Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes

Authors

Biankin AV

Waddell N

Kassahn KS

Gingras MC

Muthuswamy LB

Johns AL

Miller DK

Wilson PJ

Patch AM

Wu J

Chang DK

Cowley MJ

Grimmond SM

Doi

10.1038/nature11547

PMID: 23103869 · DOI: 10.1038/nature11547 · Journal: Nature (2012)

TL;DR

Exome sequencing and copy number analysis of 142 prospectively accrued early-stage (I/II) pancreatic ductal adenocarcinomas (PDAC) identified 16 significantly mutated genes, reaffirming known drivers (KRAS, TP53, CDKN2A, SMAD4) and uncovering novel mutated genes in chromatin modification (EPC1, ARID2), DNA damage repair (ATM), and other pathways. The study discovered frequent and diverse somatic aberrations in axon guidance pathway genes, particularly SLIT/ROBO signalling, suggesting a previously unrecognized role for these embryonic regulators in pancreatic carcinogenesis.

Cohort & data

  • 142 consecutive patients with primary operable, untreated PDAC (clinical stages I and II) recruited through the Australian Pancreatic Cancer Genome Initiative (APGI), Baylor College of Medicine, and Ontario Institute for Cancer Research as part of ICGC.
  • Informative cohort of 99 tumours with >20% cellularity and/or >=10 validated somatic mutations taken forward for detailed analysis.
  • Dataset: paad_icgc.
  • Cancer type: PAAD.
  • Assay: whole-exome-seq (SureSelect II or Nimblegen capture; SOLiD v4, GAII/HiSeq platforms; depths 65x-205x across sites). Copy number via Illumina HumanOmni1 Quad genotyping arrays.

Key findings

  • 2,016 non-silent mutations and 1,628 copy-number variations identified across 99 informative tumours; average 26 mutations per patient (range 1-116).
  • 16 significantly mutated genes defined: KRAS, TP53, CDKN2A, SMAD4, KMT2C (MLL3), TGFBR2, ARID1A, SF3B1, EPC1, ARID2, ATM, ZIM2, MAP2K4, NALCN, SLC16A4, MAGEA6.
  • KRAS mutations identified in 93% of 142 cases.
  • ATM aberrations in 8% of cohort (mutated 5%, LOH/loss 5%, two patients with both).
  • Axon guidance pathway genes enriched (P = 5.30 x 10^-5); strengthened with additional data (P = 4.67 x 10^-8).
  • SLIT2 and ROBO2 mutations in 5% of patients; focal copy-number losses of ROBO1 and SLIT2 affecting a further 15%, totalling 23% with SLIT/ROBO aberrations.
  • Class 3 semaphorins (SEMA3A, SEMA3E) amplified in 18% of patients, mutations in an additional 3%.
  • Low ROBO2 mRNA expression associated with poor survival (P = 0.04); high ROBO3 expression inversely associated with poor survival (P < 0.006).
  • High SEMA3A and PLXNA1 mRNA expression independently prognostic for poor survival on multivariate analysis.
  • Sleeping Beauty transposon mutagenesis screens in murine PDAC models independently confirmed enrichment for axon guidance genes (P = 1.6 x 10^-3).

Genes & alterations

Gene Alteration Finding
KRAS Activating mutations 93% prevalence; GTPase/MAPK pathway
TP53 Inactivating mutations Significantly mutated; DNA damage response
CDKN2A Mutations + copy-number loss G1/S checkpoint; losses confirmed by GISTIC2.0
SMAD4 Mutations + copy-number loss TGF-beta/BMP signalling; losses confirmed by GISTIC2.0
KMT2C Mutations Chromatin modification; transcription regulation
TGFBR2 Mutations TGF-beta receptor; growth regulation
ARID1A Mutations SWI/SNF complex; chromatin remodelling
SF3B1 Mutations Splicing factor; nuclear mRNA splicing
EPC1 Mutations Novel; histone acetylation; chromatin modification
ARID2 Mutations Novel; chromatin modification
ATM Mutations + LOH 8% of cohort; DNA damage repair; BRCA-mediated pathway
MAP2K4 Mutations Novel; Toll-like receptor/MAPK signalling
SLIT2 Mutations + focal losses 5% mutated; axon guidance / SLIT-ROBO pathway
ROBO1 Focal copy-number losses + mutations Axon guidance receptor; additional mutations in targeted sequencing
ROBO2 Mutations 5% mutated; low expression = poor prognosis
ROBO3 Overexpression ROBO2 inhibitor; high expression = poor survival
SEMA3A Amplification 18% amplified; high expression = poor prognosis
SEMA3E Amplification Co-amplified with SEMA3A
PLXNA1 Amplification/overexpression Semaphorin receptor; independent poor prognostic factor

Clinical implications

  • ATM aberrations in 8% of sporadic PDAC highlight BRCA-mediated DNA damage repair as a targetable pathway, with potential relevance for PARP inhibitor sensitivity.
  • Loss of SLIT/ROBO signalling may provide an alternative mechanism for deregulating MET and WNT pathways downstream of receptors; this could influence efficacy of MET inhibitors in PDAC patients with ROBO loss.
  • SEMA3A and PLXNA1 expression are independent prognostic biomarkers for poor survival in resected PDAC.
  • ROBO2 and ROBO3 expression levels may serve as prognostic biomarkers (low ROBO2 / high ROBO3 = poor prognosis).
  • Therapeutics targeting axon guidance molecules (developed for neuronal regeneration) represent unexplored candidates for cancer treatment.

Limitations & open questions

  • Median sensitivity for detecting true positive mutations estimated at only 45% due to low tumour cellularity (mean 38%), so mutation frequencies are likely underestimates.
  • Only primary resectable (stage I/II) tumours studied; mutation landscape of metastatic PDAC may differ.
  • Functional validation of axon guidance gene aberrations as true drivers (vs. passengers) remains incomplete; Sleeping Beauty data are supportive but not definitive.
  • No targeted therapy trials or drug response data presented; clinical actionability of findings requires preclinical and trial validation.
  • The study used the older gene symbol MLL3; the current HUGO symbol is KMT2C.

Citations from this paper used in the wiki

  • “We define 16 significantly mutated genes, reaffirming known mutations (KRAS, TP53, CDKN2A, SMAD4, MLL3, TGFBR2, ARID1A and SF3B1), and uncover novel mutated genes including additional genes involved in chromatin modification (EPC1 and ARID2), DNA damage repair (ATM) and other mechanisms (ZIM2, MAP2K4, NALCN, SLC16A4 and MAGEA6).” (Abstract)
  • “KRAS mutations were identified in 93% of 142 cases and tumour cellularity ranged from 5% to 85% with a mean of 38%.” (Clinical cohort section)
  • “Aberrations of ATM occurred in 8% of our cohort (mutated in 5%, LOH or loss in 5%, with two patients exhibiting both mutation and LOH or loss).” (Significantly mutated genes section)
  • “SLIT2 and ROBO2 mutations were present in 5% of patients, with focal copy-number losses of ROBO1, and SLIT2 detected by GISTIC2.0 analysis… potentially having an impact on a further 15% of the cohort.” (Axon guidance pathway genes section)
  • “Class 3 semaphorins (SEMA3A and SEMA3E) exhibited significant amplification in 18% of patients and an additional 3% harboured mutations.” (Axon guidance pathway genes section)
  • “Low mRNA expression of the ROBO2 receptor was associated with poor patient survival (P = 0.04).” (Axon guidance pathway genes section)

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