419O - Genomic profile in pulmonary neuroendocrine tumors (puNETs): the whole-exome sequencing (WES) as a strategic tool

Date 10 October 2016
Event ESMO 2016 Congress
Session Endocrine and neuroendocrine tumours
Topics Neuroendocrine Cancers
Presenter Ivana Sullivan
Citation Annals of Oncology (2016) 27 (6): 136-148. 10.1093/annonc/mdw369
Authors I.G. Sullivan1, M. Deloger2, L. Lacroix3, B. Job4, N. Dorvault5, J. Adam6, A. Honore3, L. Gianoncelli7, G. Le Teuff8, V. de Montpreville9, B. Besse1, J. Soria1, J. Scoazec3, E. Baudin10, D. Planchard1
  • 1Département D'oncologie Médicale, Gustave Roussy, 94800 - Villejuif/FR
  • 2Plateforme De Bioinformatique, Ammica, Inserm Us23/cnrs Ums3655, Gustave Roussy, 94800 - Villejuif/FR
  • 3Laboratoire De Recherche Translationnelle Et Centre De Ressources Biologiques, Gustave Roussy, 94800 - Villejuif/FR
  • 4Plateforme De Bioinformatique, Ums Ammica, Gustave Roussy, 94800 - Villejuif/FR
  • 5Inserm - U981, Gustave Roussy, 94800 - Villejuif/FR
  • 6Pathology, Gustave Roussy, 94800 - Villejuif/FR
  • 7Department Of Medical Oncology, Istituto Clinico Humanitas, 20089 - Rozzano/IT
  • 8Service De Biostatistique Et D'épidémiologie, Gustave Roussy, 94800 - Villejuif/FR
  • 9Pathology, Centre chirurgical Marie-Lannelongue, 92350 - Le Plessis-Robinson/FR
  • 10Département De M. Nucléaire Et De Cancérologie Endocrinienne, Gustave Roussy, 94800 - Villejuif/FR

Abstract

Background

Treatment of puNETs represents a clinical challenge. Although there is some evidence concerning genomic profile of puNETs, targetable molecular alterations remain unclear. WES provides insight into the genomic landscape of puNETs offering new opportunities for a precision medicine.

Methods

Fresh-frozen tumor-normal pairs from 35 typical carcinoid (TC), 4 atypical carcinoid (AC) and 9 large-cell neuroendocrine carcinoma (LCNEC) patients were consecutively collected from three European centers (GR, CCML, ICH) between Feb 2010 and Nov 2013. All specimens were reviewed by expert pathologists and those with more than 65% tumor cells on H&E were selected. Genomic DNA (gDNA) was extracted from tumor and matched normal tissue. After normalization and quality control, gDNA was captured using in-solution enrichment methodology (Human All Exon V5 + UTR–75 Mb, Agilent Technologies). Exome enriched libraries were sequenced on an Illumina HiSeq 2000 with a paired-end 2 x 100 bp protocol. Variants were called using VarScan2 against the reference genome hg19 (GRCh37). After filtering based on frequency, variants were annotated using SnpEff and SnpSift with dbSNP and dbNSFP.

Results

Fifty-nine % of TC and AC were females, 89% of LCNEC were males. Median age was 57 (18-83) yrs, 26 (54%) stage I, 16 (24%) stage II, 3 (6%) stage III and 3 (6%) stage IV. On average, 11.6 Gb of sequence were produced per sample, aiming a mean coverage of 72 X. A median of 277 (10-8470) somatic variants per sample was observed. Overall, preliminary analysis showed several somatic variants in histone modifiers as MEN1 (n = 9), EZH2 (n = 6) and HDAC5 (n = 5). Variants in genes involving SWI/SNF complex as ARID, BCL-2 and SMARCA have also been found. Regarding the mTOR pathway, several variants were observed in PIK3 family. However, none of the alterations mentioned above were enriched in any subtype. Nevertheless, TP53 (n = 6) and RB1 (n = 3) variants were observed exclusively in LCNEC.

Conclusions

Our preliminary overview of the molecular landscape in puNETS provides the basis for further analysis. Some of these variants might potentially represent an actionable target. An exhaustive bioinformatic analysis will be presented.

Clinical trial identification

Legal entity responsible for the study

Gustave Roussy

Funding

Georges Mathé/ESMO fellowship

Disclosure

All authors have declared no conflicts of interest.