Chapter 2 - University of British Columbia

can identify nearly three times as many genes when we can account for multiple types of
disruption as opposed to accounting for only a single type of alteration and (ii) the “And”
(coupled multiple hits) concept where we identify genes which are targeted my multiple
mechanisms in the sample and show that these genes can have significant biological and/or
clinical relevance.
6.1.2 Identification of a prevalent genetic alteration in lung adenocarcinoma
Genetic and epigenetic alterations have been shown to be prominent in lung adenocarcinoma.
Within genetic alterations, the majority of documented alterations have involved alterations in
gene dosage, somatic mutation, and loss of heterozygosity (LOH) or allelic imbalance (whereby
an allele or a portion of the allele is lost or gained in the tumor). In terms of allelic imbalance,
the majority of the time this event is captured as a decrease or increase in gene dosage.
However, there are also cases where allelic imbalance exists but there is no net change in gene
dosage, termed copy neutral LOH or somatic uniparental disomy (UPD). Chapter 4 discusses
the unexpected prevalence of UPD in the lung adenocarcinoma genome.
Though previous studies were done using SNP arrays on lung adenocarcinoma tumors, the
prevalence of UPD was likely underestimated due to a number of reasons. Amongst the
reasons include the use of heterogeneous samples with high normal cell contamination due to
lack of microdissection, lower resolution of alterations identifiable by previous SNP arrays, use
of non patient-matched controls as reference and movement from call-based algorithms to
algorithms which use allele specific copy number [3].
In addition to the prevalence of UPD, the other key finding from this chapter is the presence of
frequent UPD at both known and novel oncogenes. While UPD has previously been shown to
affect tumor suppressor genes such as RB1 [4], the association of UPD at oncogene loci has
not been reported as often in solid tumors. Moreover, in the previous studies in hematological
malignancies such as leukemias, lymphomas, or myeloid dysplastic syndromes, the observed
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