Perspective Commentary on Almassalha et al., "The Greater Genomic Landscape: The Heterogeneous Evolution of Cancer" Henry T. Lynch 1 , Marc Rendell 2 , Trudy G. Shaw 1 , Peter Silberstein 3 , and Binh T. Ngo 4 Abstract In this issue of Cancer Research, Almassalha and colleagues have proposed a new concept of the development of malig- nancy, that of the greater genomic landscape. They propose a stressor-related exploration of intracellular genomic sites as a response mechanism. This process can express sites with beneficial or deleterious effects, among them those that pro- mote cell proliferation. They point out that their conception is broader, although certainly inclusive, of the process of gene induction. The authors view the physical process of chromatin reorganization as central to the exploration of the genomic landscape. Accordingly, they advocate the development of agents to limit chromatin structural modification as a chemo- therapeutic approach in cancer. We found their theory relevant to understand the phenotypic heterogeneity of malignancy, particularly in familial cancer syndromes. For example, the familial atypical multiple mole melanoma (FAMMM) syn- drome, related to a gene mutation, is characterized by a diver- sity of melanocytic lesions, only some of which become malig- nant melanoma. This new conceptualization can do much to increase understanding of the diversity of malignancy in fam- ilies with hereditary cancer. Cancer Res; 76(19); 5602–4. Ó2016 AACR. In this issue of Cancer Research, Almassalha and colleagues (1) putatively provide a basis for the hereditary evolution of cancer. Interest in the genomic landscape was, in part, devel- oped by Vogelstein and colleagues (2), who noted that com- prehensive sequencing has revealed the genomic landscape of common forms of human cancer. They called attention to the fact that the landscape includes a small number of "mountain" genes (those that are altered in a high percentage of tumors) and a larger number of "hill" genes (those that are altered infrequently). They noted that studies have identified approx- imately 140 genes that can drive tumorigenesis when mutated. A typical tumor may have 2–8 of these driver genes. There are also passenger genes, mutation of which gives cells no selective growth advantage. Now, in this more detailed theory, Almassalha and collea- gues have advanced a new conception on the diversity of carcinogenesis, that of heterogeneous cellular genomic activity, typically promoted by environmental challenge (1). They offer the hypothesis that cells, faced with stressors, make use of multiple genomic loci and associated mechanisms to respond. Although the preponderance of such sites produce beneficial results, among them there may arise sites promoting unchecked proliferative activity, the origin of malignancy. Although the concept of transformative sites, either mutational or epigenetic, is not new, they go further by proposing a fundamental process of genomic sampling of some 20,000 protein-encoding sites occurring in response to stressors. They present the idea of an intracellular process of activation of genetic loci to offer adaptively beneficial properties to each individual cell. So they liken the process to evolution of whole organisms, occurring at the cellular level. They advance this concept of an ongoing dynamic process by which cells respond to their environment. They then carry forward their hypothesis to a multicellular and diverse response at the tissue level wherein different cells explore what the authors term "The Greater Genomic Landscape" to reach out to different sites for benefit as a natural and continual process. In this way, the tissue undergoes an evolutionary event, promot- ing overall multicellular survival. They propose three processes with different time constants: (i) posttranslational (proteomic occurring rapidly in seconds/hours); (ii) epigenomic (intermedi- ate – minutes/days); and (iii) mutational (days-weeks-years). Central to their hypothesis is the idea that these events require chromatin structural change to allow accessibility for gene expres- sion. They continue that repeated and multidimensional stressors promote selection of cells with increased capability to sample their internal genome. The concept is that of the origin of diverse cellular responses, some favorable, others unsuccessful, to deal with detrimental external factors. Cells that respond successfully survive, while those without beneficial stress response would tend to undergo apoptosis. Thus, the authors have created an intriguing parallel to the world of Darwinian survival of the fittest, but at a multicellular rather than a population level. The authors view mitochondrial energetics as a core feature of multicellular survival. They propose mitochondrial membrane potential ym as a key regulator of the stress response. In fact, they cite experimental evidence that disruption of ym has been shown 1 Department of Preventive Medicine, Creighton University, Omaha, Nebraska. 2 Department of Internal Medicine, Creighton University School of Medicine and the Rose Salter Medical Research Foundation, Omaha, Nebraska. 3 Department of Hematology & Oncology, Creighton University, Omaha, Nebraska. 4 Department of Dermatolo- gy, Keck USC School of Medicine and the Hoag-USC Advanced Skin Cancer Program, Los Angeles, California. Corresponding Author: Henry T. Lynch, Department of Preventive Medicine, Creighton University, 2500 California Plaza, Omaha, NE 68178. Phone: 402-280- 2942; Fax: 402-280-1734; E-mail: htlynch@creighton.edu doi: 10.1158/0008-5472.CAN-16-2319 Ó2016 American Association for Cancer Research. Cancer Research Cancer Res; 76(19) October 1, 2016 5602 on June 6, 2020. © 2016 American Association for Cancer Research. cancerres.aacrjournals.org Downloaded from Published OnlineFirst September 16, 2016; DOI: 10.1158/0008-5472.CAN-16-2319