The Case for a Pre-Cancer Genome Atlas (PCGA)

Abstract

Understanding the earliest molecular and cellular events associated with cancer initiation remains a key bottleneck to transforming our approach to cancer prevention and detection. While TCGA has provided unprecedented insights into the genomic events associated with advanced stage cancer, there have been few studies comprehensively profiling premalignant and early-stage disease or elucidating the role of the microenvironment in premalignancy and tumor initiation. In this article, we make a call for development of a "Pre-Cancer Genome Atlas (PCGA)," a concerted initiative to characterize the molecular alterations in premalignant lesions and the corresponding changes in the microenvironment associated with progression to invasive carcinoma. This initiative will require a multicenter coordinated effort to comprehensively profile (cellular and molecular) premalignant lesions and their corresponding "field of injury" collected longitudinally as the lesion progresses towards or regresses from frank malignancy across multiple tumor types. Genomic characterization of alterations in premalignant lesions and their microenvironment, for both bulk tissue and single cells, will enable development of biomarkers for early detection and risk stratification as well as allow for the development of novel targeted cancer interception strategies. The multi-institutional and multidisciplinary collaborative "big-data" effort underlying the PCGA will help usher in a new era of precision medicine for cancer detection and prevention. Cancer Prev Res; 9(2); 119-24. Ó2016 AACR. The Bottleneck for Cancer Prevention and Early DetectionOne of the critical barriers to developing new approaches for cancer detection and prevention is the lack of understanding of the key molecular and cellular changes that cause cancer initiation and progression. Unlike the extensive work that has been done profiling advanced stage tumors, few studies have comprehensively profiled the genomic alterations found in precancerous tissues. Premalignant lesions are currently characterized by histologic changes that precede the development of invasive carcinoma (1, 2). These lesions can often be identified in regions surrounding an invasive tumor, in biopsies taken from patients undergoing diagnostic evaluation for suspicion of cancer, or in samples acquired during preventive screening. Currently, limited metrics exist to identify lesions that will likely progress to carcinoma and require intervention from those that will naturally regress or remain stable (3, 4). As imaging modalities and screening guidelines advance, the number of lesions identified will grow resulting in a need for more precise risk stratification methods and effective early intervention. Characterization of the molecular alterations in premalignant lesions and the corresponding

Evolution of Premalignant Disease

“…As has been successfully completed for cancerous tumor types, an enticing initiative is to create a "Precancer Genome Atlas" (PCGA) by incorporating effort from multiple institutions worldwide to characterize the molecular alterations in premalignant lesions but importantly also the corresponding changes in the microenvironment and critically also the cellular phenotypes associated with progression to cancer (Campbell et al 2016). As informative as the PCGA may be for precancer characterization, we have herein discussed the evidence that there is an abundance of gray areas in genotype and phenotype spaces; tissues diagnosed as cancerous, precancerous, and normal can share both genetic abnormalities and phenotypic traits.…”

AJRCCM: 100-Year Anniversary.The Shifting Landscape for Lung Cancer: Past, Present, and Future

“…Although LDCT screening is arguably the main advance over the past several decades for early lung cancer detection, clinical and molecular approaches for selecting those at highest risk who would benefit from annual surveillance are emerging. Furthermore, attempts to develop a premalignant cancer genome atlas (104) for both squamous and adenocarcinoma of the lung will provide insights into the earliest cellular and molecular events associated with lung carcinogenesis, which can lead to: (1) molecular biomarkers to identify those premalignant lesions likely to progress to invasive cancer, (2) novel targets for precision-based chemoprevention trials, and (3) intermediate endpoints for evaluating therapeutic efficacy in those trials. Understanding the role of the microenvironment in early lung carcinogenesis will also lead to novel immune-based strategies for lung cancer prevention.…”

Transforming Cancer Prevention through Precision Medicine and Immune-oncology

“…Some data suggest that driver mutations in early neoplasia can differ from those in frank cancer. A critical next step for this field will be developing systematic approaches for whole-genome profiling of premalignant lesions followed longitudinally as they progress toward cancer--the recently proposed initiative “Pre-Cancer Genome Atlas” or “PCGA” (22). This initiative will provide critical insights into the molecular events (and possible sequence) in premalignant cells and their microenvironment that drive progression to invasive cancer (Figure 1), enabling precision approaches to cancer prevention and early detection.…”