title: CYP2W1 is highly expressed in adrenal glands and is positively associated with the response to mitotane in adrenocortical carcinoma.
abstract: BACKGROUND
  Adrenocortical tumors comprise frequent adenomas (ACA) and rare carcinomas (ACC). Human cytochrome P450 2W1 (CYP2W1) is highly expressed in some cancers holding the potential to activate certain drugs into tumor cytotoxins.
  
  
  OBJECTIVE
  To investigate the CYP2W1 expression in adrenal samples and its relationship with clinical outcome in ACC.
  
  
  METHODS
  CYP2W1 expression was investigated by qRT-PCR in 13 normal adrenal glands, 32 ACA, 25 ACC, and 9 different non-adrenal normal tissue samples and by immunohistochemistry in 352 specimens (23 normal adrenal glands, 33 ACA, 239 ACC, 67 non-adrenal normal or neoplastic samples).
  
  
  RESULTS
  CYP2W1 mRNA expression was absent/low in normal non-adrenal tissues, but high in normal and neoplastic adrenal glands (all P<0.01 vs non-adrenal normal tissues). Accordingly, CYP2W1 immunoreactivity was absent/low (H-score 0-1) in 72% of non-adrenal normal tissues, but high (H-score 2-3) in 44% of non-adrenal cancers, in 65% of normal adrenal glands, in 62% of ACAs and in 50% of ACCs (all P<0.001 vs non-adrenal normal tissues), being significantly increased in steroid-secreting compared to non-secreting tumors. In ACC patients treated with mitotane only, high CYP2W1 immunoreactivity adjusted for ENSAT stage was associated with longer overall survival and time to progression (P<0.05 and P<0.01, respectively), and with a better response to therapy both as palliative (response/stable disease in 42% vs 6%, P<0.01) or adjuvant option (absence of disease recurrence in 69% vs 45%, P<0.01).
  
  
  CONCLUSIONS
  CYP2W1 is highly expressed in both normal and neoplastic adrenal glands making it a promising tool for targeted therapy in ACC. Furthermore, CYP2W1 may represent a new predictive marker for the response to mitotane treatment.
authors.affiliation: Endocrine and Diabetes Unit, Department of Internal Medicine I, University Hospital, University of Wuerzburg, Wuerzburg, Germany.
authors.forename: Cristina L
authors.initials: CL
authors.lastname: Ronchi
authors.affiliation: Endocrine and Diabetes Unit, Department of Internal Medicine I, University Hospital, University of Wuerzburg, Wuerzburg, Germany.
authors.forename: Silviu
authors.initials: S
authors.lastname: Sbiera
authors.affiliation: Department of Oncology, University of Turin, San Luigi Hospital, Turin, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Volante
authors.affiliation: Endocrine and Diabetes Unit, Department of Internal Medicine I, University Hospital, University of Wuerzburg, Wuerzburg, Germany.
authors.forename: Sonja
authors.initials: S
authors.lastname: Steinhauer
authors.affiliation: Institute of Pathology, University of Wuerzburg, Wuerzburg, Germany.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Scott-Wild
authors.affiliation: Endocrine and Diabetes Unit, Department of Internal Medicine I, University Hospital, University of Wuerzburg, Wuerzburg, Germany.
authors.forename: Barbara
authors.initials: B
authors.lastname: Altieri
authors.affiliation: Comprehensive Cancer Center Mainfranken, University Hospital, University of Wuerzburg, Wuerzburg, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Kroiss
authors.affiliation: Endocrine and Diabetes Unit, Department of Internal Medicine I, University Hospital, University of Wuerzburg, Wuerzburg, Germany.
authors.forename: Margarita
authors.initials: M
authors.lastname: Bala
authors.affiliation: Department of Oncology, University of Turin, San Luigi Hospital, Turin, Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: Papotti
authors.affiliation: Endocrine and Diabetes Unit, Department of Internal Medicine I, University Hospital, University of Wuerzburg, Wuerzburg, Germany.
authors.forename: Timo
authors.initials: T
authors.lastname: Deutschbein
authors.affiliation: Division of Internal Medicine I, University of Turin, San Luigi Hospital, Turin, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Terzolo
authors.affiliation: Endocrine and Diabetes Unit, Department of Internal Medicine I, University Hospital, University of Wuerzburg, Wuerzburg, Germany; Comprehensive Cancer Center Mainfranken, University Hospital, University of Wuerzburg, Wuerzburg, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Fassnacht
authors.affiliation: Endocrine and Diabetes Unit, Department of Internal Medicine I, University Hospital, University of Wuerzburg, Wuerzburg, Germany.
authors.forename: Bruno
authors.initials: B
authors.lastname: Allolio
mesh_terms: D000306:Adrenal Cortex Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D000311:Adrenal Glands / Q000201:enzymology* / Q000473:pathology; D018268:Adrenocortical Carcinoma / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage*; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D000072467:Cytochrome P450 Family 2; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D008297:Male; D008875:Middle Aged; D008939:Mitotane / Q000008:administration & dosage*; D009363:Neoplasm Proteins / Q000096:biosynthesis*
chemical_list: D018931:Antineoplastic Agents, Hormonal; D009363:Neoplasm Proteins; D008939:Mitotane; D003577:Cytochrome P-450 Enzyme System; C509336:CYP2W1 protein, human; D000072467:Cytochrome P450 Family 2