digital-pathology-2016_posters-accepted-abstracts

19 / 19

Page 58
Digital Pathology & Pathologists 2016
December 05-06, 2016
Volume 6 Issue 5(Suppl) J Clin Exp Pathol
ISSN: 2161-0681 JCEP, an open access journal
conferenceseries .com
December 05-06, 2016 Madrid, Spain
9th World Digital Pathology & Pathologists Congress
Genomic analysis of intra-tumor heterogeneity unveil cancer evolution
Koshi Mimori
Kyushu University Beppu Hospital, Japan
The ultimate goal of our study is to improve the clinical outcomes for patients with malignancies, particularly of the
gastrointestinal (GI) tract; however, such tumors are often refractory to treatment. One of the main causes of this
intractability is the genomic heterogeneity of cancer, which complicates the development of genetically based therapeutics.
We have proposed two approaches to clarifying when or how malignant cells acquire genomic heterogeneity. One addresses
inter-tumor heterogeneity and the other addresses intra-tumor heterogeneity. In order to assess genomic heterogeneity in
samples from human cancers, we have applied next generation sequencing and super-computational analysis with simulation.
We believe that understanding the development of genomic heterogeneity in cancer cells can help elucidate the evolution of
malignancy and may suggest interventions to eliminate the progression of malignancy and ultimately improve prognosis for
affected patients. Our work to date has focused primarily on characterizing inter-tumor genomic heterogeneity in cases of
esophageal cancer, which is the most intractable malignancy among GI cancers. Based on mutational signatures in 144 cases of
Japanese esophageal squamous cell carcinoma (ESCC), the diverse patients could be clustered into three risk-factor subtypes:
(1) Environmental factors, i.e., drinking and smoking, (2) polymorphisms in the aldehyde dehydrogenase 2 (ALDH2) gene
and (3) Polymorphisms in the cytochrome P450 2A6 (CYP2A6) gene. To address the analysis of genomic variability within a
primary tumor, we employed a novel approach, analyzing multiple regions within a tumor to identify genomic heterogeneities
and to determine as much as possible about the order in which they arose. Computational analysis with simulation allowed us
to deduce the evolution of a tumor’s heterogeneity. In this study, we dissected multiple samples from mutually exclusive tumor
regions of nine cases of colorectal cancers and interrogated them with exome sequencing, gene copy number analysis, DNA
methylation arrays and microarray-based gene expression studies. In each case, we were able to identify “founder” mutations,
which were detected in all regions sampled and progresser mutations that were found in some regions but not all. We found
that founder mutations were associated with aging. At the gene copy number level, focal amplifications were observed to
occur more frequently in founder mutations, while focal deletions were more common in progresser mutations. Epigenetic
annotation indicated that CpG-island hyper methylation was an age-related, early event in tumor development and that global
hypomethylation was a feature of tumor progression. This multidimensional survey, coupled with computational simulation,
revealed that most intra-tumor genomic heterogeneity is likely to be generated by “neutral evolution” not by “Darwin's
Theory of Evolution”. In other words, most mutations observed in a tumor arise incidentally and are neutral in terms of tumor
progression. Such neutral mutations are called “passenger mutations”, to distinguish them from the “driver mutations” that
actively promote tumor cell proliferation. This may suggest that the refractoriness to treatment observed in some tumors may
be caused when a therapeutic treatment has the unintended effect of converting one or more passenger mutations to driver
mutations, thereby conferring therapeutic resistance.
J Clin Exp Pathol 2016, 6:5(Suppl)