The webpage of Bernard S. Strauss, Professor Emeritus at University of Chicago provides the following summary of research work conducted by him over his career.
During the period from 1960 until about 2008 this laboratory was involved in studies on DNA repair and on the mechanism of mutation, particularly attempting to understand the role of polymerases and editing nucleases.
So, we presume he knows a thing or two about mutations, and he is not happy with big science related to mutations. In fact, he is so angry that he published a letter in DNA Repair in Aug 2013 with very strongly worded conclusion (h/t: @dangraur).
What does seem clear is that the cancer genome project and the cancer atlas are examples of the inefficiency that is the consequence of funding large projects without accompanying large ideas. To be fair, given the impetus of the new technology it was probably impossible not to set these machines on to the available tumors in the expectation of finding druggable targets. However, the suggestion of the Lawrence paper that the ultimate solution will probably involve . . . massive amounts of whole genome sequencing amounts to a dogged adherence to a failed strategy similar to the massive attacks on the trenches by the Generals of World War I.
Calling government-funded GWAS projects ‘inefficient’ and comparing them with WW I? We thought only lowly places like Homolog.us blog use such words and metaphors.
The rest of his letter explains why is so angry and it appears that he reached the same conclusion as Mike White did with ENCODE. The large and wasteful studies making major discoveries did not have any ‘control’.
The conclusion of the paper is that most of the mutations recognized as drivers are really false positives, the result of not having properly calculated control mutation rates. When this is done correctly according to the statistical technique described in the Supplemental Information, the number of drivers in lung cancer reduces to 11. This paper then gives us a list of the genes thathave survived; all but HLA-A (according to the authors) represent the usual suspects having been implicated earlier and independently of the cancer genome project. We may be grateful that TP53 survives their screening and is one of the select few. RB1, the retinoblastoma protein has survived and is also on this particular list.
This massive sequencing project joins the multitude of genomewide association studies as products of the mesmerizing advances in sequencing technology and the urge to indiscriminately apply these machines. The meager results of such studies could have been predicted. In fact, they were predicted, among other places in a set of letters to Science (2007;315:762764). What we learn is not so much about which genes to target for therapy but rather about the complexity of the mutation process in multicellular organisms.
There is another possible lesson from the cancer genome project: gene mutation is necessary but perhaps not sufficient to the initiation of cancer. I do understand that as a surgeon pointed out tome, all cancers are different and that the basis for this difference may well be the different mutational patterns of different tissues.However, as the Lawrence paper points out, mutation frequencies among different tumor types vary by a factor of 1000. Some are mutators, some are not. While we know that particular mutations(e.g. BRCA1,2, RB1) undoubtedly and importantly affect the progression of tumors, it is not clear that any particular mutation or class of mutations has initiated the process. It seems striking that there is now almost no attention to the initiating event or events in malignancy. I still have no idea as to whether the initiating events need be gene mutations, chromosomal changes, epigenetic changes induced by environmental influences or just unfortunate stochastic events. It is as if we had abandoned the hypothesis that there is a unique initiating event.