Single Nucleotide Polymorphisms In Paclitaxel-related Peripheral Neuropathy And Differences In Immunological Profiles Of Different Metastases In Melanoma

Background Chemotherapy induced peripheral neuropathy(CIPN)is a common dose-limiting drug adverse effect affecting patients’ quality of life.Paclitaxel is a common chemotherapy regimen and it is crucial to identify markers correlated with peripheral sensory neuropathy(PSN)induced by paclitaxel.Previous studies mostly focused on clinicopathological factors and the conclusions are inconsistent.Recently along with the development of pharmacogenomics,several single nucleotide polymorphisms(SNP),which might be associated with grade 2/3 paclitaxel induced PSN,have been identified.However similar study is in short in Han Chinese in Beijing(CHB)population.This study aims at finding SNPs associated with grade 2/3 paclitaxel induced PSN in CHB population.Methods We enrolled 216 CHB patients who received paclitaxel in Peking Union Medical College Hospital from May.2014 to Dec.2016.DNA was isolated from peripheral blood.Patients were followed up and PSN was assessed by well-trained physicians according to NCI-CTCAE criteria.We included all SNPs possibly associated with grade 2/3 paclitaxel induced PSN reported in genome wide association study(GWAS)studies as well as other literatures in other races with minor allele frequency(MAF)>0.05 in CHB population.Genotyping for candidate SNPs was performed on Sequenom MassARRARY iPLEX platform.We then analysed the association between SNPs as well as clinicopathological factors with grade 2/3 PSN induced by paclitaxel.Results Eventually 209 patients were included in the analysis,Among the 34 candidate SNPs meeting quality control,we identified that only rs4141404:C>A(LIMK2)was significantly associated(OR 4.32,95%CI 2.37-7.89,adjusted p<0.0001)with grade 2/3 PSN.Rs501461:T>G(GLIS3)(OR 1.77,95%CI 1.07-2.92,p=0.027,adjusted.p=0.75)did not reach significance after Bonferroni adjustment.History of receiving platinum compound was assocociated with grade 2/3 PSN(OR 1.99,95%CI 1.07-3.69,p=0.03).In multivariate logistic regression analysis,both rs4141404:C>A(LIMK2)and history of receiving platinum compound were associated with grade 2/3 PSN.Conclusion This is the first independent pharmacogenomics study of paclitaxel induced PSN carried out in the largest Chinese Han cohort ever and we provide support of the association between rs4141404:C>A(LIMK2)and grade 2/3 PSN.History of receiving platinum compound as a clinicopathological factor might increase the risk of development of grade 2/3 PSN induced by paclitaxel.The identification of this SNP could facilitate individualized paclitaxel chemotherapy.Background Melanoma is one of the most invasive skin cancers.Along with the development of immunotherapy,the overall survival of advanced melanoma patients has improved significantly.Clinical study reveals that melanoma patients with liver metastases response worse compared with those with lung metastases.The crucial role of immune system in tumor development and regulation has long been noted.Investigation of the immune profile of different metastases sites will enable better understanding of their characteristics,and provide insight to clinical treatment strategy.Methods Apply tumor dicrodissection to formalin formalin-fixed paraffin-embedded(FFPE)autopsy samples of 10 patients from Peter MacCallum Cancer Centre.Identify mRNA expression level with nCounter Nanostring(?)platform and carry out differential expression analysis across liver metastases vs.non-liver metastases.ClueGO was utilized to perform gene ontology analysis.Validate the result of Nanostring with SYBR Green(?)reverse transcriptase quantitative PCR(qPCR).Perform immunohistochemistry(IHC)study of the top differential expression gene in surgery biopsy samples.CD3 and PD-L1 IHC were applied on all samples and Vectra automated digitial quantitive system was used for quantitation.Results One liver sample was excluded for z-score>3.0.Eventually 9 livers,21 non-livers and 5 normal samples were included.The top differential expression gene between liver metastasis and non-liver metastasis is C-Reactive Protein(CRP).The significant differential expression genes mainly involve complement activation pathway.For the sample sample,qPCR shows high correlation data with Nanostring.Further examination in 3 surgery liver metastases and 7 non-liver metastases with CRP IHC shows similar results as well.CD3 and PD-L1 were low expressed in both tumor core and invasive margin in liver and non-liver metastases and there is no significant difference between the two group.Conclusion The main different immune genes profiling between liver metastases and non-liver metastases of melanoma patients are tumor derived CRP and complement.This result could prove target treatment strategy towards clinical immunotherapy.