title: Biomarker-based treatment selection in early-stage rectal cancer to promote organ preservation.
abstract: BACKGROUND
  Total mesorectal excision (TME) remains commonplace for T1-2 rectal cancer owing to fear of undertreating a small proportion of patients with node-positive disease. Molecular stratification may predict cancer progression. It could be used to select patients for organ-preserving surgery if specific biomarkers were validated.
  
  
  METHODS
  Gene methylation was quantified using bisulphite pyrosequencing in 133 unirradiated rectal cancer TME specimens. KRAS mutation and microsatellite instability status were also defined. Molecular parameters were correlated with histopathological indices of disease progression. Predictive models for nodal metastasis, lymphovascular invasion (LVI) and distant metastasis were constructed using a multilevel reverse logistic regression model.
  
  
  RESULTS
  Methylation of the retinoic acid receptor β gene, RARB, and that of the checkpoint with forkhead and ring finger gene, CHFR, was associated with tumour stage (RARB: 51·9 per cent for T1-2 versus 33·9 per cent for T3-4, P < 0·001; CHFR: 5·5 per cent for T1-2 versus 12·6 per cent for T3-4, P = 0·005). Gene methylation associated with nodal metastasis included RARB (47·1 per cent for N- versus 31·7 per cent for N+; P = 0·008), chemokine ligand 12, CXCL12 (12·3 per cent for N- versus 8·9 per cent for N+; P = 0·021), and death-associated protein kinase 1, DAPK1 (19·3 per cent for N- versus 12·3 per cent for N+; P = 0·022). RARB methylation was also associated with LVI (45·1 per cent for LVI- versus 31·7 per cent for LVI+; P = 0·038). Predictive models for nodal metastasis and LVI achieved sensitivities of 91·1 and 85·0 per cent, and specificities of 55·3 and 45·3 per cent, respectively.
  
  
  CONCLUSIONS
  This methylation biomarker panel provides a step towards accurate discrimination of indolent and aggressive rectal cancer subtypes. This could offer an improvement over the current standard of care, whereby fit patients are offered radical surgery.
authors: School of Cancer Sciences, Vincent Drive, University of Birmingham, Birmingham, B15 2TT, UK.
authors: K J
authors: KJ
authors: Leong
authors: A
authors: A
authors: Beggs
authors: J
authors: J
authors: James
authors: D G
authors: DG
authors: Morton
authors: G M
authors: GM
authors: Matthews
authors: S P
authors: SP
authors: Bach
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics*; D015820:Cadherins / Q000235:genetics; D018797:Cell Cycle Proteins / Q000235:genetics; D054377:Chemokine CXCL12 / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics; D064550:Death-Associated Protein Kinases / Q000235:genetics; D005260:Female; D006801:Humans; D008207:Lymphatic Metastasis; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000235:genetics; D059351:Organ Sparing Treatments / Q000379:methods*; D018579:Patient Selection; D000075223:Poly-ADP-Ribose Binding Proteins; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D012372:ROC Curve; D018168:Receptors, Retinoic Acid / Q000235:genetics; D012004:Rectal Neoplasms / Q000235:genetics / Q000473:pathology / Q000601:surgery*; D044767:Ubiquitin-Protein Ligases; D018631:ras Proteins / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; C515255:CXCL12 protein, human; D015820:Cadherins; D018797:Cell Cycle Proteins; D054377:Chemokine CXCL12; C099972:H-cadherin; C117307:KRAS protein, human; D009363:Neoplasm Proteins; D000075223:Poly-ADP-Ribose Binding Proteins; D011518:Proto-Oncogene Proteins; D018168:Receptors, Retinoic Acid; C082925:retinoic acid receptor beta; C412002:CHFR protein, human; D044767:Ubiquitin-Protein Ligases; C579096:DAPK1 protein, human; D064550:Death-Associated Protein Kinases; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins