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Poster Discussion session - Translational research 2

2302 - Characterization through whole exome sequencing of individuals presenting extreme phenotypes of high and low risk to develop tobacco-induced non-small lung cancer (NSCLC)


21 Oct 2018


Poster Discussion session - Translational research 2


Translational Research

Tumour Site


Jose Luis Perez Gracia


Annals of Oncology (2018) 29 (suppl_8): viii649-viii669. 10.1093/annonc/mdy303


J.L. Perez Gracia1, M.J. Pajares2, J.P. Fusco1, M. Andueza1, V. Segura3, M.I. Mora4, E. Guruceaga5, R. Sanchez Bayona1, A. Gurpide1, J.M. Lopez-Picazo1, I. Gil-Bazo1, J.P. de Torres6, J. Zulueta6, R. Pio2, I. Melero7, M.F. Sanmamed1, M. Rodriguez-Ruiz1, A. Gonzalez Neira8, L. Montuenga2, A. Patiño-Garcia4

Author affiliations

  • 1 Oncology, Clinica Universidad de Navarra, 31008 - Pamplona/ES
  • 2 Program In Solid Tumors And Biomarkers, Cima, Universidad de Navarra, 31008 - Pamplona/ES
  • 3 Idisna And Bioinformatics Unit, Cima, Universidad de Navarra, 31008 - Pamplona/ES
  • 4 Pediatrics And Cima Lab Diagnostics, Clinica Universidad de Navarra, Pamplona/ES
  • 5 Proteomic, Bioinformatic And Biostatistics, Universidad de Navarra, 31008 - Pamplona/ES
  • 6 Pneumology, Clinica Universidad de Navarra, 31008 - Pamplona/ES
  • 7 Laboratory Of Immunology, Clinica Universidad de Navarra, 31008 - Pamplona/ES
  • 8 Human Genetics, CNIO, Madrid/ES


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Abstract 2302


Individual susceptibility to carcinogens may depend on the genetic background. We sequenced the constitutional exome of individuals presenting extreme phenotypes of sensitivity and resistance to develop tobacco-induced NSCLC. We hypothesized that such selection would enrich the frequencies of the alleles that contribute to the trait.


From an identification cohort (n = 3,631) we selected 100 caucasian heavy smokers that either developed NSCLC -specifically adenocarcinoma- at an early age (cancer-cohort, n = 50) or that did not present NSCLC or any other tumors at an advanced age (cancer-free cohort, n = 50). We sequenced their germline DNA using the Agilent Human Exome Capture v5, which includes 21,522 genes (357,999 exons). We selected genetic variants located in the exonic regions and splice sites of the genes evaluated; that codified for non-synonymous codons; and that showed allelic differences >15% between both cohorts.


The mean age for the cancer and cancer-free cohorts was 50 (range 34-55) and 78 years (72-90). Mean tobacco consumption was 44 (range 6-72) and 55 pack-years (20-124). Median exome sequencing coverage was 96% at > 10X and median depth was 97X. We identified 229 differential variants between both cohorts, located in 189 genes. The most significant variants (p < 10-4) are shown in the table. Twenty genes or family genes included >3 differential genetic variants (range 3-25): ADAMTS, ALPK2/3, ankyrins, APOL4, CCDC, CRIPAK, FYCO1, HLA-A, keratins, mucins, olfactory receptors, PDPR, PRAME family, RFPL2, RP1L1, SAMD9, SLC transporters, anoctamins, TTN, and ZNF family.


We identified genetic variants associated with individuals presenting extreme phenotypes of high and low risk to develop tobacco-induced NSCLC. These variants warrant further study to characterize their impact in the development of these extreme phenotypes.

Clinical trial identification

Legal entity responsible for the study

Universidad de Navarra.


Spanish Society of Medical Oncology, Fundación SEOM and Fundación Salud 2000, Government of Navarra.

Editorial Acknowledgement


All authors have declared no conflicts of interest.Table: 1837PD

GeneFunctionNucleotide and protein changep-value
Overrepresented in extreme cases
ALPK2Tumour-suppressor gene down-regulated by oncogenic KRASNM_052947:exon13:c.A6469G:p.I2157V4.4753E-05
DEPDC7Cell signal transductionNM_001077242:exon3:c.G574A:p.A192T NM_139160:exon3:c.G547A:p.A183T0.00078817
HLA-AAntigen presentationNM_001242758:exon2:c.G302A:p.S101N0.00013506
NM_001242758:exon2:c.C256G:p.Q86E NM_002116:exon2:c.C256G:p.Q86E0.00020408
HNRNPCL1Nucleosome assemblyNM_001013631:exon2:c.A764G:p.D255G0.0004611
PRAMEF2Negative regulation of apoptosis, cell differentiation, transcription; Positive regulation of cell proliferationNM_023014:exon3:c.A674G:p.Y225C0.00092831
Overrepresented in extreme controls
CRIPAKNegative regulator of p21-activated protein kinase 1NM_175918:exon1:c.A862G:p.S288G7.1046E-05
EPHA3Putative tumor suppressorNM_005233:exon16:c.T2770C:p.W924R0.00099993
OR1S1Olfactory receptor 1S1NM_001004458:exon1:c.A13G:p.S5G0.00092807

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