Will we cure cancer by sequencing thousands of genomes?
© Nicholson; licensee BioMed Central Ltd. 2013
Received: 4 September 2013
Accepted: 6 November 2013
Published: 13 December 2013
The promise to understand cancer and develop efficacious therapies by sequencing thousands of cancers has not occurred. Mutations in specific genes termed oncogenes and tumor suppressor genes are extremely heterogeneous amongst the same type of cancer as well as between cancers. They provide little selective advantage to the cancer and in functional tests have yet to be shown to be sufficient for transformation. Here I discuss the karyotyptic theory of cancer and ask if it is time for a new approach to understanding and ultimately treating cancer.
KeywordsCancer genome Cancer Karyotype Oncogenes Tumor suppressor genes
“We can carry on and sequence every piece of DNA that ever existed, but I don’t think we will find any Achilles heels.”- James Watson, Cancer World 2013
By 2005 hundreds of gene mutations had been identified in individual cancers, it was unclear however, how prevalent these gene mutations were in cancers and which were specific to a certain type of cancer, if any. To answer these questions it was proposed to sequence thousands of cancers .
Consistent with these findings the effects of mutations in oncogenes and tumor suppressors are now thought to be small. Indeed, modeling the effects of mutations in oncogenes and tumor suppressor genes indicate they provide very little selective advantage to the cancer, a “surprisingly small” 0.4% . Functional tests of oncogenes and tumor suppressor genes further call into question the role these mutations play in carcinogenesis. Initial tests of oncogenes and tumor suppressor genes as transforming agents were largely performed in a mouse cell line NIH/3T3, which is considered a model for normal cells. Yet, this line has ~70 chromosomes instead of 40 , becomes transformed with a mere change in culturing conditions , can lose the postulated initiating oncogenes without change in carcinogenicity , and above all is by itself tumorigenic [14, 15]. Despite these well-documented caveats NIH/3T3 cells are still used for transformation assays by scientists . It may be argued that other lines, such as the human embryonic kidney 293 cell line (HEK293) and mammary epithelial cell line MCF10A have been successfully used to identify oncogenes and tumor suppressor genes as transforming agents. These lines, however, are prone to transformation and are known to have abnormal karyotypes . Indeed, transformation by oncogenes, such as ras, are typically only successful when they are activated by viral promoters reaching levels of expression hundreds of fold higher than what is ever actually seen in cancer and in which the karyotypes are altered [18, 19]. Even then, only after long latencies of many cell generations will minute fractions of transfected cells ever transform into cancer [20–22]. The consistent finding that mutations in cancer are largely heterogeneous has been hard to reconcile with the idea that only mutations in specific genes are the cause of cancer—as some sequencing studies suggest .
An alternative theory of cancer
If the karyotype is central to carcinogenesis and not individual genes, will we cure cancer by sequencing thousands of genomes or is it time for a new approach?
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