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In follow up to my previous post outlining concerns and conflicts to the recent “Bad Luck” cancer study, here is a technical article that I submitted to the journal Science.  For whatever reasons, they did not want to publish it.  Some of the original misinterpretations were brought about by the news editor’s summary.  Here is my original manuscript complete with references for the conflicts between conclusions and the study parameters.

This is a game changing study and its wording is of delicate importance.  Previous to this study, the NIH and CDC had concluded that 85-90% of cancer cause is due to external factors with only a small percentage being attributed to genetics.  Despite this, an inordinate amount of funding has been dedicated to detection and treatment instead of prevention. This study has the power to influence how much energy, funding and resources are dedicated to understanding and eliminating the environmental (external) causes of cancer.

Acknowledgements:

Deepest gratitude to Rebe Feraldi MS, LCACP and Jessee Carrato for their valuable insights and also to Rebe for her time to do a thorough review.

Rebe and I subsequently submitted a letter to Science asking for clarification.

____________________

Abstract:

The recent study, Variation in Cancer Risk Among Tissues Can Be Explained by the Number of Stem Cell Divisions. , published in the January 2, 2015 edition of Science by Cristian Tomasette and Bert Vogelstein elegantly shines light on the previously overlooked notion that many cancer types arise randomly from errors during stem cell divisions.

However, as outlined below, there is a significant dissonance between the study’s data parameters and the statements and conclusions set forth in the study’s title and abstract. As a member of (American Association for the Advancement of Science) AAAS, I feel it is in the spirit of science to demand clear, objective articles whose data and conclusions are congruous and are not overtly vulnerable to misinterpretation by the vast majority of the media, science writers, and the public. Of further concern, these statements could be deceiving for those making informed decisions regarding research funding and public policy.

The primary aspect of the study data parameters which lacks congruity with the study conclusions and abstract is as follows: Six of the top eleven most frequently occurring cancer types were not included in this study and are thus, not reflected in the study conclusions. Among these cancers are: prostate, breast, uterine, urinary bladder, kidney and Non Hodgkin’s Lymphoma, collectively, responsible for nearly 20% or 1/5 of cancer deaths in the US in 2014 and their incidence rate an even higher contribution.[1] There is a substantial body of evidence demonstrating that each of these omitted cancer types is highly influenced by a variety of environmental factors. These environmental factors include infectious agents[2], endogenous[3] and exogenous hormones, xenobiotic compounds[4], certain heavy metals[5], certain pharmaceuticals, specific industrial and organic chemicals[6], alcohol consumption[7], glycemic control[8], and aflatoxin[9]. Per the American Cancer Society (ACS), “environmental factors (as opposed to heredity factors) account for an estimated 75%-80% of cancer cases and deaths in the US.”[10] Although we may eventually find that these environmental factors drive accelerated “random” error events, it is not possible to draw an objective, statistically meaningful conclusion about environmental and heredity vs. “random” influences on cancer as a whole based on the limited data parameters set forth in this study.

Although the aforementioned cancers types (excluded from the study) are presumably part of the one-third of “tissues [that] were not included in [the] analysis”12, their predominance represents a substantial and statistically significant percentage of cancers in the US. It is understandable that “the requisite parameters were not found in the literature or [their] estimation was difficult to derive”12. However, in light of these major exclusions, the conclusions drawn by the authors in the title and in the abstract of the paper should reflect this gross exclusion. Because the exclusion is not highlighted, the stated study conclusions are ambiguous and, as we have seen in the media, are vulnerable to misinterpretation.

Furthermore, the random cancer incidents demonstrated in the study do not parallel the incidence of various cancer types reported by the CDC and NIH. In some cases, like lung and colorectal cancer, they are flip-flopped. This suggests that influences exist outside of the random events like immunity[11] and well-known tumor suppressor genes, which are not accounted for in the study. The article should clarify that the study conclusion merely represents a statistical probability of a random cancer cell events in a given tissue type over a lifetime but does not represent the ultimate fate of any cancer type or cell. The data presented from the study does not provide sufficient evidence for the following statement in the abstract:

“These results suggest that only a third of the variation in cancer risk among tissues is attributable to environmental factors or inherited predispositions. The majority is due to “bad luck,” that is, random mutations arising during DNA replication in normal, noncancerous stem cells. This is important not only for understanding the disease but also for designing strategies to limit the mortality it causes.[12]

Did the authors intend that their conclusion was based only on “tissues” that were included in their study? Or were they implying that “only one third of [all] cancer risk is attributable to environmental factors or inherited predispositions?12” Below is a sampling from hundreds of various headlines from six prestigious media organizations that understandably misinterpreted the conclusion of the study article.

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“Most cancers are ’caused by bad luck – not lifestyle’: Scientists claim 65% of cases are down to random mistakes in genes that we can do nothing about” Jenny Hope of the Daily Mail Jan. 1 2015

“Two-Thirds of Cancer Due to Bad Luck, Study Finds” by Mary Elizabeth Dallas of CBS News reported Jan. 1 2015

“Most cancers are caused by bad luck not genes or lifestyle, scientists say.” By Sara Knapton for the Telegraph Jan. 1 2015

“Bad luck of random mutations plays predominant role in cancer”. Science Daily Jan. 1 2015

“Scientists: Random Gene Mutations Primary Cause of Most Cancer” by Ben Brumfield on CNN

“Biological bad luck blamed in two-thirds of cancers” by Will Dunham of Reuters

******

In addition to the ambiguity of the abstract, the title implies the study is based on overall cancer risk. It would be more accurate to change the wording from “cancer risk” to “some cancer types”.

