SHARED AND NON-SHARED MUTATIONS IN APC AND TP53 GENES IN PAIRED PRIMARY AND METASTATIC COLORECTAL CANCER FROM SYNCHRONOUS AND METACHRONOUS PATIENTS

Abstract

BackgroundMutational cascades in colorectal cancer (CRC) between the primary tumor (pCRC) and liver metasta-sis (LM) are poorly understood in individual patients. We focused on differences in specific APC and TP53 mutations between pCRC and synchronous and metachronous LM in a set of 87 paired CRC samples. The two genes were selected because they are known to be among the most mutated genes in this setting.MethodsDNA from pCRC and LM tumor tissue was subjected to whole exome sequencing to identify APC and TP53 mutations. Structure-activity predictions for TP53 were obtained from the literature.ResultsThe overall frequency of APC mutations in pCRC was 52.8 % and in LM 49.4%. The TP53 mutation frequency in pCRC was 54.0% and in LM it was 64.3%. In synchronous patients, with a median time of 5.5 months between pCRC and LM operations the distribution of mutations already changed be-tween pCRC and LM. In metachronous patients, with a median 25-month difference between the op-erations, mutation frequencies changed extensively. The results highlight a striking plasticity of the metastatic process involving appearance and disappearance of mutations between pCRC and LM. Some mutations were shared by pCRC and LM of several patients, probably implicating their role in the metastatic process. Conversely, a set of mutations was detected only in pCRC of single patients which may suggest that they represented silent bystander mutations.ConclusionsThe paired pCRC-LM setting offered a unique possibility to identify variants that may contribute to metastasis formation. We could define sets of APC and TP53 mutations probably contributing and not contributing to metastasis formation. The results tentatively propose the defined mutations as clinical biomarkers for stage II and III CRC and warrant further studies with larger number of patients.