Abstract 5028: Whole exome sequencing and genetic association of gemcitabine/carboplatin induced thrombocytopenia in non-small cell lung cancer patients
Authors: Björn Niclas , Svedberg Anna , Sigurgeirsson Benjamín , Pradhananga Sailendra , Brandén Eva , Koyi Hirsh , Lewensohn Rolf , Petris Luigi De , Rodríguez-Antona Cristina , Apellániz-Ruiz María , Lundeberg Joakim , Gréen Henrik 
Published: July 2017

Abstract
Introduction: Chemotherapy induced myelosuppression is a clinically relevant problem for cancer treatments, affecting both quality of life and response to treatment. Severe hematological toxicities such as thrombocytopenia can lead to dose reductions, postponement or cessation of treatment and there is a need to identify patients at risk before the start of treatment to allow for personalized medicine.
The aim of this study was to use whole exome sequencing to identify genetic markers for gemcitabine and carboplatin induced thrombocytopenia that can be used to guide future treatments.
Methods: 212 non-small cell lung cancer patients treated with gemcitabine and carboplatin were included. Blood samples were whole exome sequenced using Nextera Rapid Capture Exome kit and Illumina HiSeq 2500. Patients’ thrombocyte counts were measured at baseline and during the first treatment cycle. The thrombocyte nadir value and the relative decrease of the nadir value from baseline were used as thrombocytopenia toxicity parameters. Coding SNVs as well as whole gene-regions and complete pathways were investigated using the following statistical methods:
A) Association of common SNVs/INDELs with thrombocytopenia using linear regression in PLINK.
B) Association of the combined effect of common and rare variants within a gene-region with thrombocytopenia using the region based association test SKATO, in the R-package SKAT.
C) All genes including SNVs/INDELs in A) or a gene-regions in B) with p&lt;0.001 were used as input for the online tool ConsensusPathDB-human to find overrepresented predefined pathways.
Results: The study associated A) 103 SNVs/INDELs and B) 21 genes to thrombocytopenia (p&lt;0.001). The pathway analysis C) identified 28 enriched pathways (p&lt;0.05). Potentially important pathways for gemcitabine/carboplatin induced thrombocytopenia identified were: Hemostasis (ITGB1, SERPINA5, SERPINC1, JMJD1C, DOCK8 and CAPZA2), Factors involved in megakaryocyte development and platelet production (JMJD1C, DOCK8 and CAPZA2) and Vitamin B9 (folate) metabolism (FOLR3 and MTHFD1L).
Single SNVs, INDELs and genes can be of importance for induced toxicity. However, special interest should be given to the variants and genes in the pathways above. Two of the pathways link back to thrombocytopenia via platelet production and hemostasis and include, JMJD1C and DOCK8, previously associated with thrombocyte formation and mean platelet volume. The pathway concerning folate metabolism links back to gemcitabine’s and carboplatin’s mode of action via the involvement of folate in thymidylate and DNA synthesis. Further, folate is necessary for the rapid synthesis of blood cells in the bone marrow.
Conclusion: The identified genetic markers and pathways are associated with chemotherapy induced thrombocytopenia and provide a strong foundation for further investigation.
Citation Format: Niclas Björn, Anna Svedberg, Benjamín Sigurgeirsson, Sailendra Pradhananga, Eva Brandén, Hirsh Koyi, Rolf Lewensohn, Luigi De Petris, Cristina Rodríguez-Antona, María Apellániz-Ruiz, Joakim Lundeberg, Henrik Gréen. Whole exome sequencing and genetic association of gemcitabine/carboplatin induced thrombocytopenia in non-small cell lung cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5028. doi:10.1158/1538-7445.AM2017-5028