Somatic targeted mutation profiling of colorectal cancer precursor lesions

Abstract

Background Most colorectal cancers (CRC) arise from precursor lesions. This study aimed to characterize the mutation profile of colorectal cancer precursor lesions in a Brazilian population. Methods In total, 90 formalin-fixed paraffin-embedded colorectal precursor lesions, including 67 adenomas, 7 sessile serrated lesions, and 16 hyperplastic polyps, were analyzed by next-generation sequencing using a panel of 50 oncogenes and tumor suppressor genes. The genetic ancestry of the patients was estimated. Results Somatic driver mutations were identified in 66.7% of cases, including alterations in APC (32.2%), TP53 (20.0%), KRAS (18.9%), BRAF (13.3%) and EGFR (7.8%). Adenomas displayed a higher number of mutations, mainly in APC, compared to serrated polyps (73.1% vs. 47.8%, p = 0.026). Advanced adenomas had a significantly higher frequency of mutation in KRAS and a high overall mutation rate than early adenomas (92.9% vs. 59%, p = 0.006). A high degree of ancestry admixture was observed in the population studied, with a predominance of European components (mean of 73%) followed by African (mean of 11.3%). No association between genetic ancestry and type of lesions was found. The mutation profile of Brazilian colorectal precursor lesions exhibits alteration in APC, KRAS, TP53, and BRAF at different frequencies according to lesion type. Conclusions These results bestow the knowledge of CRC's biologic history and support the potential of these biomarkers for precursor lesions detection in CRC screening of the Brazilian population.

Further Study on Field Cancerization in the Human Colon

“…While studying nondysplastic crypts underneath the neoplastic canopy of nonpolypoid and polypoid sporadic colon adenomas (30), we noticed that some of the crypts in the pedicle exhibited haphazardly distributed Ki67-labeled cells and p53upregulated cells, reaching the luminal aspect of nondysplastic crypts (30). It was suggested that the relocation of the normal Ki67 domains in the cells of the crypts of the stalk and the occurrence of p53-up-regulated cells in the same crypts evolved as a result of somatic mutations (29). This suggestion was validated in a recent mega-analysis of colorectal transcriptomes of histologically normal mucosa adjacent to colorectal carcinomas (CRC) (31).…”

Patient‐derived xenograft model in colorectal cancer basic and translational research

“…Although GEMMs and carcinogenic‐induced models are important tools in basic research and drug discovery of CRC, they still fail to remodel some critical features of clinical trials 38 . These models lack genetic consistency, a diversified diet, varied lifestyle, and an equal microbiome similar to human CRCs, all of which affect the disease's onset and course 39,40 . Moreover, the absence of inter‐tumoral heterogeneity because of poor genetic heterogeneity in inbred mice compared to outbred humans also decreases the potential of results in translational clinical research.…”

“… 38 These models lack genetic consistency, a diversified diet, varied lifestyle, and an equal microbiome similar to human CRCs, all of which affect the disease's onset and course. 39 , 40 Moreover, the absence of inter‐tumoral heterogeneity because of poor genetic heterogeneity in inbred mice compared to outbred humans also decreases the potential of results in translational clinical research. These differences urge us to develop new models that more exactly display the characteristics of human CRCs.…”