Abstract 4757: Whole exome sequencing reveals a distinct mutation pattern in metastatic small cell lung cancer compared to non-small cell lung cancer
Authors: Saber Ali , Kok Klaas , Terpstra Martijn M. , Timens Wim , Aukema Sijmen , Hiltermann T. Jeroen , Groen Harry J. M. , van den Berg Anke 
Published: August 2015

Purpose: Lung cancer is divided into two main groups, small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), the latter subdivided in squamous, large cell and adenocarcinoma. Many studies have shown intra-tumor heterogeneity in lung cancer with multiple minor clones characterized by their own specific mutational landscape. These minor clones can become predominant under selective pressure caused by therapy. Aim of our study is to investigate the relation between primary lung cancer and multiple distant metastases using whole exome sequencing.

Materials and methods: Normal tissue, primary lung tumor, and multiple metastases were obtained from 2 SCLC and 3 NSCLC patients resulting in a total of 29 samples (Table 1). DNA was isolated from total, macro-dissected, or laser micro-dissected tissue to obtain a purity of at least 80% tumor cells. Library preparation was based on the SureSelect All Exon V5 bait (Agilent) and paired-end sequencing was done using Illumina® HiSeq2000. Genome analysis toolkit (GATK) was used to analyze data and the 1000-Genome database was used to remove single nucleotide polymorphisms.

Patients' characteristics and overview of sequenced metastases samplesSubtypeSexAge at diagnosisCOPDSmokingPack yearTime interval between diagnosis and death (days)No. of somatic mutationsMetastasesLarge cell carcinomaMale65YesYes302308446Lymph node (1x)Adrenal gland (1x)Squamous cell carcinomaMale68YesYes&gt;100111306Liver (1x)Spleen (1x)Heart (1x)AdenocarcinomaFemale51NoNo02579Liver (1x)Lymph nodes (2x)Ovary (1x)Vertebra (1x)Jejunum (1x)Small cell carcinoma-1Female79YesYes&gt;508347Liver (1x)Adrenal gland (1x)Small cell carcinoma-2Female58YesYes406260Liver (1x)Lymph nodes (4x)

Results: In four patients more than 70% of the observed variants were true somatic mutations. In the adenocarcinoma patient, only 32% of the variants were called as true somatic mutations. After excluding personal variants, 79 to 446 true somatic mutations were observed in any of the tumor samples of the five lung cancer patients (Table 1). Comparison of the mutations observed in the primary and metastatic samples revealed that around 50% of the mutations were shared between all tumor samples of the three NSCLC patients, whereas more than 95% of mutations were shared in all samples of the two SCLC patients.

Conclusion: We found a high percentage of metastasis specific mutations in NSCLC patients. In contrast, SCLC patients show a limited number of metastasis specific mutations, consistent with the aggressiveness of these tumor and the very poor prognosis.

Citation Format: Ali Saber, Klaas Kok, Martijn M. Terpstra, Wim Timens, Sijmen Aukema, T. Jeroen Hiltermann, Harry J. M. Groen, Anke van den Berg. Whole exome sequencing reveals a distinct mutation pattern in metastatic small cell lung cancer compared to non-small cell lung cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4757. doi:10.1158/1538-7445.AM2015-4757