Integrative genome analyses identify key somatic driver mutations of small cell lung cancer

Authors

Peifer M

Fernandez-Cuesta L

Sos ML

George J

Seidel D

Kasper LH

Plenker D

Leenders F

Sun R

Zander T

Menon R

Koker M

Dahmen I

Mueller C

Di Cerbo V

Schildhaus HU

Altmueller J

Baessmann I

Becker C

de Wilde B

Vandesompele J

Boehm D

Ansen S

Gabler F

Wilkening I

Heynck S

Heuckmann JM

Lu X

Carter SL

Cibulskis K

Banerji S

Getz G

Park KS

Rauh D

Gruetter C

Fischer M

Pasqualucci L

Wright G

Wainer Z

Russell P

Petersen I

Chen Y

Stoelben E

Ludwig C

Schnabel P

Hoffmann H

Muley T

Brockmann M

Engel-Riedel W

Muscarella LA

Fazio VM

Groen H

Timens W

Sietsma H

Thunnissen E

Smit E

Heideman DAM

Snijders PJF

Cappuzzo F

Ligorio C

Damiani S

Field J

Solberg S

Brustugun OT

Lund-Iversen M

Saenger J

Clement JH

Soltermann A

Moch H

Weder W

Solomon B

Soria JC

Validire P

Besse B

Brambilla E

Brambilla C

Lantuejoul S

Lorimier P

Schneider PM

Hallek M

Pao W

Meyerson M

Sage J

Shendure J

Schneider R

Buettner R

Wolf J

Nuernberg P

Perner S

Heukamp LC

Brindle PK

Haas S

Thomas RK

Doi

10.1038/ng.2396

PMID: 22941188 · DOI: 10.1038/ng.2396 · Journal: Nature Genetics (2012)

TL;DR

This study performed integrative genomic analysis of small-cell lung cancer (SCLC) by sequencing 29 exomes, 2 whole genomes, and 15 transcriptomes, complemented by SNP array analysis of 63 tumors. The authors found universal inactivation of TP53 and RB1, identified recurrent mutations in histone-modifying genes (CREBBP, EP300, KMT2A), and discovered potentially targetable alterations including FGFR1 amplifications and PTEN mutations. Cross-species comparison with mouse SCLC models validated key findings.

Cohort & data

  • 99 surgically resected SCLC specimens from the Clinical Lung Cancer Genome Project (CLCGP) consortium
  • Exome sequencing: 27 tumors + 2 cell lines (n=29)
  • Whole-genome sequencing: 2 tumors
  • Transcriptome sequencing: 15 tumors
  • SNP array (Affymetrix 6.0): 63 tumors
  • Mouse model validation: 20 SCLC tumors from p53/Rb1 conditional knockout mice
  • Validation cohort: 26 additional tumors + 34-45 cell lines (gene-specific)
  • Cancer type: SCLC
  • Dataset: sclc_clcgp

Key findings

  • SCLC exhibits an extremely high mutation rate of 7.4 +/- 1 protein-changing mutations per million base pairs, consistent with tobacco carcinogen exposure (elevated C:G>A:T transversions).
  • Universal biallelic inactivation of TP53 and RB1 in all 29 sequenced cases, with CNLOH enrichment confirming these as early clonal events.
  • CREBBP/EP300 mutations clustered in the HAT domain at an overall frequency of 18% (point mutations, indels, gene rearrangements); mutations were mutually exclusive, suggesting epistasis.
  • Functional validation showed CREBBP HAT domain mutations (Gly1411Arg, Asp1435Tyr, Ser1432Pro) significantly reduced H3K18 acetylation in Crebbp/Ep300 double-knockout MEFs (P<0.05 to P<0.0001, one-way ANOVA with Bonferroni correction).
  • KMT2A (MLL) recurrently mutated at Ile960 (Ile960Met).
  • FGFR1 focal amplification in 6% of cases (copy number >= 3.5), validated by FISH in an independent set of 51 tumors (3/51, 6%).
  • MYCL amplification in 5/63 (8%), MYCN in 4/63 (6%), MYC in 1/63; all mutually exclusive (total 16%).
  • SLIT2 mutated in 5/29 exome cases with clustered mutations (2 nonsense, 1 frameshift, 2 missense); overall 10% in extended cohort (n=89).
  • PTEN mutations in 3/29 cases with proven/likely loss of phosphatase activity.
  • No significant difference in genomic architecture between surgically resected (early-stage) and autopsy (late-stage) specimens.

