TP53 Y220C mutations in colorectal carcinoma (CRC): A genomic landscape study.

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Background: Inactivating genomic alteration (GA) of the TP53 tumor suppressor gene leads to inactivation of p53 protein and is currently the most frequently associated GA across all cancers. Colorectal cancer is a common and lethal subtype of cancer, in the top 5 for incidence, prevalence and cancer-related deaths worldwide. TP53 is the second most frequent GA identified in clinically advanced CRC. It has been postulated that GA in TP53 not only affects the molecular biology of malignant cells but also impacts the tumor microenvironment in CRC. This GA is currently untargetable by approved drugs however, recently a novel approach designed to revert to wild type functioning of TP53 inactivated by Y220C base substitution has gained significant clinical interest. Methods: 67,301 cases of clinically advanced CRC underwent hybrid capture based comprehensive genomic profiling to assess all classes of GA. Cases were sequenced to a mean coverage depth of 650X with microsatellite instability (MSI) status and tumor mutation burden (TMB) determined from the sequencing data and PD-L1 expression measured by immunohistochemistry using the DAKO tumor proportional staining system (low positive set at 1-49% staining and high positive set at ≥50% staining). Results: 422 (0.6%) of the CRC featured the TP53 Y220C GA (Y220C+). When compared with the CRC that were TP53 Y220C negative (Y220C-), the Y220C+ cases were of similar age, gender and number of GA per tumor. The Y220C- cases has significantly higher frequencies of MSI status (6.1% vs 2.2%; p=.0007) and TMB levels greater >10 mutations/Mb (8.7% vs 4.7%; p=.004). The Y220C+ featured lower frequencies of GA in PIK3CA (12.9% vs 18.6%; p=.002), BRAF (8.8% vs 10.1%; NS) and PTEN (7.4% vs 8.3%, NS) and a higher frequency of ERBB2 amplification (5.0% vs 2.7%; p=.004). GA in APC , KRAS , NRAS , BRCA2 , EGFR and MET were similar in both Y220C+ and Y220C- CRC. PD-L1 low expression was similarly infrequent (12.1% to 16.7% range) in both groups. Conclusions: The potentially targetable TP53 Y220C short variant mutation is uncommon in clinically advanced CRC but is associated with unique genomic and biomarker characteristics. Further research might elucidate subpopulations or CRC subtypes with a greater frequency of this mutation who might benefit from a novel targeted therapy.