Validity of mutations as a cancer chronometer.

Abstract

e15015 Background: Staging is devised to assess prognosis, and ultimately direct the management of cancer. Though staging systems don't necessarily confirm chronological progression from stage I to IV, there is near consensus that advanced stages are 'later' versions of a given cancer. This is reflected in the philosophy and efforts to identify 'early' cancer in screening programs. Tumor Mutational Burden (TMB) is one measure of the degree of proliferation, thus can be utilized as a molecular clock (Vogelstein), a surrogate for chronology. Since TMB is currently a clinical metric provided to oncologists in routine practice, proper interpretation of TMB is critical. We hypothesized that (i) metastatic disease is a ‘different’, rather than 'later' manifestation of a given cancer. Furthermore, we hypothesized that (ii) proliferation rates would be mirrored by the TMB, and lastly, that (iii) TMB will correlate with clinical virulence. Methods: (i) We mined the publicly-available TCGA database (cbioportal.org) for TMB from 558 samples spanning 5 whole genome & whole exome neoplasm datasets (Breast, Colon, Renal cell, Pancreatic, Cervical cancers). (ii) We compared the TMB in Burkitt's lymphoma, a highly proliferative neoplasm, with follicular lymphoma, a classically quiescent malignancy. (iii) We compared the TMB in skin squamous cell carcinoma (SSCC), a cancer with negligible impact on survival, with Acute Myelogenous Leukemia (AML), a highly lethal malignancy despite aggressive therapy. Results: (i) The 95% Confidence Intervals (CI) surrounding the median TMB were overlapping without statistical significance across ALL stages within EVERY histology examined. (ii) To our surprise, the TMB 95% CI were overlapping between the 2 subsets of B-cell lymphoma examined. (iii) TMB was substantially higher in SSCC (median of ̃800) compared to a mere 8 in AML. Conclusions: Assuming validity of Vogelstein’s molecular clock model, mutational probing does not support the concept that a stage IV malignancy is a chronologically delayed manifestation of a given neoplasm. Rather, we suggest an alternative approach where aggressive/metastatic cancers are inherently 'different' with unique abilities rather than a ‘later’ edition of a monodirectional succession. We also posit that cells that live for years (follicular lymphoma) can accumulate comparable levels of TMB as Burkitt's because the limited life span in Burkitt's (days to weeks) precludes the accumulation of high TMB. Finally, the clinical outcome cannot be discerned from the degree or mutability— which is rationally a predictor of immune susceptibility. It's noteworthy that the observed levels of mutations in SSCC, reflective of the sun mutagenicity, is more than 3-fold of that reported for melanoma (̃274) but this fact is rarely presented in cancer genomic landscapes, and may explain the rarity of metastatic SSCC owing to the immune clearance of metastases unlike the skin surface devoid of such immune access.