Of further concern, the authors also make recommendations that could influence the direction and funding of research and public policy. Because of the excluded types of cancer and overall data, the following statement from the article is not scientifically objective and should be removed or clarified:

Moreover, we show that these stochastic influences are in fact the major contributors to cancer overall, often more important than either hereditary or external environmental factors.”

The authors go on to conclude that,

“These results suggest that only a third of the variation in cancer risk among tissues is attributable to environmental factors or inherited predispositions.”

Although compelling, it is premature to assign exact figures and conclusions based on such limited data.

Ultimately, because of its limited data parameters, this study lacks the merit necessary for forming decisions around research funding and public policy. The broad statements in this article could be misinterpreted by non-science policy makers potentially leading to uninformed decisions about a wide range of issues from allocation of research funds to public health recommendations.

Because the media headlines were so grossly misinterpreted and misleading to the public, corrections and clarifications should be made available as a press release. This act would be in the interest of the integrity of the scientific community and in good faith to the non-science public.

[1] Based on calculations from statistical data in ACS (2014).

[2] Yidya Vedham Ph. D., Mukesh Verma Ph. D. Cancer-Assoicated Infectious Agents and Epigenetic Regulation Cancer Epigenetics Methods in Molecular Biology Nov. 8, 2014 Vol. 1238, pp333-354 Doi: 10.1007/978-1-4939-1804-1_18

[3] Tim Key; Endogenous Hormones Breast Cancer Collaborative Group Steroid hormone measurements from different types of assays in relation to body mass index and breast cancer risk in postmenopausal women: Reanalysis of eighteen prospective studies. Steroids. Oct. 7, 2014. Doi: 10.1016/j.steroids.2014.09.001

[4] Hye-Rim Lee;  Kyung-A Hwang;  Kyung-Chul Choi. The estrogen receptor signaling pathway activated by phthalates is linked with transforming growth factor-β in the progression of LNCaP prostate cancer models. International Journal of Oncology. May 22, 2014. Pp595-602 Doi: 10.3892/ijo.2014.2460

[5] García-Lestón, J; Roma-Torres, J; Vilares, M; Pinto, R; Prista, J; Teixeira, JP; Mayan, O; Conde, J; Pingarilho, M; Gaspar, JF; Pásaro, E; Méndez, J; Laffon, B. Genotoxic effects of occupational exposure to lead and influence of polymorphisms in genes involved in lead toxicokinetics and in DNA repair. Environ Int, 2012 vol. 43 pp. 29-36

 

[6] Guo, H; Bassig, BA; Lan, Q; Zhu, Y; Zhang, Y; Holford, TR; Leaderer, B; Boyle, P; Qin, Q; Zhu, C; Li, N; Rothman, N; Zheng, T. Polymorphisms in DNA repair genes, hair dye use, and the risk of non-Hodgkin lymphoma. Cancer Causes Control, 2014 vol. 25(10) pp. 1261-70

[7] Qian Zhong, Ganggang Shi, Yanmei Zhang, Lei lu, Daniel Levy, Shuping Zhong. Alteration of BRCA1 Expression Affects Alcohol-induced Transcription of RNA Pol III-Dependent Genes. Gene Vol 556, Issue 1, Feb. 1, 2015 74-79.

[8] Juhyun Park;  Sung Yong Cho;  Young Ju Lee;  Seung Bae Lee;  Hwancheol Son;  Hyeon Jeong. Poor Glycemic Control of Diabetes Mellitus Is Associated with Higher Risk of Prostate Cancer Detection in a Biopsy Population. PLOS Sept. 18, 2014. Doi: 10.1371/journal.pone.0104789

[9] Xi-Dai Long;  Dong Zhao;  Xiao-Qiang Mo;  Chao Wang;  Xiao-Ying Huang;  Jin-Guang Yao;  Yun Ma;  Zhong-Hua Wei;  Min Liu;  Li-Xiao Zeng;  Jian-Jun Zhang;  Feng Xue;  Bo Zhai;  Qiang Xia. Genetic Polymorphisms in DNA Repair Genes XRCC4 and XRCC5 and Aflatoxin B1–related Hepatocellular Carcinoma. Epidemiology Sept 2013, Vol. 24 Issue 5 pp. 671-81. Doi: 10.1097/EDE.0b013e31829d2744

[10] ACS (2014). Cancer Facts & Figures 2014, Atlanta. American Cancer Society, 2014. Available at: http://www.cancer.org/acs/groups/content/@research/documents/webcontent/acspc-042151.pdf

[11] Junko Kishikawa, Kazushige Kawai, Nelson Tsuno, Hironori Yamaguchi, Soichiro Ishihara, Eiji Sunami, Toshiaki Watanabe. Characteristics and Pronosis of Colorectal Cancer Assoicated with Rheumatic Disease. International Surgery, Dec. 30, 2014 , Doi: 10.9738/INTSURG-D-14-00154.1

[12] Cristian Tomasetti, Bert Vogelstein. Variation in Cancer Risk Among Tissues Can Be Explained by the Number of Stem Cell Divisions. Science 2 January 2015 Vol. 347 no. 6217 pp. 78-81. DOI:10.1126/science.1260825

Acknowledgements:

Deepest gratitude to Rebe Feraldi MS, LCACP and Jessee Carrato for their valuable insights and also to Rebe for her time to do a thorough review.

 

 

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