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Progression in Bronchial Dysplasia

Posted in CANCER BIOLOGY & Innovations in Cancer Therapy, Genome Biology, Genomic Testing: Methodology for Diagnosis, International Global Work in Pharmaceutical, Molecular Genetics & Pharmaceutical, Pharmaceutical Industry Competitive Intelligence, tagged Cancer - General, Digital polymerase chain reaction, DNA, health, London, Lung cancer, Paul Dear, Respiratory Research on March 9, 2013| Leave a Comment »

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.

Genomics of bronchial epithelial dysplasia (pharmaceuticalintelligence.com)
N-Cadherin Expression Is Associated with Acquisition of EMT Phenotype and with Enhanced Invasion in Erlotinib-Resistant Lung Cancer Cell Lines (plosone.org)
Long-Term Success Rates Shown For Eradication Of Barrett’s Esophagus After Endoluminal Therapies (medicalnewstoday.com)
The potential for PI3K pathway inhibitors in Lung Cancer (pharmastrategyblog.com)
ERCC1 Isoform Expression and DNA Repair in Non–Small-Cell Lung Cancer

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