In the PNAS Early Edition this week, a trio of investigators at the National Institute of Environmental Health Sciences reports the crystal structure of a human DNA polymerase λ variant, which they say forms "a natural base-base mismatch with Watson-Crick-like geometry." This variant, the authors write, is "poised to misinsert dGTP opposite a template T," such that the resulting mismatch "has Watson-Crick geometry consistent with a tautomeric or ionized base pair, with the pH dependence of misinsertion consistent with the latter."
In a letter published online ahead of print this week, Barbara Parsons at the Food and Drug Administration's National Center for Toxilogical Research says that Attolini et al. neglected to consider that "many, or perhaps most, tumors are polyclonal in origin" when developing their retracing the evolutionary steps in cancer — or RESIC — approach they reported in PNAS. Parsons adds that "the common assumption that all clinically relevant tumor mutations can be identified by DNA sequencing … also is based on tacit acceptance of monoclonal tumor origin," and therefore, "significant proportions of tumor mutations are being missed."
In a reply to Parsons, researchers at the Dana-Farber Cancer Institute and Harvard School of Public Health, who developed RESIC, say that while they "agree that some cancers may primarily have a polyclonal origin that results in genetically heterogeneous tumors," their approach, as implemented in their paper, is not affected by this principle. However, the authors say that they intend to evaluate "several refinements to our algorithm" that are dependent upon the source of cancer heterogeneity. To Parsons' concerns over the power of sequencing for mutation detection, members of the RESIC team suggest that "the 95 percent sensitivity provided by copy number alteration detection using the Agilent 244A array comparative genomic hybridization platform is sufficient," for this purpose, though they plan to "further develop our approach as more quantitative data emerge from ongoing cancer genome projects and as we learn more about the interactions between cancer cells and microenvironmental niches."
Researchers at the Stanford University School of Medicine describe in PNAS this week a "molecular mechanism linking VHL [von Hippel-Lindau gene] loss to induction of the CDCP1 gene through the HIF-1/2 pathway in renal cancer," and show that "Fyn, which forms a complex with CDCP1 and mediates its signaling to PKCδ, is a HIF-1 target gene." In its mechanistic analysis, the Stanford team found that CDCP1 regulates PKCδ phosphorylations and "signal transduction from CDCP1 to PKCδ leads to its activation, increasing migration of CC-RCC [clear cell renal cell carcinoma]."