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Progression in Bronchial Dysplasia

Curator and Reporter: Larry H Bernstein, MD, FCAP

 

Genomic evidence of pre-invasive clonal expansion, dispersal and progression in bronchial dysplasia

F McCaughan, CP Pipinikas, SM Janes, PJ George, PH Rabbitts and PH Dear
MRC Laboratory of Molecular Biology, Cambridge, Centre for Respiratory Research, Royal Free and University College Medical School, London, University College London Hospitals, London, Leeds Institute of Molecular Medicine, St James’s University Hospital, Leeds, UK
J Pathol 2011; 224: 153–159   http://dx.doi.org/10.1002/path.2887
http://www.jpathol.com/Genomic evidence of pre-invasive clonal expansion, dispersal and progression in bronchial dysplasia
http://www.ncbi.nlm.nih.gov/pubmed/21506132
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3378694/

The term ‘field cancerization’ is used to describe an epithelial surface that has a propensity to develop cancerous lesions, and in the case of the

  • aerodigestive tract this is often as a result of chronic exposure to carcinogens in cigarette smoke.

The clinical endpoint is the development of multiple tumours,

  • either simultaneously or sequentially in the same epithelial surface.

The mechanisms underlying this process remain unclear; one possible explanation is that

  • the epithelium is colonized by a clonal population of cells that are at increased risk of progression to cancer.

We now address this possibility in a short case series, using individual genomic events as molecular biomarkers of clonality. In squamous lung cancer the most common genomic aberration is 3q amplification. We use a digital PCR technique to

  • assess the clonal relationships between
  • multiple biopsies in a longitudinal bronchoscopic study,
  • using amplicon boundaries as markers of clonality.

We demonstrate that clonality can readily be defined by these analyses and confirm that

  • field cancerization occurs at a pre-invasive stage and that
  • pre-invasive lesions and
  • subsequent cancers are clonally related.

We show that while the amplicon boundaries can be shared between different biopsies,

the degree of 3q amplification and the internal structure of the 3q amplicon varies from lesion to lesion. Finally, in this small cohort, the degree of 3q amplification corresponds to clinical progression.
Keywords: clonality; bronchial dysplasia; molecular copy-number counting
Conflict of interest: A patent for molecular copy-number counting has been applied for by the UK Medical Research Council. Paul Dear is named on the patent application..

The term ‘field cancerization’ was first coined many years ago and the potential underlying biological processes have been studied and discussed at length,

  • particularly in cancers of the aerodigestive tract .

Three possible mechanisms for field cancerization have been mooted in lung cancer.

  • an epithelial surface exposed to repeated insult, such as cigarette carcinogens,
    • could develop multiple separate dysplastic foci that
    • do not originate from a single clone but share similar genetic aberrations
      • as a result of the common carcinogenic insult.
    • In time, one or more of these foci may progress to cancer.
  • a mutant clone expands and migrates to colonize the epithelial surface,
    • without breaching the basement membrane, and
    • molecular divergence results in subclonal populations that may or may not progress.
  • In the third explanation an established cancer spreads to form multifocal clonal tumours.

In the past shared mutations (particularly of TP53 ) or patterns of loss of heterozygosity (LOH) have been the main biomarkers used

  • to infer the presence or absence of a clonal relationship between separate biopsies
  • from a single individual in lung cancer and pre-invasive bronchial dysplasia.

It could be argued that defining a specific shared mutation in TP53,

  • a gene with multiple different mutational hotspots,
  • with or without supportive LOH studies,
  • is more suggestive of clonality than LOH patterns alone.

multiple, anatomically distinct biopsies from an individual with widespread mild dysplasia

  • had a common mutation in TP53,
    • indicating epithelial colonization at a pre-invasive stage.

recently – 70 multifocal lung cancers from 30 individuals suggested,

  • on the basis of both LOH and TP53 mutational analysis,
  • in 77% of individuals the lesions were clonally related.

a digital PCR technique, microdissection molecular copy-number counting (μMCC), can provide detailed high-resolution information on

  • structural genomic events
  • in archived pre-invasive bronchial biopsies, in which
    • the amount of available tissue for analysis is significantly limited and the DNA is of poor quality.

We used this approach to show that 3q amplification is consistently observed in high-grade, but

  • not low-grade, bronchial dysplastic lesions, and that
  • the likely focus of this amplification is SOX2,
    • consistent with recent results from other groups.

This study was prompted by an observation that at very low resolution (2 Mb)

  • a high-grade lesion and
  • a subsequent cancer appeared to share amplicon boundaries.

Therefore, these reasearchers used ultra high-resolution analysis of

  • shared amplicon boundaries
  • to define clonal relationships between
  • microdissected biopsies taken from
  • anatomically distinct parts of the bronchial tree in the same individuals.

Discussion

Field cancerization in the bronchial tree is often described, both in clinical practice and in terms of molecular biomarkers, but the mechanism and natural history of this process remains unclear.  These data, using precisely delineated amplicon boundaries as genomic biomarkers, confirm that

  • clonal expansion and dispersal of cells occurs and that
  • subclonal populations emerge with varying molecular characteristics and clinical outcomes.

A consistent observation in the current cases is that

  • the amplitude of 3q amplification predicts which lesion is likely to progress; and further,
  • there is incremental 3q amplification in those lesions that do progress.

The progression of dysplasia to invasion is generally held to reflect ongoing selection of  clonally advantageous genetic events. However, the contribution of regional genomic events to neoplastic progression is a focus of some debate—whether

  • it is of pathogenic consequence or
  • an epiphenomenon reflecting genome instability.

3q amplification may be

  • selectively neutral or it may be
  • a critical stage in the development of squamous lung cancer.

In support of the latter, the almost uniform finding of 3q amplification in invasive squamous lung cancer

  • its selection in the progression to invasion
    • points to a significant and perhaps obligate role
    • in the pathogenesis of SQC.

Whether SOX2 is the main target of this amplification or one of a number of target oncogenes that are co-amplified remains unclear.

English: Bronchial anatomy detail of alveoli a...

English: Bronchial anatomy detail of alveoli and lung circulation. Français : Anatomie pulmonaire: détail des alvéoles et de la circulation pulmonaires . (Photo credit: Wikipedia)

copy neutral LOH cancer

copy neutral LOH cancer (Photo credit: Wikipedia)

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