Project description:Introduction: The majority of pulmonary carcinoid (PC) tumors can be cured by surgical resection alone, but a significant proportion of patients experience recurrences. PC is insensitive to conventional chemotherapy, and it would be necessary to reveal the molecular mechanisms of metastasis and develop targeted therapeutics. Methods: We performed the comprehensive whole-exome sequencing (WES) of primary tumors and corresponding normal lung tissues from 14 PC patients (including 4 patients who developed postsurgical distant metastasis) and the RNA sequencing of primary tumors from 6 PC patients (including 4 patients who developed postsurgical distant metastasis). Exon array-based gene expression analysis was performed in 25 PC. Results: We identified a total of 139 alterations in 136 genes. MUC6 and SPTA1 were recurrently mutated with the frequency of 21 % (3/14) and 14% (2/14), respectively. The mucin protein family genes including MUC2, MUC4 and MUC6 were mutated in 36% (5/14) in a mutually exclusive manner. The pathway analysis of mutated genes revealed the enrichment of genes involved in the mitogen-activated protein kinase (MAPK) signaling, regulation of actin cytoskeleton and focal adhesion, and transforming growth factor (TGF)-β signaling pathways. RNA sequencing reveals a total of 8 novel fusion transcripts including one derived from chromosomal translocation between the TRIB2 and PRKCE genes. All the 8 fusion genes were detected in primary PC that had developed metastasis after surgical resection. We identified 14 genes (DENND1B, GRID1, CLMN, DENND1B, NRP1, SEL1L3, C5orf13, TNFRSF21, TES, STK39, MTHFD2, OPN3, MET, and HIST1H3C) up-regulated in 5 PC that had relapsed after surgical resection. Conclusions: In this study we identified novel somatic mutations and chromosomal rearrangements by examining clinically aggressive cases that had developed postsurgical metastasis. It is essential to validate their clinical significance in an independent larger patient cohort.

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Whole-exome and RNA sequencing of pulmonary carcinoid reveals chromosomal rearrangements associated with recurrence (Affymetrix)

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