Abstract 5026: Association to drug-induced leukopenia using whole-exome sequencing of non-small cell lung cancer patients on gemcitabine/carboplatin regimen
Authors: Svedberg Anna , Sigurgeirsson Benjamín , Björn Niclas , Pradhananga Sailendra , Brandén Eva , Koyi Hirsh , Lewensohn Rolf , Petris Luigi De , Rodríguez-Antona Cristina , Apellániz-Ruiz María , Lundeberg Joakim , Gréen Henrik 
Published: July 2017

A classical non-small cell lung cancer (NSCLC) chemotherapy treatment is gemcitabine in combination with carboplatin. The treatment is known to cause severe hematological toxicity such as leukopenia, which can lead to chemotherapy cessation or even death. It would therefore a priori be of advantage to identify patients at risk of severe leukopenia to allow for a personalized treatment approach. In this study we aim to identify genetic markers for chemotherapy induced leukopenia in non-small cell lung cancer.

In total, 212 non-small cell lung cancer patients treated with gemcitabine and carboplatin regimen were included in the study. Whole blood extracted DNA was prepared with Nextera Rapid Capture kit and whole exome sequenced using Illumina HiSeq 2500. Leukopenia was assessed from leukocyte particle count at baseline and the first cycle nadir values.

The statistical approach was to study association of single common variants (MAF &gt; 0.01) to leukopenia using linear regression in PLINK and association of genes (common and rare variants) to leukopenia using SKATO in the R-package SKAT. An enrichment analysis, with input from the association results (p &lt; 0.001), was performed using the online tool ConsensusPathDB-human to identify overrepresented pathways. A prediction model was created from the single variant analysis results (n=10 causal and n=10 protective) using weighted genetic risk score from the R-package PredictABEL.

The single variant analysis of common variants identified 133 variants (p &lt; 0.001) and the gene based analysis identified 54 genes (p &lt; 0.001). The pathway analysis identified 20 enriched pathways (p &lt; 0.05). A prediction model was created to assess the risk of leukopenia.

The top pathway, HIF-1-alpha transcription factor network, overlaps with four genes (HDAC7, NDRG1, HK2 and CP). It can be of interest to leukopenia as regulation of HIF-1 alpha is essential for maintenance of hematopoietic stem cells in the bone marrow hypoxic niche. It has also been shown that HIF-1 alpha knocked mice are more sensitive to myelosuppressive treatment compared to unknocked mice, supporting the involvement of the pathway in chemotherapy induced myelosuppression.

We have identified variants located in genes and pathways likely to be involved in leukocyte sensitivity after exposure of gemcitabine and carboplatin. A prediction model has been created to estimate the risk that patients will suffer from severe leukopenia. The biological connection of the pathway HIF-1-alpha transcription factor network to leukopenia supports the relevance of these results. Further studies on this are of interest to improve identification of patients at high risk of severe leukopenia after gemcitabine and carboplatin treatment.

Citation Format: Anna Svedberg, Benjamín Sigurgeirsson, Niclas Björn, Sailendra Pradhananga, Eva Brandén, Hirsh Koyi, Rolf Lewensohn, Luigi De Petris, Cristina Rodríguez-Antona, María Apellániz-Ruiz, Joakim Lundeberg, Henrik Gréen. Association to drug-induced leukopenia using whole-exome sequencing of non-small cell lung cancer patients on gemcitabine/carboplatin regimen [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 5026. doi:10.1158/1538-7445.AM2017-5026