title: Ribonucleotide reductase large subunit (RRM1) gene expression may predict efficacy of adjuvant mitotane in adrenocortical cancer.
abstract: OBJECTIVE
  Mitotane is the most broadly used systemic therapy for adrenocortical carcinoma (ACC), but its mechanism of action and possible predictors of treatment response are currently poorly defined. Our aim was to evaluate the gene expression of ribonucleotide reductase large subunit 1 (RRM1) and excision repair cross-complementation group 1 (ERCC1) in ACC as potential biomarkers for clinical outcome and response to mitotane.
  
  
  METHODS
  Forty-five and 47 tissue samples from two cohorts (Orbassano, Italy; Wuerzburg, Germany) of completely resected ACC were centrally analyzed using real-time PCR for RRM1 and ERCC1 expression. Fifty-four patients received surgery alone and 38 received adjuvant mitotane after surgery. Clinical and pathologic features were highly comparable in the two series. H295R and SW-13 ACC cell lines were also used for pharmacologic tests.
  
  
  RESULTS
  ERCC1 gene expression was not associated to clinical outcome. In contrast, high RRM1 gene expression was associated to shorter disease-free survival (DFS) and overall survival at both univariate and multivariate analysis. In patients with low RRM1 gene expression, adjuvant mitotane was associated with improved DFS, whereas this effect was lost in cases with high RMM1 expression. In vitro mitotane induced strong up regulation of RRM1 transcription (up to 25-fold increase) in mitotane-insensitive SW-13 but not in mitotane-sensitive H295R cells. Furthermore, RRM1 silencing in SW-13 cells induced sensitivity to mitotane.
  
  
  CONCLUSIONS
  Our in vitro and in vivo data indicate that RRM1 gene expression is functionally associated to mitotane sensitivity and support a possible role of RRM1 determination as a novel molecular biomarker predicting response to adjuvant mitotane in ACC.
authors.affiliation: Department of Clinical and Biological Sciences, University of Turin, San Luigi Hospital, Orbassano, Turin, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Volante
authors.forename: Massimo
authors.initials: M
authors.lastname: Terzolo
authors.forename: Martin
authors.initials: M
authors.lastname: Fassnacht
authors.forename: Ida
authors.initials: I
authors.lastname: Rapa
authors.forename: Antonina
authors.initials: A
authors.lastname: Germano
authors.forename: Silviu
authors.initials: S
authors.lastname: Sbiera
authors.forename: Fulvia
authors.initials: F
authors.lastname: Daffara
authors.forename: Paola
authors.initials: P
authors.lastname: Sperone
authors.forename: Giorgio
authors.initials: G
authors.lastname: Scagliotti
authors.forename: Bruno
authors.initials: B
authors.lastname: Allolio
authors.forename: Mauro
authors.initials: M
authors.lastname: Papotti
authors.forename: Alfredo
authors.initials: A
authors.lastname: Berruti
mesh_terms: D000293:Adolescent; D000306:Adrenal Cortex Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000235:genetics; D045744:Cell Line, Tumor; D017024:Chemotherapy, Adjuvant; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics*; D018572:Disease-Free Survival; D004720:Endonucleases / Q000096:biosynthesis / Q000235:genetics*; D005260:Female; D005819:Genetic Markers; D006801:Humans; D008297:Male; D008875:Middle Aged; D008939:Mitotane / Q000627:therapeutic use*; D034622:RNA Interference; D034741:RNA, Small Interfering; D012262:Ribonucleoside Diphosphate Reductase; D016896:Treatment Outcome; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis / Q000235:genetics*; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; D005819:Genetic Markers; D034741:RNA, Small Interfering; D025521:Tumor Suppressor Proteins; D008939:Mitotane; C475286:RRM1 protein, human; D012262:Ribonucleoside Diphosphate Reductase; C071447:ERCC1 protein, human; D004720:Endonucleases