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MUTATIONS IN "CANCER GENES"

What we provide. We analyze mutations in the DNA of solid tumours and integrate the data from the perspectives of clinical oncologists, researchers and Big pharma.

Mutations in tumors. High throughput DNA analyses of primary and metastatic tumors reveal hundreds of mutations in different genes relative to DNA from normal somatic tissues. Universities, Institutions, biotechnology and pharmaceutical companies and various consortia are using this mutational profile to classify patients and to develop drug targets against “cancer gene” products or their network members. The hope is that such bioinformatics-based classifiers will identify a subset of patients in each type of cancer who can then receive a personalized drug combination, such as Erbitux and Vectibix for colorectal patients with wild type alleles of the KRAS gene.

The clinical reality, however, is that mutations in “cancer genes” represent a minute fraction of the thousands of perturbations in a cancer genome. Deficiencies, duplications, unbalanced translocations, extrachromosomal amplifications, inversions and epigenomic alterations are widespread in solid metastatic tumors. The functional ramifications of these alterations far exceed those of single base pair mutations, especially in the context of the development of resistance to chemotherapeutic drugs and monoclonal antibody therapies.

Our analyses. We have examined the somatic alterations in the DNA from breast, colorectal, lung, brain, ovary, testis, kidney and skin tumours, amongst others, and distilled such data in the context of segmental aneuploidy, epigenetics, cell lethality, cell heterogeneity, tumor pathology, drug combinations and patient survival.

We have published our findings in Nature Biotechnology, in Genetic Engineering and Biotechnology News, in various interviews with magazines such as Newsweek and in different Blogs.

We find that the bioinformatic prioritizations of mutations in "cancer genes" that emerge from various Cancer Genome Megaprojects, are of low scientific and commercial impact and are of little clinical value. They are poor surrogates for histopathological, cytological and clinical data. In short, the bulk of the mutations in primary tumors are clinically irrelevant at the level of the individual patient. However, our rigorous criteria allow us to identify which ones may be commercially useful and where they fit in terms of therapeutic strategies.

The way forward: analysis of single cancer cells. Analysis of total nucleic acids from a primary or metastatic tumour results in the pooling of genomic and transcriptomic information which cannot be deconvoluted. The precious information on the original contents of individual cells is lost and all that remains is the "average" signature of that tumour upon which patient treatment may be based. This problem is completely circumvented when single cells from a tumour are used for diagnosis. This yields high quality knowledge.

For example, detailed molecular analysis of single disseminated cells isolated from the bone marrow and lymph nodes of the same patient after curative resection of the primary breast tumour, allows for an information rich data set. First, it is found that single disseminated cells from breast and esophageal tumors contain grossly abnormal genomes. Second, the scrambled genomes in the cells from the bone marrow are different to the scrambled genomes found in the lymph nodes of the same patient. No two disseminated cells shared the same chromosomal aberrations. These primary clinical data, generated by Professor Christoph Klein's group at the department of pathology, University of Regensburg, Germany, have been published in Cancer Cell and The Lancet and the data have far reaching implications for cancer therapeutics and various Cancer Genome Megaprojects.

In contrast to the current preoccupation with mutations in “cancer genes”, it is clear that other larger genomic changes generate far more variability in primary and metastatic tumours upon which selection can act. These large genomic changes will generally overwhelm the single base pair mutations in terms of the metastatic outcome for a patient, as well as being more influential in the development of drug resistance. The current emphasis on mutations in tumors and on the use of tissue culture systems as surrogates for finding cures for cancer, continues to be a major diversion from the central clinical and therapeutic issues. The crucial clinical steps involve the metastatic spread of cells, their disordered social interactions, their invasion of surrounding tissues and organs and the replacement of vital organs by tumor tissue which will ultimately kill the patient.

In cancer, very little makes sense except in the light of metastasis.

METASTASIS

Professor David Tarin of the University of California, San Diego has highlighted a number of critical issues in clinical oncology in Breast Disease, in Clinical Cancer Research and in Cancer Research. He has emphasized the level of understanding that is required in different biomedical specialities in order to make clinical use of the data. In Molecular Oncology, he points out how many ideas propounded by some high profile molecular investigators are muddled, clinically inapplicable and unconvincing. He reveals how they lack a profound lack of understanding of the pathogenesis of metastatic behaviour in naturally occurring neoplasms.

Professor Tarin stresses that the behaviour of tumours, be they expansive, infiltrative, metastatic and so forth, is determined by the interactions between the neoplastic cells and the normal cell communities in the neighbourhood. The widespread belief among cancer researchers is that cancer cells grow as a ball of delinquent cells in vacuo. This reveals a lack of familiarity with the basic pathology of natural neoplasms. Tumors are maladjusted living entities whose micro-anatomical, micro-physiological and micro-biochemical properties are determined by the dynamic interactions between the cell lineages and unstable cell types within them.

The way forward. Drawing clinically realistic conclusions for the treatment of an individual cancer patient from the mutational analyses of a massively heterogeneous cell population of a primary tumour, requires far more than the clinically low-value bioinformatic analyses that prioritize genes as "cancer genes”. It is in this area that we provide high quality guidance.

2008, Miklos, G. L. G, Baird, P. J. & Haines, I.E. Genetic Engineering and Biotechnology News, May 1, 29, #9, 6-8. Cancer stem cells: fact or fiction.

2007, Miklos, G. L. G. & Baird, P. J. Genetic Engineering and Biotechnology News, May 1, pp 6-10. Curing Cancer: Running On Vapor.

2007, Sharon Begley interviews George  L Gabor Miklos for Newsweek, March, This Is No Way To Cure Cancer.

2007, Miklos, G. L. G. & Baird, P. J. Deans world, July 22, Cancer Cures And Blockbuster Drugs; Who Can Handle The Truth. 

2007, Miklos, G. L. G. and Baird, P. J.; Barnesworld, March 5. The Latest Surge In The War On Cancer – Tour De Force Or Tour De Farce.

2005, Miklos, G. L. G. Nature Biotechnology, 23, 535-537. The Human Cancer Genome Project - One More Misstep In The War On Cancer.

2008, Stoecklein, N et al., Cancer Cell, 13, 441-453. Direct genetic analysis of single disseminated cancer cells for prediction of outcome and therapy selection in esophageal cancer.

2002, Klein et al., The Lancet, 360, 683-689. Genetic heterogeneity of single disseminated tumour cells in minimal residual cancer.

2008, Tarin, D, Clinical Cancer Research, 14, 1923-1925. Comparisons of metastases in different organs: biological and clinical implications.

2007, Tarin, D. Breast Disease, 26, 13-25. New insights into the pathogenesis of breast cancer metastasis.

2007, Tarin, D. Molecular Oncology, 1, 265-266. Response to "Is metastasis predetermined?"

2005, Tarin, D. Cancer Research, 65, 5996-6000. The fallacy of Epithelial mesenchymal transition in neoplasia.