Low HIP1R mRNA and protein expression are associated with worse survival in diffuse large B-cell lymphoma patients treated with R-CHOP

• Low HIP1R transcript or protein levels are associated with worse survival in independent R-CHOP-treated DLBCL series.
• High HIP1R transcript or protein levels are associated with GCB-DLBCL subtype.
• HIP1R protein frequency expression could potentially be applicable for subtyping of DLBCL cases.

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 (FOXP1hi/HIP1Rlo phenotype) exhibited poorer OS (P = 0.0038) and PFS (P = 0.0134). Multivariate analysis showed that HIP1R < 30% or FOXP1hi/HIP1Rlo 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.