TY  - UNPB
EP  - 292
AV  - none
Y1  - 2009/12//
A1  - McCaughan, F.
M1  - Doctoral
PB  - UCL (University College London)
UR  - https://discovery.ucl.ac.uk/id/eprint/19030/
N1  - Authorisation for digitisation not received
N2  - 3q amplification is the most common genomic aberration in squamous lung cancer,
suggesting that a ?driver? oncogene for squamous lung cancer resides within the 3q
amplicon. Studying preinvasive disease has the theoretical advantage of identifying the key
early molecular events in the pathogenesis of squamous lung cancer. This thesis was based
on developing a method (microdissection-Molecular Copy-number Counting - ?MCC) for
the analysis of regional genome structure in archived biopsies and then applying this
method to the analysis of the 3q amplicon in a rare collection of preinvasive bronchial
lesions.
Molecular Copy-number Counting was adapted and validated for the assessment of copynumber
variation in degraded DNA extracted from microdissected formalin-fixed paraffin-embedded
biopsies. This approach should be generally applicable, both in basic cancer
research, and in the stratification of treatment based on the analysis of genome structure in
clinical biopsies. A further series of experiments on high molecular weight DNA from
peripheral blood raised unexpected technical issues about the effect of DNA integrity on
single molecule PCR; evidence is provided suggesting that DNA sequences with very high
melting temperature external to the target sequence may inhibit PCR efficiency.
?MCC was applied to a series of low- and high-grade dysplastic lesions. There were a
number of novel findings. Firstly, genome evolution is a dynamic process and corresponds
to histological grade. All high-grade, but no low-grade lesions, showed gain or
amplification of 3q relative to 3p. No low-grade lesions progressed to cancer. Secondly,
the minimal commonly amplified region was narrowed to a 3.5Mb region encompassing 17
genes with the two outstanding candidates being PIK3CA and SOX2. Finally, for three
individual patients, the analysis of series of biopsies sampled longitudinally allowed new
observations on clonal expansion and suggested incremental regional amplification may be
important in the progression of preinvasive lesions to invasive cancer.
TI  - 3q amplification in preinvasive lesions of the bronchial epithelium
ID  - discovery19030
ER  -