Low HIP1R mRNA and protein expression are associated with worse survival in diffuse large B-cell lymphoma patients treated with R-CHOP.
Huntingtin-interacting protein 1-related (HIP1R) is an endocytic protein involved in receptor trafficking, including regulating cell surface expression of receptor tyrosine kinases. We have previously shown that low HIP1R protein expression was associated with poorer survival in diffuse large B-cell lymphoma (DLBCL) patients from Denmark treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone). In this multicenter study, we extend these findings and validate the prognostic and subtyping utility of HIP1R expression at both transcript and protein level. Using data mining on three independent transcriptomic datasets of DLBCL, HIP1R transcript was preferentially expressed in germinal center B-cell (GCB)-like DLBCL subtype (P<0.01 in all three datasets), and lower expression was correlated with worse overall survival (OS; P<0.01) and progression-free survival (PFS; P<0.05) in a microarray-profiled DLBCL dataset. At the protein level examined by immunohistochemistry, HIP1R expression at 30% cut-off was associated with GCB-DLBCL molecular subtype (P=0.0004; n=42), and predictive of OS (P=0.0006) and PFS (P=0.0230) in de novo DLBCL patients treated with R-CHOP (n=73). Cases with high FOXP1 and low HIP1R expression frequency (FOXP1(hi)/HIP1R(lo) phenotype) exhibited poorer OS (P=0.0038) and PFS (P=0.0134). Multivariate analysis showed that HIP1R<30% or FOXP1(hi)/HIP1R(lo) subgroup of patients exhibited inferior OS and PFS (P<0.05) independently of the International Prognostic Index. We conclude that HIP1R expression is strongly indicative of survival when utilized on its own or in combination with FOXP1, and the molecule is potentially applicable for subtyping of DLBCL cases.
Department of Immunology, School of Medical Sciences, Universiti Sains Malaysia, 16150 Kelantan, Malaysia. Electronic address: kahkeng@usm.my.
Kah Keng
KK
Wong
Department of Pathology, School of Medical Sciences, Universiti Sains Malaysia, 16150 Kelantan, Malaysia; Advanced Medical and Dental Institute, Universiti Sains Malaysia, Bertam, 13200 Kepala Batas, Pulau Pinang, Malaysia.
Ewe Seng
ES
Ch'ng
Department of Immunology, School of Medical Sciences, Universiti Sains Malaysia, 16150 Kelantan, Malaysia.
Suet Kee
SK
Loo
Department of Medicine, School of Medical Sciences, Universiti Sains Malaysia, 16150 Kelantan, Malaysia.
Azlan
A
Husin
Oncology Department, Biodonostia Research Institute, San Sebastian 20014, Spain.
María Arestin
MA
Muruzabal
Department of Pathology, Odense University Hospital, Odense, Denmark.
Michael B
MB
Møller
Department of Haematology, Roskilde Hospital, Roskilde, Denmark.
Lars M
LM
Pedersen
Department of Hematology, Hospital Universitario Cruces, Barakaldo, Spain.
María Puente
MP
Pomposo
Department of Pathology, Hospital Universitario Cruces, Barakaldo, Spain.
Ayman
A
Gaafar
Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom.
Alison H
AH
Banham
Department of Pathology, Odense University Hospital, Odense, Denmark.
Tina M
TM
Green
Oncology Department, Biodonostia Research Institute, San Sebastian 20014, Spain; Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom; IKERBASQUE, Basque Foundation for Science, Bilbao, Spain.
Charles H
CH
Lawrie
D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D058846:Antibodies, Monoclonal, Murine-Derived; D000971:Antineoplastic Combined Chemotherapy Protocols; D019540:Area Under Curve; D014408:Biomarkers, Tumor / Q000032:analysis*; D003520:Cyclophosphamide; D018572:Disease-Free Survival; D004317:Doxorubicin; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy* / Q000401:mortality; D008297:Male; D008840:Microfilament Proteins; D008875:Middle Aged; D011241:Prednisone; D011379:Prognosis; D012333:RNA, Messenger / Q000032:analysis; D012372:ROC Curve; D000069283:Rituximab; D012680:Sensitivity and Specificity; D046888:Tissue Array Analysis; D033921:Vesicular Transport Proteins / Q000032:analysis / Q000096:biosynthesis*; D014750:Vincristine; D055815:Young Adult
D048868:Adaptor Proteins, Signal Transducing; D058846:Antibodies, Monoclonal, Murine-Derived; D014408:Biomarkers, Tumor; C489537:HIP1R protein, human; D008840:Microfilament Proteins; C571759:R-CHOP protocol; D012333:RNA, Messenger; D033921:Vesicular Transport Proteins; D000069283:Rituximab; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D011241:Prednisone
Diffuse large B-cell lymphoma; HIP1R; Subtyping; Survival