Genome-based predictors for HCC outcomes: a matter of tumor and/or stroma

To the Editor:

We appreciate the response by Yujin Hoshida (1) regarding our interpretation (2) of his failure to identify tumor-associated survival genes when using the informative gene panel approach described in his recent study (3). Hoshida argues that the informative gene panel contains many genes reported to be silenced in human tumors and thus insists that the lack of tumor-derived survival genes in his recent study is not due to the methodology used. Hoshida concludes that the reason they are unable to identify tumor-derived survival associated genes is due to the type of recurrence they are studying. A majority of cases in their cohorts have a late-recurrence, rather than early-recurrence commonly found with cases from most Asian cohorts. It is commonly believed that late-recurrence is largely contributed by the development of additional new tumor lesions due to high carcinogenic activities in an at-risk liver while early-recurrence is mainly attributed to metastatic disease. His conclusion implies that no measurable molecular change in the original HCC can be used to predict the development of a new HCC, i.e., de novo HCC, rather the ability to develop new HCC is only dictated by the liver microenvironment. This is an interesting idea but should be interpreted cautiously. We believe such a conclusion is premature based on the current body of evidence. Numerous tumor suppressor genes and oncogenes have been identified to be responsible for the development of HCC. For example, p53, APC, beta-catenin and Myc, along with the transcripts of their downstream targets, are frequently disregulated in HCC. The transcripts associated with these molecular signaling pathways should be readily detectable in tumor cells. It is conceivable that some of these transcripts could be predictive of the carcinogenic activity common to HCC. While the informative gene panel may contain many tumor suppressor genes, many other important genes apparently are not included. Because of the availability of the whole-genome DASL platform, such an uncertainty can now be formally addressed. The mechanism for HCC recurrence is currently unclear. Both early- and late-recurrences can be independently attributed to metastatic and de novo HCC. Our preliminary experiments suggest that a tumor-derived gene signature could be found to be predictive for HCC late-recurrence (Budhu et al, unpublished data). This is analogous to the recent findings that both tumor and non-tumor-derived gene signatures can predict HCC early-recurrence in multiple cohorts (4–9). Thus, the jury is still out and further studies are needed.