title: Soluble HLA-G is a differential prognostic marker in sequential colorectal cancer disease stages.
abstract: The expression of HLA-G by tumour cells is an established mechanism to escape recognition and immune mediated destruction, allowing tumour survival, growth and metastasis. However, the prognostic value of soluble HLA-G (sHLA-G) remains unknown. Mucinous carcinoma (MC) is a distinct form of colorectal cancer (CRC) found in 10 to 15% of patients, which has long been associated with poor response to treatment. To investigate the prognostic value of plasma sHLA-G levels in CRC patients, preoperative plasma sHLA-G levels were determined by ELISA in CRC patients (n = 133). In addition, the local expression of HLA-G in tumour biopsies was assessed using tissue microarray analysis (n = 255). Within the high 33rd percentile of sHLA-G levels (265-890 U/mL; n = 44) we observed higher frequency of MC patients (p = 0.012; Chi-square), and higher sHLA-G levels in patients with vascular invasion (p = 0.035; two-tailed t-test). Moreover, MC patients had significantly higher sHLA-G levels compared to those with adenocarcinoma not otherwise specified (p = 0.036; two-tailed t-test). Surprisingly, while stage II patients showed negative correlation between sHLA-G levels and liver metastasis free survival (LMFS) (p = 0.041; R = -0.321), in stage III patients high sHLA-G levels were associated with significantly longer LMFS (p = 0.002), and sHLA-G levels displayed positive correlation with LMFS (p = 0.006; R = 0.409). High HLA-G expression in tumours was associated with poor cancer specific overall survival in stage II to III (p = 0.01), and with shorter LMFS in stage II patients (p = 0.004). Our findings reveal that sHLA-G levels are associated with distinct progression patterns in consecutive disease stages, indicating a potential value as surrogate marker in the differential prognosis of CRC.
authors.affiliation: Liver Metastasis Research Group, Department of Surgery, The Basil Hetzel Institute, University of Adelaide, South Australia.
authors.forename: Chandra
authors.initials: C
authors.lastname: Kirana
authors.affiliation: Division of Surgical Pathology, The Royal Adelaide Hospital, North Terrace Adelaide, South Australia.
authors.forename: Andrew
authors.initials: A
authors.lastname: Ruszkiewicz
authors.affiliation: Department of Pathology and Molecular Medicine, Wakefield Biomedical Research Unit, University of Otago, Wellington, New Zealand.|Department of Surgery, The Wakefield Clinic, Wakefield Hospital, Wellington, New Zealand.
authors.forename: Richard S
authors.initials: RS
authors.lastname: Stubbs
authors.affiliation: Department of Medical Oncology, The Queen Elizabeth Hospital, Adelaide, South Australia.|Department of Physiology, School of Medicine, University of Adelaide, South Australia.
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Hardingham
authors.affiliation: Department of Surgery, University of Adelaide, The Queen Elizabeth Hospital, Woodville, South Australia.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Hewett
authors.affiliation: Liver Metastasis Research Group, Department of Surgery, The Basil Hetzel Institute, University of Adelaide, South Australia.|Department of Surgery, University of Adelaide, The Queen Elizabeth Hospital, Woodville, South Australia.
authors.forename: Guy J
authors.initials: GJ
authors.lastname: Maddern
authors.affiliation: Liver Metastasis Research Group, Department of Surgery, The Basil Hetzel Institute, University of Adelaide, South Australia.
authors.forename: Ehud
authors.identifier: 0000-0002-6062-411X
authors.initials: E
authors.lastname: Hauben
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology; D000368:Aged; D014408:Biomarkers, Tumor / Q000378:metabolism*; D015179:Colorectal Neoplasms / Q000378:metabolism* / Q000473:pathology*; D018450:Disease Progression; D005260:Female; D059951:HLA-G Antigens / Q000378:metabolism*; D006801:Humans; D008297:Male; D011379:Prognosis
chemical_list: D014408:Biomarkers, Tumor; D059951:HLA-G Antigens
keywords: HLA-G; colorectal cancer; liver metastasis; mucinous carcinoma; prognostic biomarker; tumour immune evasion; vascular invasion