Going beyond the genetic view of cancer

To the Editor:

Kendall et al. recently reported in PNAS novel oncogene (co) amplifications in human lung cancer (1). However, these changes were detected in less than 20% of the investigated specimens. Accordingly, the authors' findings (1) suggest that the majority of these tumors probably harbors frequently occurring (nongenetic) abnormalities such as epigenetic modifications (2) and aneuploidy (3). Moreover, dynamic protein-based phenomena—for instance, (insulin-driven) “oncoprotein metastasis” explicable by an extension of physical string theory into (sub)cellular biology and potentially treatable with cell-permeable (retinoblastoma protein-derived) tumor suppressor peptides entering both neoplastic cells and morphologically normal, yet likely premalignant cells (4)—may have also contributed to the genesis of these neoplasias.

In future studies, it therefore should be worthwhile embarking ab initio on a global analysis of human cancer samples addressing all the above (genetic, epigenetic, chromosomal, and protein-based) levels of possible malignant alterations. Interestingly, this perception is supported by a study showing colocalization of hypomethylation with an amplicon at 1q21-q23 in certain lung adenocarcinomas and consequently proposing an integrative strategy in exploring human cancer tissues (2). Along these lines, it could be rewarding for Kendall et al. (1) to check in their samples whether there are any hypomethylations in the promoter regions of the oncogenes they focused on and any tumor suppressor gene promoter hypermethylations. If validated, such aspects would further add to an approach “outside the genome” that has previously been recognized as a promising path toward a better understanding and therapy of human cancer (5).