title: Overexpression of cytochrome P450 2A6 in adrenocortical carcinoma.
abstract: Cytochrome P450-mediated metabolism of chemotherapeutic agents contributes to chemotherapy resistance in multiple malignancies. Adrenocortical carcinoma is known to have a poor response to adjuvant therapies; however, the mechanism remains unknown. Recent comprehensive genetic analyses of adrenocortical carcinomas demonstrated recurrent copy number gains in multiple cytochrome P450 genes prompting investigation into whether cytochrome P450 overexpression potentiates adrenocortical carcinoma chemoresistance.
  
  
  
  We determined the expression patterns of 6 cytochrome P450 genes (CYP2A6, CYP2A7, CYP2A13, CYP2B6, CYP2S1, and CYP4F2) predicted to be amplified in adrenocortical carcinoma (n = 29) relative to normal adrenal cortex (n = 10). Gene copy numbers were determined with the TaqMan copy number assay. Gene silencing was performed via small interfering RNA (siRNA) in the adrenocortical carcinoma cell line NCI-H295R and treated with mitotane and cisplatin.
  
  
  
  Of the 6 cytochrome P450 genes tested, CYP2A6 was overexpressed with a 55-fold mean increase compared to normal adrenal samples (P < .05). Immunohistochemical analysis confirmed protein overexpression. Copy gains of CYP2A6 were found in 26% (7/27) of adrenocortical carcinoma specimens. Silencing of CYP2A6 in NCI-H295R cells resulted in decreased cell viability and increased chemosensitivity (P < .05).
  
  
  
  Frequent upregulation in adrenocortical carcinomas and the reversal of chemoresistance in adrenocortical carcinoma cells via enforced silencing suggest a role for CYP2A6 in adrenocortical malignancy.
authors.affiliation: Yale Department of Surgery & Yale Endocrine Neoplasia Laboratory, Yale School of Medicine, New Haven, CT.
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Murtha
authors.affiliation: Yale Department of Surgery & Yale Endocrine Neoplasia Laboratory, Yale School of Medicine, New Haven, CT.
authors.forename: Taylor C
authors.initials: TC
authors.lastname: Brown
authors.affiliation: Yale Department of Surgery & Yale Endocrine Neoplasia Laboratory, Yale School of Medicine, New Haven, CT.
authors.forename: Jill C
authors.initials: JC
authors.lastname: Rubinstein
authors.affiliation: Department of Oncology-Pathology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Felix
authors.initials: F
authors.lastname: Haglund
authors.affiliation: Department of Oncology-Pathology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: C Christofer
authors.initials: CC
authors.lastname: Juhlin
authors.affiliation: Department of Oncology-Pathology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Catharina
authors.initials: C
authors.lastname: Larsson
authors.affiliation: Yale Department of Surgery & Yale Endocrine Neoplasia Laboratory, Yale School of Medicine, New Haven, CT.
authors.forename: Reju
authors.initials: R
authors.lastname: Korah
authors.affiliation: Yale Department of Surgery & Yale Endocrine Neoplasia Laboratory, Yale School of Medicine, New Haven, CT. Electronic address: tobias.carling@yale.edu.
authors.forename: Tobias
authors.initials: T
authors.lastname: Carling
mesh_terms: D000306:Adrenal Cortex Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D018268:Adrenocortical Carcinoma / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D000368:Aged; D000704:Analysis of Variance; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001707:Biopsy, Needle; D065637:Cytochrome P-450 CYP2A6 / Q000235:genetics*; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy / Q000379:methods; D011379:Prognosis; D018570:Risk Assessment; D018709:Statistics, Nonparametric; D015854:Up-Regulation
chemical_list: D000970:Antineoplastic Agents; D003577:Cytochrome P-450 Enzyme System; C585710:CYP2A6 protein, human; D065637:Cytochrome P-450 CYP2A6