bbc 2015

BeNeLux Bioinformatics Conference – Antwerp, December 7-8 2015
Abstract ID: P
Poster
10th Benelux Bioinformatics Conference bbc 2015
P61. THE DETECTION OF PURIFYING SELECTION DURING TUMOUR
EVOLUTION UNVEILS CANCER VULNERABILITIES
Jimmy Van den Eynden 1* & Erik Larsson 1 .
Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, The Sahlgrenska Academy, University
of Gothenburg, Sweden. * jimmy.van.den.eynden@gu.se
Identification of somatic mutation patterns indicative of positive selection arguably has become the major goal of cancer
genomics. This is motivated by a search for cancer driver genes and pathways that are recurrently activated in tumours
but not normal cells, thus providing possible therapeutic windows. However, cancer cells additionally depend on a large
number of basic cellular processes, and elevated sensitivity to inhibition of certain essential non-driver genes has been
demonstrated in some cases. While such vulnerability genes should in theory be identifiable based on strong purifying
(negative) selection in tumors, these patterns have been elusive and purifying selection remains underexplored in cancer.
We established a new methodology and, using mutational data from 25 TCGA tumor types, we show for the first time
that negative selection in candidate vulnerability genes can be detected.
INTRODUCTION
Recently it was shown that a hemizygous deletion of the
well–known tumour suppressor gene TP53 creates
therapeutic vulnerability in colorectal cancer due to
concomitant loss of the neighbouring gene POLR2A (Liu
et al., 2015).
As any damaging mutation occurring in the single allele of
a hemizygously deleted essential gene, like POLR2A, is
expected to lead to cell death, we hypothesized that
purifying selection in these genes could be unveiled by
demonstrating a lower number of damaging mutations
then could be expected in the absence of any selection.
Therefore we used the POLR2A case as a proof-ofconcept
to develop a methodology to detect purifying
selection in large genome sequencing datasets.
METHODS
Mutation and copy number data from 25 different cancers
types and 7,871 samples were downloaded from the
TCGA data portal and pooled together in a large pancancer
dataset. Different mutational functional impact
scores were calculated using Annovar. Copy number data
were analyzed using Gistic 2.0 to differentiate POLR2A
copy number neutral from hemizygously deleted samples.
RESULTS & DISCUSSION
POLR2A was found to be hemizygously deleted in 29% of
all samples. As expected, in over 99% this deletion was
part of the TP53 (driving) deletion on chromosome 17.
POLR2A was mutated 228 times in 2.3% of all samples.
While 14 nonsense mutations and small out-of-frame
insertions or deletions occurred in the copy number
neutral group, none of these damaging mutations were
found in the deletion group (p=0.03, fisher test),
suggesting purifying selection against this type of
mutations.
Next to these truncating mutations, also missense
mutations that have a damaging effect on the gene’s
protein function are expected to be selected against.
Therefore we predicted the functional impact of all
mutations using different functional impact scores. The
median (PolyPhen-2) functional impact score was found
to significantly lower in the deletion group compared to
the copy number neutral group (p=0.002, Wilcoxon test,
fig.1), further confirming that purifying selection has
taken place in POLR2A during tumour evolution.
These preliminary findings confirm that purifying
selection is detectable in vulnerability genes like POLR2A
and this approach could be used to detect other, new
candidate vulnerability genes.
FIGURE 1. Negative selection against POLR2A high impact mutations in
hemizygously deleted tumour samples.
REFERENCES
Liu, Y., Zhang, X., Han, C., Wan, G., Huang, X., Ivan, C., … Lu, X.
(2015). TP53 loss creates therapeutic vulnerability in colorectal
cancer. Nature, 520(7549), 697–701.
http://doi.org/10.1038/nature14418
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