of relapse-free survival (RFS) was tumour staging. Analyses restricted to stage III showed a trend towards a shorter RFS in KRAS-mutated (P=0.005), BRAF wt (P=0.009) and pMMR tumours (P=0.036). Deficient mismatch repair tumours significantly demonstrated higher TS (median 3.1 vs 1.4) and TP (median 5.8 vs 3.5) expression relative to pMMR (P<0.001) and show higher DPD expression (median 14.9 vs 7.9, P=0.027) and EGFR content (median 69 vs 38, P=0.037) relative to pMMR.
  
  
  CONCLUSIONS
  Present data suggesting that both TS and DPD are overexpressed in dMMR tumours as compared with pMMR tumours provide a strong rationale that may explain the resistance of dMMR tumours to 5FU-based therapy.
authors.affiliation: Oncopharmacology and Pathology Departments, Centre Antoine-Lacassagne, Nice, France.
authors.forename: M-C
authors.initials: MC
authors.lastname: Etienne-Grimaldi
authors.affiliation: Surgery Department, CHU Nice, Nice, France.
authors.forename: A
authors.initials: A
authors.lastname: Mahamat
authors.affiliation: Clinique Saint-George, Nice, France.
authors.forename: M
authors.initials: M
authors.lastname: Chazal
authors.affiliation: Inserm U490, Hôpital Georges Pompidou, Paris, France.
authors.forename: P
authors.initials: P
authors.lastname: Laurent-Puig
authors.affiliation: Inserm UMR 1068 (CRCM), CHU Timone, Marseille, France.
authors.forename: S
authors.initials: S
authors.lastname: Olschwang
authors.affiliation: Inserm U381, CHRU de Strasbourg, Strasbourg, France.
authors.forename: M-P
authors.initials: MP
authors.lastname: Gaub
authors.affiliation: Oncopharmacology and Pathology Departments, Centre Antoine-Lacassagne, Nice, France.
authors.forename: J-L
authors.initials: JL
authors.lastname: Formento
authors.affiliation: Oncopharmacology and Pathology Departments, Centre Antoine-Lacassagne, Nice, France.
authors.forename: P
authors.initials: P
authors.lastname: Formento
authors.affiliation: Oncopharmacology and Pathology Departments, Centre Antoine-Lacassagne, Nice, France.
authors.forename: A
authors.initials: A
authors.lastname: Sudaka
authors.affiliation: Institut Gustave Roussy, Villejuif, France.
authors.forename: V
authors.initials: V
authors.lastname: Boige
authors.affiliation: Surgery Department, CHU Nice, Nice, France.
authors.forename: A
authors.initials: A
authors.lastname: Abderrahim-Ferkoune
authors.affiliation: Surgery Department, CHU Nice, Nice, France.
authors.forename: D
authors.initials: D
authors.lastname: Benchimol
authors.affiliation: Hôpital St Antoine, Paris, France.
authors.forename: T
authors.initials: T
authors.lastname: André
authors.affiliation: Hôpital St Antoine, Paris, France.
authors.forename: S
authors.initials: S
authors.lastname: Houry
authors.affiliation: Surgery Department, CHU Grenoble, Grenoble, France.
authors.forename: J-L
authors.initials: JL
authors.lastname: Faucheron
authors.affiliation: Surgery Department, CHU Grenoble, Grenoble, France.
authors.forename: C
authors.initials: C
authors.lastname: Letoublon
authors.affiliation: Surgery Department, CHU Lyon Sud, Lyon, France.
authors.forename: F-N
authors.initials: FN
authors.lastname: Gilly
authors.affiliation: Surgery Department, Institut Paoli Calmettes, Marseille, France.
authors.forename: J-R
authors.initials: JR
authors.lastname: Delpero
authors.affiliation: Institut Gustave Roussy, Villejuif, France.
authors.forename: P
authors.initials: P
authors.lastname: Lasser
authors.affiliation: Surgery Department, CHU Toulouse, Toulouse, France.
authors.forename: B
authors.initials: B
authors.lastname: Pradere
authors.affiliation: Surgery Department, CHU Clermont-Ferrand, Clermont-Ferrand, France.
authors.forename: D
authors.initials: D
authors.lastname: Pezet
authors.affiliation: Pathology Department, Centre Jean Perrin, Clermont-Ferrand, France.
authors.forename: F
authors.initials: F
authors.lastname: Penault-Llorca
authors.affiliation: Oncopharmacology and Pathology Departments, Centre Antoine-Lacassagne, Nice, France.
authors.forename: G
authors.initials: G
authors.lastname: Milano
mesh_terms: D000230:Adenocarcinoma / Q000201:enzymology / Q000235:genetics* / Q000401:mortality; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000401:mortality; D053843:DNA Mismatch Repair; D004252:DNA Mutational Analysis; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000378:metabolism*; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology / Q000627:therapeutic use; D005602:France; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000235:genetics* / Q000401:mortality; D011110:Polymorphism, Genetic; D016016:Proportional Hazards Models; D011446:Prospective Studies; D013940:Thymidylate Synthase / Q000378:metabolism*
chemical_list: D000964:Antimetabolites, Antineoplastic; D014408:Biomarkers, Tumor; D042943:Dihydrouracil Dehydrogenase (NADP); D013940:Thymidylate Synthase; D005472:Fluorouracil