A GENETIC VARIANT OF MLH1, A GENE INVOLVED IN DNA MISMATCH REPAIR, IS AN INDEPENDENT PREDICTOR OF OVERALL SURVIVAL IN DIFFUSE LARGE B-CELL LYMPHOMA TREATED WITH R-CHOP
Background. Several drugs utilized in diffuse large B cell lymphoma (DLBCL) treatment rely on DNA damage for tumor killing. Host genetic variability in genes repairing DNA damage may affect response to drugs and prognosis. Aims. We verified the impact of DNA repair genes SNPs on prognosis of R-CHOP treated DLBCL. Methods. The study was based on 163 consecutive DLBCL treated with R-CHOP and provided with a prospectively collected dataset. At diagnosis, age >60 years was observed in 104/163 (63.8%) cases, ECOG PS >1 in 21/163 (12.9%), extranodal sites >1 in 41/163 (25.2%), Ann Arbor stage III-IV in 85/163 (52.1%), bulky in 46/163 (28.2%), LDH elevation in 75/163 (46.0%), IPI >2 in 55/163 (33.7%). Median follow-up was 48 months. Thirty-five SNPs from 18 genes were analyzed on patients’ germline DNA. These included SNPs affecting: i) mismatch repair (MLH1rs1799977/rs1800734); ii) base excision repair (XRCC1rs1799782/rs25487, OGG1rs1052133); iii) nucleotide excision repair (ERCC1rs3212986, ERCC2rs1052555/ rs13181/rs1799793/ rs238406, ERCC4rs1800067/rs3136038, ERCC5rs17655, ERCC6rs2228528/rs2228529/rs3793784, XPArs1800975, XPCrs222799/ rs2228000/rs2607775/rs2228001); iv) double strand break repair (BRCA1rs49868507rs17999507rs799917, BRCA2rs144848, LIG4rs1805388, XRCC2rs3218536, XRCC3rs17997947rs861539, XRCC4rs1805377, XRCC6rs5751129/rs132788); and v) direct reversal (MGMTrs16906252/rs2308321/rs12917). Clinical endpoints were overall survival (OS) and event free survival (EFS). Informed consent was obtained. Results. Univariate analysis controlled for multiple comparisons identified MLH1rs1799977 as the sole DNA repair SNP predicting OS in R-CHOP treated DLBCL. Patients carrying the MLH1rs1799977 AG/GG genotype displayed an increased risk of death (HR:3.23; 4-years OS: 55.5%) compared to AA carriers (4-years OS: 80.9%) (P=.0002; q=.009; Fig.1A). Multivariate analysis selected MLH1rs1799977 (HR:3.14; P=.0004) as an independent predictor of OS, along with IPI (HR:1.38; P=.0377) and bulky disease (HR:2.56; P=.0044). Accordingly, when combined to IPI, MLH1rs1799977 refined the clinical prognostication of DLBCL. The poor prognosis heralded by MLH1rs1799977 AG/GG genotype in DLBCL is due to first and second line treatment failure. Patients carrying the MLH1rs1799977 AG/GG genotype displayed an increased risk of failing R-CHOP (HR:1.66; 4-years EFS: 48.3%) compared to AA carriers (4-years EFS: 62.2%) (P=.0399; Fig.1B). Multivariate analysis identified MLH1rs1799977 (HR:1.66; P=.0498) as an independent predictor of EFS, along with IPI (HR:1.61; P<.0001) and bulky disease (HR:1.84; P=.0215). Also, patients carrying the MLH1rs1799977 AG/GG genotype displayed an increased risk of failing second line platinum-based regimens (HR: 3.04; 4-year OS from salvage: 16.0%) compared to AA carriers (4-year OS from salvage: 57.3%) (P=.0050; Figure 1C). By bivariate analysis, MLH1rs1799977 predicted OS from salvage independent of having (P=.0020) or having not (P=.0480) consolidated with SCT. Conclusions. MLH1rs1799977 is an independent predictor of survival in DLBCL treated with R-CHOP. The biologic plausibility of this association is supported by four lines evidence: i) MLH1rs1799977 is a nonsynonymous SNP causing the I219V amino acidic substitution on MLH1, a gene of the mismatch repair pathway; ii) in silico, MLH1rs1799977 is predicted to have deleterious consequences; iii) in vitro, the G variant allele of MLH1rs1799977 associates with reduced MLH1 protein expression; iv) loss of MLH1 in tumor cells is known to induce refractoriness to doxorubicin and platinum compounds. Consistently, DLBCL carriers of the MLH1rs1799977 AG/GG genotypes displayed poor OS possibly due to altered MLH1 expression
