University of Cologne Small Cell Lung Cancer 2015

Overview

One hundred ten small cell lung cancer (SCLC) whole genomes from 152 fresh-frozen clinical specimens collected under IRB approval; 42 were excluded for insufficient DNA quality/quantity. At the time of publication, this was the first comprehensive somatic whole-genome analysis of SCLC and remains the largest whole-genome SCLC cohort. Most cases were treatment-naive; only 5 were obtained at relapse. Complementary assays included RNA-seq (n=81), Affymetrix SNP 6.0 arrays (n=142), and an independent validation cohort of 112 samples (28 exomes + 84 targeted).

Composition

  • Cancer type: SCLC (Small Cell Lung Cancer); primary lung n=106, metastatic n=4 among the WGS cases; median tumor content 84%.
  • Sample count: 110 tumor + matched normal WGS pairs passing QC; 152 total specimens collected.
  • Clinical fields: treatment status (naive vs relapsed), smoking history (median 45 pack-years among smokers; known for 88%), follow-up (median 69 months; 31% alive at last follow-up), pathology by ≥2 independent pathologists with IHC.
  • WGS: Illumina HiSeq 2000 (TruSeq DNA PCR-free libraries, paired-end 2×100 bp, ≥30× tumor and normal); reference genome NCBI37/hg19; BWA v0.6.1-r104 alignment.
  • Transcriptome: RNA-seq on 81 specimens (71 overlapping WGS + 10 additional).
  • Copy number: Affymetrix SNP 6.0 arrays on 142 specimens (103 of WGS + 39 additional).
  • Validation cohort: 28 fresh-frozen exomes + 9 SCLC cell lines (prior published data) + 75 fresh-frozen/FFPE samples sequenced with a 22-gene custom Agilent SureDesign targeted panel (≥200× coverage).
  • Mouse models: 8 SCLC tumors from Trp53;Rb1 double-knockout and Trp53;Rb1;Rbl2 triple-knockout mice analyzed by WES (n=6) or WGS (n=2).

Assays / panels (linked)

  • whole-genome-seq — primary cohort, ≥30× coverage.
  • whole-exome-seq — validation cohort fresh-frozen (28 samples + mouse tumors).
  • rna-seq — transcriptome sequencing on 81 specimens; neuroendocrine subtype definition.
  • affymetrix-snp6 — copy number profiling on 142 specimens.
  • targeted-dna-seq — 22-gene custom validation panel on FFPE samples.
  • immunohistochemistry — chromogranin A, synaptophysin, CD56, Ki67; protein-level validation of key drivers.

Papers using this cohort

  • PMID:26168399 — George et al. 2015, “Comprehensive genomic profiles of small cell lung cancer,” Nature.

Notable findings derived from this cohort

  • Bi-allelic inactivation of TP53 and RB1 is obligatory in SCLC: found in 100% and 93% of non-chromothriptic tumors respectively, often through complex genomic rearrangements; mutation burden averages 8.62 nonsynonymous mutations/Mb with a heavy-smoking C>A transversion signature PMID:26168399.
  • NOTCH-family genes (NOTCH1–4) are recurrently inactivated in 25% of human SCLC; mouse TKO models confirm Notch activation suppresses SCLC initiation and neuroendocrine differentiation and extends survival PMID:26168399.
  • Recurrent oncogenic TP73 rearrangements (introns 1–3 breakpoints) produce dominant-negative N-terminally truncated isoforms (p73Δex2/3) in 7% of cases; total TP73 somatic alteration rate 13% PMID:26168399.
  • Two chromothriptic tumors with wild-type RB1 showed CCND1 overexpression as an alternative Rb-pathway inactivation mechanism; SCLC subclonal diversity threefold lower than lung adenocarcinoma (p=0.00023) PMID:26168399.

Sources

  • cBioPortal study: sclc_ucologne_2015

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