Pitfalls and perspectives in cancer genomes NGS studies: implications for predictive, preventive and personalized medicine (PPPM)

Abstract

Great increase in Whole Genome Sequencing (WGS )a nd Next Generation Sequencing (here: NGS-CA) approaches were witnessed in the past few years, since cataloging or landscaping all possible cancer aberrations appears to be both scientifically relevant and useful for therapeutic strategies. This search has been performed through Medline using NGS with appropriate cancer types/subtypes definitions and paying particular attention to the major overviews from groups on both sides of the Atlantic (i.e., Michael Stratton and Bert Vogelstein: [1] and [2]). Although the most utilized instruments-technologies so far are the 454 pyrosequencing apparatuses and the Illumina platform, technology is continuously developing, such as the Ion-Torrent machines (see below). The scope here is to overview general pitfalls and perspectives in the whole area of NGS-CA studies and to suggest probable trends and prudent recommendations. Pitfalls 1. Much fewer reports are present today for pediatric tumors and particularly leukemia/lymphoma in comparison to adult cases (ratio 1:10 / 1:20). This is scientifically counterproductive, as major breakthroughs in our understanding of human cancer often originated from pediatric cancer (also next point). No WGS-NGS studies have been published so far on neuroblastoma or other pediatric tumors [3]. 2. It is apparent that many mutations appeared before the time of malignant transformation in an age/dependent fashion. Although the “mutator phenotype” [1][2] is still discussed, this already suggests that some “drivers” may be irrelevant for malignancy onset. Further discrepancies concern the proportion of oncogenes/TSG and the strategies for targeting the relative mutations (today essentially PKi) [1][2]. 3. NGS-CA are biased toward a genetic analysis of malignancies, defined as CAN-GEN approach [4]. I previously have [4] and refer here to CAN-EPI for alterations at the epigenetic level (scarcely studied by NGS-CA), to CAN-CHROM for aneuploidy/variation in chromosomes (difficult to study) and to UP-CAN for mechanism(s) upstream-responsible for cancer-aberration induction (essentially ignored by NGS-CA studies). 4. Strategies dictated by NGS-CA studies (particularly, in cases of alterations in EGFR and ALK in lung cancer and BRAF in melanoma – tested in other tumors) universally showed that the eventual remissions are brief/ insufficient. Similarly, so called “Lazarus effects” were described approximately ten years ago and are resurrected now for justifying more sequencing expeditions.