Genes & alterations

  • TP53 — inactivating mutations (universal, 100%); biallelic via mutation + LOH/CNLOH; early clonal event
  • RB1 — inactivating mutations (universal, 100%); biallelic via mutation + deletion/LOH; early clonal event
  • CREBBP — inactivating point mutations, indels, and gene fusions in HAT domain (18% overall); haploinsufficient tumor suppressor
  • EP300 — inactivating mutations in HAT domain; mutually exclusive with CREBBP
  • KMT2A — recurrent missense mutation (Ile960Met); histone methyltransferase
  • PTEN — inactivating missense mutations (3/29, 10%); loss of phosphatase activity activating PI3K pathway
  • SLIT2 — truncating and missense mutations (10%); candidate novel tumor suppressor
  • EPHA7 — mutations identified; candidate tumor suppressor (previously described in lymphoma)
  • FGFR1 — focal amplification (6%); potential therapeutic target
  • MYCL — focal amplification (8%); mutually exclusive with other MYC family members
  • MYCN — focal amplification (6%); mutually exclusive with MYCL and MYC
  • MYC — focal amplification (rare, 1 case)
  • SOX2 — broad 3q gains (less focal than in squamous-cell lung cancer)
  • CCNE1 — focal amplification at 19q12
  • NFIB — amplification in mouse SCLC; copy number gain in 3 human samples
  • COBL — identified as candidate driver gene
  • PIK3CA — no mutations observed (notable negative finding)

Clinical implications

  • FGFR1-amplified SCLC (6%) may benefit from FGFR inhibitors, which were already in clinical testing for squamous-cell lung cancer at the time of publication.
  • PTEN-mutant SCLC (10%) harbors PI3K pathway activation, representing a potential therapeutic vulnerability.
  • Universal TP53/RB1 inactivation confirms these are obligate events in SCLC pathogenesis and cannot serve as therapeutic targets themselves.
  • Loss of RB1 may be mechanistically involved in EGFR-mutant lung adenocarcinoma trans-differentiation to SCLC under therapeutic pressure (one case with shared TP53 mutation but SCLC-restricted RB1 mutation).
  • Histone modification (CREBBP/EP300/KMT2A) as a major altered pathway class in SCLC opens potential avenues for epigenetic therapeutic strategies.

Limitations & open questions

  • Limited sample size (29 exomes) for a tumor with extremely high mutational background; statistical power to detect low-frequency drivers is constrained.
  • Specimens were surgically resected, representing a minority of SCLC cases (most are treated with chemoradiation without surgery), though the authors show genomic similarity to autopsy specimens.
  • No matched normal for copy number in the mouse analysis (array-CGH based).
  • Functional validation was limited to CREBBP HAT domain mutations; other candidate drivers (SLIT2, EPHA7, COBL) lack functional characterization in this study.
  • The study predates immunotherapy and does not assess TMB as a potential biomarker for checkpoint inhibitor response despite the high mutation rate.
  • Whether FGFR inhibitors have clinical activity in FGFR1-amplified SCLC remains unproven.

Citations from this paper used in the wiki

  • “In all cases we found evidence for inactivation of TP53 and RB1 and identified recurrent mutations in histone-modifying genes, CREBBP, EP300, and MLL.” (Abstract)
  • “SCLC exhibits an extremely high mutation rate of 7.4 protein-changing mutations per million basepairs.” (Results, p.3)
  • “Focal amplifications affected 8p12 including FGFR1 (6% with copy number >=3.5)” (Results, p.2)
  • “Together, these filters yielded a list of likely driver genes in SCLC: TP53, RB1, PTEN, CREBBP, EP300, SLIT2, MLL, COBL, and EPHA7” (Results, p.3)
  • “CREBBP/EP300 mutations…confirmed an overall mutation frequency of 18% (point-mutations, indels, and gene rearrangements)” (Results, p.4)
  • “All three mutations significantly reduced acetylation of histone 3 lysine 18 (H3K18)” (Results, p.4)

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