Prognostic Significance Of rs6773853 Susceptibility Locus In B-Cell Non-Hodgkin’s Lymphoma
Authors: Xin Lee Joycelyn Jie , En Tan Glorijoy Shi , Tan Chee Hian , Pan Summer , Khor Chiea Chuen , Liu Jianjun , Foo Jia Nee , Tan Soo Yong , Ng Siok Bian , Tao Miriam , Lim Soon Thye , Tang Tiffany 
Published: October 2019

Abstract

Background
A recent genome-wide association study (GWAS) including 253 Chinese individuals from Singapore with B-cell Non-Hodgkin Lymphoma (B-NHL), a new susceptibility locus, rs6773853 was identified between BCL6 (B-cell lymphoma protein 6) and LPP (lipoma preferred partner) on chromosome 3q27. This was significantly associated with an increased risk of B-NHL; Odds ratio (OR) per-copy of the risk allele = 1.44 and diffuse large B-cell lymphoma (DLBCL) OR = 1.47. The aims of this study were to determine the prognostic significance of rs6773853 in a case-only analysis of B-NHL patients and to determine if there were any differences in patients and tumor characteristics in B-NHL patients with rs6773853 locus present and absent.

Methods
Genome-wide genotyping to identify germline mutations from DNA of patients' blood samples have been described. Patient, tumour and treatment data were obtained from clinical and pathology databases as well as electronic and hardcopy of medical records. Fluorescent in-situ hybridization testing for BCL6 translocations using breakapart probes were performed on tumor samples whenever possible. Patients were compared in a two-way (homozygous wild-type [WT] versus presence of 1 or more copies of the risk allele of rs6773853) and three-way (homozygous WT versus heterozygous carrier versus homozygous variant of rs6773853) manner. Prognostic factors were analyzed first by univariate analysis. A multivariate Cox regression model was then fitted including all factors showing statistical significance on univariate analysis to identify the best predictors of overall survival.

Results
Clinical and pathologic data were available for 245 B-NHL patients in whom GWAS was performed. The minor allele of rs6773853 locus was identified in 127 patients: 100 were homozygous and 27 were heterozygous carriers. The WT genotype was present in 118 patients. There were no statistically significant differences in the clinical and tumor characteristics or treatment received in both 2-way (Table 1) and 3-way analyses. On univariate analysis, age >60 years, ECOG 2–4, B symptoms, advanced stage, aggressive B-NHL, 2 or more extra-nodal sites, elevated LDH, high-risk IPI and a personal history of another cancer were associated with a poorer OS. On multivariate analysis the presence of rs6773853 locus was independently associated with a poorer OS. (Table 2) The frequencies of BCL6 translocations were 17.9% (7/39) and 20.8% (10/48) in the B-NHL with rs6773853 locus absent and present respectively.

Conclusions
The rs6773853 susceptibility locus to B-NHL is independently prognostic of a poorer OS. This may be related to its close proximity to BCL6, the transcriptional repressor that tightly regulates the germinal centre reaction, although exploratory analysis showed that rs6773853 did not confer a greater risk of BCL6 translocations. Further functional studies and fine mapping will investigate the role of BCL in the tumorigenesis of these B-NHL patients with rs6773853.

Disclosures:
No relevant conflicts of interest to declare.