title: mRNA gene expression correlates with histologically diagnosed chemotherapy-induced hepatic injury.
abstract: BACKGROUND
  Chemotherapy-induced hepatic injuries (CIHI) are an increasing problem facing hepatic surgeons. It may be possible to predict the risk of developing CIHI by analysis of genes involved in the metabolism of chemotherapeutics, previously established as associated with other forms of toxicity.
  
  
  METHODS
  Quantitative reverse transcriptase-polymerase chain reaction methodology (q-RT-PCR) was employed to quantify mRNA expression of nucleotide excision repair genes ERCC1 and ERCC2, relevant in the neutralization of damage induced by oxaliplatin, and genes encoding enzymes relevant to 5-flurouracil metabolism, [thymidylate synthase (TS), thymidine phosphorylase (TP) and dihydropyrimidine dehydrogenase (DPD)] in 233 hepatic resection samples. mRNA expression was correlated with a histopathological injury scored via previously validated methods in relation to steatosis, steatohepatitis and sinusoidal obstruction syndrome.
  
  
  RESULTS
  Low-level DPD mRNA expression was associated with steatosis [odds ratio (OR) = 3.95, 95% confidence interval (CI) = 1.53-10.19, P < 0.003], especially when stratified by just those patients exposed to chemotherapy (OR = 4.48, 95% CI = 1.31-15.30 P < 0.02). Low expression of ERCC2 was associated with sinusoidal injury (P < 0.001). There were no further associations between injury patterns and target genes investigated.
  
  
  CONCLUSIONS
  Predisposition to the development of CIHI may be predictable based upon individual patient expression of genes encoding enzymes related to the metabolism of chemotherapeutics.
authors: Division of Cancer Surgery, The Alfred Hospital Department of Pathology, The Alfred Hospital, Melbourne, Victoria, Australia. charlespilgrim@hotmail.com
authors: Charles H C
authors: CH
authors: Pilgrim
authors: Kate
authors: K
authors: Brettingham-Moore
authors: Alan
authors: A
authors: Pham
authors: William
authors: W
authors: Murray
authors: Emma
authors: E
authors: Link
authors: Marty
authors: M
authors: Smith
authors: Val
authors: V
authors: Usatoff
authors: Peter M
authors: PM
authors: Evans
authors: Simon
authors: S
authors: Banting
authors: Benjamin N
authors: BN
authors: Thomson
authors: Michael
authors: M
authors: Michael
authors: Wayne A
authors: WA
authors: Phillips
mesh_terms: D000970:Antineoplastic Agents / Q000009:adverse effects*; D056486:Chemical and Drug Induced Liver Injury / Q000201:enzymology / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D015179:Colorectal Neoplasms / Q000473:pathology; D004268:DNA-Binding Proteins / Q000235:genetics; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000235:genetics; D004720:Endonucleases / Q000235:genetics; D005234:Fatty Liver / Q000139:chemically induced* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D005472:Fluorouracil / Q000378:metabolism / Q000633:toxicity*; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008099:Liver / Q000737:chemistry / Q000187:drug effects* / Q000473:pathology; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000556:secondary; D016017:Odds Ratio; D009944:Organoplatinum Compounds / Q000009:adverse effects*; D000077150:Oxaliplatin; D012333:RNA, Messenger / Q000032:analysis*; D012189:Retrospective Studies; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018570:Risk Assessment; D012307:Risk Factors; D012720:Severity of Illness Index; D013939:Thymidine Phosphorylase / Q000235:genetics; D013940:Thymidylate Synthase / Q000235:genetics; D014739:Victoria; D051759:Xeroderma Pigmentosum Group D Protein / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D009944:Organoplatinum Compounds; D012333:RNA, Messenger; D000077150:Oxaliplatin; D042943:Dihydrouracil Dehydrogenase (NADP); D013940:Thymidylate Synthase; C543750:TYMP protein, human; D013939:Thymidine Phosphorylase; C071447:ERCC1 protein, human; D004720:Endonucleases; D051759:Xeroderma Pigmentosum Group D Protein; C497292:ERCC2 protein, human; D005472:Fluorouracil