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Cancer is a complex disease capable of manifesting itself as many different disease phenotypes occurring in virtually any tissue of the body. This complexity can be the result of inherited single gene mutations in germline DNA, the accumulation of acquired genomic alterations over time, or the combination of both germline mutations and somatic genomic alterations.1 There are many examples of inherited or de novo mutations in the germline contributing to cancer susceptibility. These mutations include single nucleotide polymorphisms (SNPs), small insertions and deletions (InDels), as well as structural variants such as copy number variants, translocations, and inversions. In addition, somatic genetic and epigenetic changes are known to be involved in the earliest steps of cancer initiation within normal cells and during the proliferation of these transformed cells to form a precursor or in situ cancer.2 As transformed cells continue to grow, they undergo further genomic alterations taking on the invasive, immortal, and eventually metastatic properties common to most types of cancer. Mutations in specific and well-characterized genes, occurring during these earliest steps of tumor formation, appear to cause further genetic instability within the tumor cells resulting in the accumulation of even more deleterious genomic alterations, sometimes referred to as acquiring a “mutator phenotype.”3 The summation of these genetic, epigenetic, and genomic events provides the tumor cells with a distinct growth advantage characteristic of cancer and which can confer resistance to therapy. In addition, there remains an open question about the potential for viral genomes to interact with the human genome throughout life to initiate the molecular changes that can result in cancer.

Recent and rapid advances in the technology supporting molecular biologic and genomic studies and novel methods in bioinformatic analysis of large-scale data sets have substantially increased our knowledge of both normal and abnormal cell growth, especially as these phenotypic changes relate to the genome. Improvements in whole genome sequencing (WGS), whole exome sequencing (WES) through targeted exome capture, RNA sequencing for expression, bisulfate sequencing for DNA methylation as a mechanism of epigenetic gene modification, and the development of a wide variety of bioinformatic tools for the interpretation of genomic data have empowered new insights into classic cell biology and biochemistry of tumor cells.

As our knowledge of signaling pathways, genomic networks, intra- and extracellular communication, cell-cycle regulation, programmed cell death, and cell differentiation has progressed, we have come to understand the very heterogeneous nature of both the tumor and the surrounding host tissue in which it resides. We now know that the tumor is far less clonal than originally thought. Its genomic and cellular heterogeneity or multi-clonal nature is seen at the level of the tumor genome and this is manifested within the tumor by differing states of cellular differentiation and function. Even further, the genomic changes that characterize the primary tumor usually differ from those found in the tumor's various metastatic sites.4 This tumor heterogeneity is also illustrated ...

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