Decoding Cancer Through Epigenetics

Why chromatin & epigenetics

“Cancer is a disease of the chromatin, because the genetic contributions to phenotypes are entrusted to the chromatin.”

Pioneering the functional decoding of the non-coding cancer genome by revealing how chromatin determines genome interpretation, how genetic and environmental processes generate cancer-associated epigenomic variation, and how variation across both the unique and repetitive genome controls malignant cell states and drives cancer evolution.

Dr. Mathieu Lupien is a Senior Scientist at the Princess Margaret Cancer Centre, University Health Network, and Professor at the University of Toronto. His research has challenged the prevailing view of cancer as primarily a disease of genetic mutations by establishing that another layer of heritable information, the organization of DNA into chromatin, determines which portions of the genome a cell can use and, consequently, its identity and behaviour.

Dr. Lupien has pioneered the use of chromatin to functionally decode the non-coding genome, identify the regulatory consequences of inherited and somatic genetic variation, and uncover epigenomic alterations capable of driving malignant cell states. More recently, his work has defined how genetic alterations and environmental and metabolic pressures generate epigenomic variation that provides a substrate for cancer evolution, and has revealed a previously unrecognized role for the repetitive genome in controlling cancer-cell self-renewal and stemness. Collectively, his discoveries have helped move cancer research from cataloguing changes in DNA sequence to understanding variation in how the genome is interpreted.

The Work

The cells of the human body contain essentially the same DNA sequence, yet they acquire profoundly different identities because each uses different portions of that genome. Dr. Lupien recognized early that the organization of DNA around nucleosomes contains information that determines which genomic sequences are available for use by a particular cell.

In landmark work published in 2008, Dr. Lupien and colleagues demonstrated that the cell-type-specific function of the pioneer transcription factor FOXA1 is determined by the chromatin environment in which its DNA-recognition sequences reside. The study established that cell-type-specific regulatory elements could be distinguished by their chromatin state and that mapping these states could therefore provide a functional annotation of the non-coding genome. It showed that the same transcription factor can recognize the same DNA motif yet engage different genomic locations in different cell states because only selected sites are presented within a permissive chromatin context. This established chromatin as a fundamental layer of biological information that determines how the same genome is interpreted differently across cell types, thereby defining regulatory potential and cellular identity.

Dr. Lupien subsequently applied this principle to one of the major problems created by human genomics, understanding genetic variants that lie outside protein-coding genes. His group demonstrated that inherited cancer-risk variants preferentially reside within chromatin-defined regulatory elements and showed that individual variants can alter transcription-factor recruitment and gene regulation. He then extended this approach to mutations acquired during tumour development, demonstrating that somatic mutations distributed across non-coding regulatory elements can converge on the control of cancer genes. These studies helped establish a framework for interpreting genetic variation according to its function rather than simply its position in the DNA sequence.

This work also expanded the concept of what constitutes a cancer driver. Rather than requiring mutations to recur within an individual gene or at the same genomic position, Dr. Lupien and colleagues showed that alterations dispersed across multiple regulatory elements can converge on the same cancer gene or transcriptional program. This led to approaches that consider regulatory plexuses, comprising the regulatory elements controlling a gene, and cistromes, comprising the regulatory elements engaged by a transcription factor, as functional units in which cancer-driving alterations can accumulate.The work opened a route to identifying non-coding cancer drivers that are missed to conventional mutation-recurrence analyses.

A further challenge to the mutation-centred view of cancer came from Dr. Lupien's collaboration with Dr. Michael Taylor and colleagues studying pediatric ependymoma. Their work identified an aggressive childhood brain tumour characterized by profound epigenomic abnormalities despite an absence of recurrent genetic drivers, helping establish pediatric ependymoma as the first recognized human cancer driven predominantly by chromatin-based epigenomic alterations in the absence of recurrent genetic drivers. The finding demonstrated that disruption of genome interpretation, through epigenomic variations, can itself become a defining feature of malignancy rather than merely a downstream consequence of genetic mutation.

These discoveries prompted a further question, what generates cancer-associated chromatin variation? Dr. Lupien's work showed that both genetic alterations and environmental pressures can reshape the epigenome in cancer. His group demonstrated that structural variants can rewire chromatin states and regulatory activity across solid cancers. In triple-negative breast cancer, they showed that treatment-associated metabolic stress affecting the methionine cycle can drive epigenomic reprogramming during the acquisition of chemotherapy resistance. Work with Dr. Michael Taylor in pediatric ependymoma further connected the hypoxic tumour environment as a source of change to cellular metabolism to alter chromatin states.Together, these studies established metabolism as an important intermediary through which environmental pressures can reshape genome interpretation in cancer.

More recently, Dr. Lupien extended his studies to the repetitive genome. His group showed that transposable elements associated with pluripotent states can be reactivated and co-opted as oncogenic regulatory elements in solid cancer. In acute myeloid leukemia, working with Dr. John Dick and colleagues, his group demonstrated that epigenomic variation over transposable element distinguishes leukemia stem cells from differentiated cells and, through targeted chromatin editing, that specific elements are required to maintain leukemia stem-cell self-renewal.These discoveries established the repetitive genome as a previously overlooked reservoir of regulatory information capable of controlling pluripotency, cancer stemness and tumour propagation.

The Impact

Dr. Lupien's discoveries have contributed to a fundamental expansion of how the cancer genome is understood, from a DNA sequence containing genes and mutations to a functional genome whose interpretation depends on chromatin state. His early work helped establish the now widely used principle that chromatin annotation identifies cell-type-specific regulatory elements. This framework subsequently became central to interpreting the large number of disease-associated variants discovered through genome-wide association studies and to searching the non-coding genome for somatic cancer drivers.

His work has also broadened the mechanisms considered capable of generating cancer heterogeneity. Genetic mutations remain fundamental, but they cannot fully explain the diversity of cellular states found within tumours. By defining chromatin variants and demonstrating how genetic alterations and metabolic pressures can generate changes in genome interpretation, Dr. Lupien's research has helped establish epigenomic heterogeneity as an additional substrate for tumour evolution. This has important implications for precision oncology because genetically similar cancer cells can occupy distinct epigenomic states with different behaviours and therapeutic vulnerabilities.

The discovery that transposable elements can encode pluripotent regulatory programs and sustain cancer stem-cell self-renewal further expands the portion of the human genome considered functionally relevant to cancer. It connects two major advances in contemporary cancer biology, the recognition of non-mutational epigenetic reprogramming as a hallmark of cancer and the emerging realization that repetitive DNA carries regulatory information, to tumour plasticity, self-renewal and cancer evolution.

Where cancer genomics taught us to identify what is altered in the DNA sequence of a tumour, Dr. Mathieu Lupien's work has helped reveal how a tumour interprets that sequence. His discoveries have expanded cancer biology from genes to the non-coding and repetitive genome, from individual mutations to distributed regulatory systems, and from genetic alterations to chromatin variants that define selectable cell states. In doing so, his work has established variation in genome interpretation as a fundamental dimension of cancer biology, one that helps explain cancer initiation, heterogeneity and evolution while revealing new opportunities for precision cancer medicine.