Role of proliferation-related genes as predictive factors for adjuvant therapy in colon cancer.

Abstract

e15664 Background: Adjuvant Therapy (AT) is recommended in colon cancer (CC) to enhance surgical cures, by few percentages, typically in node positive stages. Many patients don’t derive benefits from AT but are difficult to identify currently. Ten-year data from the MOSAIC study indicates that AT’s impact on recurrence is limited to 30 months post-surgery. This timeframe aligns with the predicted period between stem cell activation and clinical recurrence. Chemotherapy, therefore, primarily targets the proliferative progenitors facilitating the innate immune effectors (e.g. NK cells) interception of recurrence events (optimizing the ratio). By identifying proliferative capacities through DNA findings could optimize patient selection. We hypothesized that an intrinsic DNA events drive early recurrence and denote AT beneficiaries. To test this hypothesis, we focused on a set of genes relevant to the cell cycle and report on copy number alterations (CNA). Methods: Patients in stages 2 and 3 CC in the cancer genome atlas (TCGA) were categorized into those who recurred within the first 30 months (R); or the remaining population (N). Cyclins and Cyclin dependent kinases (CDK) would be relevant if amplified in R and cell cycle inhibitors would be relevant if amplified in N. Here we report on gene amplification of E2F1, RB, p21, CDKs, CCNE1, CCNB1 CCNA1, MCM2, MCM5, MCM7, and RFC2. Results: Cyclins E, A and B are amplified in R substantially more than in N (17% v 2%; 11% v 0% and 6% v 3%, respectively). Similarly, p21 is amplified in 6% in N v 0% in R. E3F amplification is similar in both R and N groups and RB is amplified, paradoxically, in the R (28%) v 9% in N. Conclusions: The findings highlight the potential role of intrinsic DNA events mediating proliferation in predicting recurrence following surgery in a time frame that is relevant to AT. Identifying such markers may enhance patient selection and reduce unnecessary toxicity from ineffective treatments. Relevant DNA events are certainly not limited to CNAs studied in this work and need to expand to include relevant mutational and rearrangement events (gain- or loss of function, based on the physiologic roles). Given the stability of DNA confirmation of these findings is feasible even in archival material. Moreover, unsupervised analysis of the mediators of recurrence in relevant postoperative times is valid and promising. Further studies with independent larger datasets are needed to validate these observations.