Single Nucleotide Polymorphism in Inflammatory Gene RNASEL Predicts Outcome After Radiation Therapy for Localized Prostate Cancer

Abstract

Purpose-To study associations between single nucleotide polymorphisms (SNPs) in RNASEL, a gene implicated in inflammation and prostate cancer risk, and outcomes following radiation therapy (RT). Experimental Design-We followed participants in the prospective US Health Professionals Follow-Up Study treated with RT for early-stage prostate cancer. Three SNPs were genotyped based on previously determined functional and biological significance. We used multivariable Cox proportional hazards models to assess per-allele associations with the primary outcome defined as time to a composite endpoint including development of lethal prostate cancer or biochemical recurrence.Results-We followed 434 patients treated with RT for a median of 9 years. On multivariate analysis, the rs12757998 variant allele was associated with significantly decreased risk of the composite endpoint (HR: 0.65; 95% CI: 0.45-0.94; p = 0.02) driven by decreased biochemical recurrence (HR: 0.60; 95% CI: 0.40 -0.89; p = 0.01) and men treated with external beam (HR: 0.58; 95% CI: 0.36 -0.93; p = 0.02). In contrast, in 516 men from the same cohort treated with radical prostatectomy, we found no significant impact of this variant on outcome. Furthermore, the rs12757998 variant allele significantly modified the association between androgen deprivation therapy and outcomes following RT (p-interaction = 0.02).Conclusion-We demonstrate an association between RNASEL SNP rs12757998 and outcome after RT for prostate cancer. This SNP is associated with increased circulating C-reactive protein and interleukin-6, suggesting a potential role for inflammation in the response to radiation. If validated, genetic predictors of outcome may help inform prostate cancer management.

RNASEL R462Q Mutation in Prostate Cancer

“…In addition, there is evidence to show that RNASEL can interact with the androgen receptor (AR) to promote tumor progression (8). Further, Schoenfeld et al reported that RNASEL variants are associated with outcomes after radiation therapy (9). In addition to the etiological studies, therefore, investigating the association between the RNASEL Arg462Gln polymorphism and PC progression/outcome may provide more valuable and unique information to predict outcome and eventually be used to help guide treatment.…”

Pre-radiotherapy identification of individual genomic profile to avoid, by resort to customized radiosensitizers, the risk of radioresistance development in patients with localized prostate cancer

“…Hence, low inflammatory RNASEL SNP rs 12757998 gene-dependent protein levels seem to be responsible, instead, for the CaP cell apoptosis decrease-induced radioresistance. 5 With high esteem towards Bristow et al's 1 research work, it is foreseeable that more and more detailed pre-radiotherapy CaP genomic profile assessment-in the field of properly customized healthcare-might allow, by a possible resort to suitable personalized radiosensitizer measures, favourable radiation therapy optimization opportunities to be reached. 6 …”

Genetic predisposition markers for prostate cancer

“…Гомозиготное носительство аллеля А rs12 757 998 было ассоциировано с повышенным риском РПЖ (ОШ 1,63) и высоким показателем Гли-сона ( 7, ОШ 1,90). В то же время в более позднем исследовании [33] показано, что носительство аллеля А rs12 757 998 связано с лучшими результатами луче-вой терапии по показателям динамики простатспе-цифического антигена (ПСА) (ОШ 0,60) и выживае-мости (ОШ 0,65). Эти 2 эффекта свидетельствуют о сложном взаимодействии процессов воспаления и иммунитета в развитии РПЖ и последующей реак-ции пациента на лучевую терапию.…”