Abstract IA026: Novel insights into colorectal pre-cancers from hereditary cancer syndromes: From omics to interception

Abstract

Abstract It has been an effort of more than three decades to obtain a detailed annotation of the genomic events initially described in the seminal multi-step genetic model of the colorectal adenoma-carcinoma sequence by Vogelstein, Kinzler, and Fearon. Initial genomic studies conducted in colorectal premalignancy interrogated restricted numbers of lesions and assessed only a handful of genomic aberrations. Therefore, the deployment of next-generation sequencing technologies allowed for an updated and expanded understanding of the genomic landscape of premalignancy. This first generation of studies used bulk sequencing (mostly whole exome sequencing of biopsies or crypts) in early adenomas from patients with Familial Adenomatous Polyposis (FAP), identifying a large number of oncogenic mutations (>200 somatic hits in 25 adenomas), early clonal selection, and a mutational rate that overlapped with early-stage carcinomas. In fact, consistent with mathematical models of carcinogenesis, a quarter of the mutational load (all passenger mutations) observed in adenomas was present in adjacent, apparently normal, mucosa. This provided direct evidence that most of the genomic variation present in colorectal cancers is accumulated prior to the acquisition of a driver event in at-risk tissues, with the variation probably secondary to the self-renewal process of stem cells. Moreover, expression profiling of pre-cancers combined with mutational assessment enabled the study of the immune landscape of pre-malignancy as well as the catalogue of mutated neoantigens. Most of the studies on genomic annotation of intestinal carcinogenesis have come mainly from the study of premalignant lesions from hereditary CRC syndrome patients, which are thought to recapitulate the progression of the two major pathways: FAP for chromosomal instability (non-hypermutant) and Lynch Syndrome for mismatch repair deficiency (hypermutant). There are several intrinsic advantages of using hereditary cancer syndromes for molecular characterization of premalignancy: (I) the accelerated pace of carcinogenesis, (II) the abundance of tissue to perform analysis, and (III) frequent and close surveillance of patients. The knowledge generated in hereditary premalignancy has subsequently been translated to sporadic pre-cancers, including interrogation of the application of the consensus molecular sub-classification (CMS) to pre-cancers. The current iteration of -omics studies in pre-cancers fostered by the NCI Pre-Cancer Atlas and the Human Tumor Atlas Network has brought in-depth analysis of premalignancy, leveraging state-of-the-art single-cell sequencing tools. Ultimately, the wealth of genomic knowledge acquired in pre-cancers has started to be translated at the cancer interception level with the design and implementation of clinical trials using immune-modulators and vaccine approaches. Citation Format: Eduardo Vilar-Sanchez. Novel insights into colorectal pre-cancers from hereditary cancer syndromes: From omics to interception [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr IA026.