International Science Index


The Role and Importance of Genome Sequencing in Prediction of Cancer Risk


The role and relative importance of intrinsic and extrinsic factors in the development of complex diseases such as cancer still remains a controversial issue. Determining the amount of variation explained by these factors needs experimental data and statistical models. These models are nevertheless based on the occurrence and accumulation of random mutational events during stem cell division, thus rendering cancer development a stochastic outcome. We demonstrate that not only individual genome sequencing is uninformative in determining cancer risk, but also assigning a unique genome sequence to any given individual (healthy or affected) is not meaningful. Current whole-genome sequencing approaches are therefore unlikely to realize the promise of personalized medicine. In conclusion, since genome sequence differs from cell to cell and changes over time, it seems that determining the risk factor of complex diseases based on genome sequence is somewhat unrealistic, and therefore, the resulting data are likely to be inherently uninformative.

References: C. Tomasetti, B. Vogelstein, “Variation in cancer risk among tissues can be explained by the number of stem cell divisions,” Science, vol. 347, pp. 78–81, 2015.
[2] N. A. Ashford, et al., “Cancer risk: role of environment,” Science, vol. 347, p. 727, 2015.
[3] C. Wild, P. Brennan, M. Plummer, F. Bray, K. Straif, J. Zavadil, “Cancer risk: role of chance overstated,’’ Science, vol. 347, p.728, 2015.
[4] J. D. Potter, R. L. Prentice, “Cancer risk: tumors excluded,” Science, vol. 347, p. 727, 2015.
[5] C. Gotay, T. Dummer, J. Spinelli, “Cancer risk: prevention is crucial,” Science, vol. 347, p. 728, 2015.
[6] M. Song, E. L. Giovannucci, “Cancer risk: many factors contribute,” Science, vol. 347, pp. 728–729, 2015.
[7] M. O’Callaghan, “Cancer risk: accuracy of literature,” Science, vol. 347, p. 729, 2015.
[8] J. T. Leek, R. D. Peng, “What is the question? Mistaking the type of question being considered is the most common error in data analysis,” Science, vol. 347, pp. 1314-1315, 2015.
[9] D. Wodarz, A. G. Zauber, “Cancer: Risk factors and random chances.” Nature, vol. 517, pp. 563–564, 2015.
[10] C. R. Weinberg, D. Zaykin, “Is Bad Luck the Main Cause of Cancer?” JNCI J Natl Cancer Inst, vol. 107, djv125, 2015.
[11] A. I. Rozhok, G. M. Wahl, J. A. DeGregori, “Critical Examination of the “Bad Luck” Explanation of Cancer Risk,” Cancer Prev Res, vol. 8, pp. 762–764, 2015.
[12] C. C. Harris, “Cause and Prevention of Human Cancer,” Carcinogenesis, vol. 36, S1, 2015.
[13] S. Wu, S. Powers, W. Zhu, Y. A. Hannun, “Substantial contribution of extrinsic risk factors to cancer development,” Nature, vol. 529, pp. 43-47, 2015.
[14] National Cancer Institute, Surveillance, Epidemiology, and End Results Program; Accessed on 01/11/2016, Sub (1973-2014)
[15] J. K. Pedersen, et al. “Cancer and aging: Epidemiology and methodological challenges,” Acta Oncologica, vol. 55, pp. 7-12, 2016.
[16] P. D. Adams, H. Jasper, K. L. Rudolph, “Aging-Induced Stem Cell Mutations as Drivers for Disease and Cancer,” Cell Stem Cell, vol. 16, pp. 601-612, 2015.
[17] A. S. Ahmad, N. Ormiston-Smith, P. D. Sasieni, “Trends in the lifetime risk of developing cancer in Great Britain: Comparison of risk for those born in 1930 to 1960,” Br J Cancer, vol. 3, pp. 943-647, 2015.
[18] J. E. Lucas, G. Sapiro, “Cancer: What's luck got to do with it?” Significance, vol. 12, pp. 40–42, 2015.
[19] Centers for Disease Control and Prevention. Current Cigarette Smoking Among Adults—United States, 2005–2014. Morbidity and Mortality Weekly Report, vol. 64, pp. 1233–1240, 2015.
[20] J. Gray, & et al. “State of the evidence: the connection between breast cancer and the environment,” Int. J. Occup. Environ. Health, vol. 15, pp. 43–78, 2009.
[21] H. Shimizu, R. K. Ross, L. Bernstein, R. Yatan, B. E. Henderson, “Cancers of the prostate and breast among Japanese and white immigrants in Los Angeles County,” Br. J. Cancer, vol. 63, pp. 963–966, 1991
[22] N. J. Roberts, J. T. Vogelstein, G. Parmigiani, K. W. Kinzler, B. Vogelstein, V. E. Velculescu, ”The predictive capacity of personal genome sequencing,” Sci Transl Med, vol. 4, pp. 133-158, 2012.
[23] C. S. Haas, C. J. Creighton, X. Pi, I. Maine, A. E. Koch, G. K. Haines, S. Ling, A. M. Chinnaiyan, J. Holoshitz, “ Identification of genes modulated in rheumatoid arthritis using complementary DNA microarray analysis of lymphoblastoid B cell lines from disease-discordant monozygotic twins,” Arthritis Rheum, vol. 54, pp. 2047-2060, 2006.
[24] K. A. Metcalfe, G. A. Hitman,R. E. Rowe, M. Hawa, X. Huang, T. Stewart, R. D. Leslie, “Concordance for type 1 diabetes in identical twins is affected by insulin genotype,” Diabetes Care, vol. 24, pp. 838-842, 2001.
[25] W. Czyz, J. M. Morahan, G. C. Ebers, S. V. Ramagopalan, “Genetic, environmental and stochastic factors in monozygotic twin discordance with a focus on epigenetic differences,” BMC Medicine, vol. 10, p. 93, 2012.
[26] J. Y. Kim, K. D. Siegmund, S. Tavaré, D. Shibata, “Age-related human small intestine methylation: Evidence for stem cell niches,” BMC Med, vol. 3, p. 10, 2005.
[27] S. Kozar, E. Morrissey, A. M. Nicholson, M. van der Heijden, H. I. Zecchini, R. Kemp, S. Tavaré, L. Vermeulen, D. J. Winton, “Continuous clonal labeling reveals small numbers of functional stem cells in intestinal crypts and adenomas,” Cell Stem Cell, vol. 13, pp. 626–633, 2013.
[28] A. Gómez-Ramos, R. Sanchez-Sanchez, A. Muhaisen, A. Rábano, E. Soriano, J. Avila, “Similarities and Differences between Exome Sequences Found in a Variety of Tissues from the Same Individual,” PloS One, vol. 9, e101412, 2014.
[29] E. Ruark, et al. “Mosaic PPM1D mutations are associated with predisposition to breast and ovarian cancer,” Nature, vol. 493, pp. 406-410, 2013.