The Lie That p53 Mutations Are the Mechanism Behind Lung Cancer

For five decades, the anti-smokers have been trying to come up with some mechanism by which they can claim that smoking causes lung cancer. They still have not succeeded. The best story that they have been able to concoct is that the circumstantial formation of benzo[a]pyrene adducts at lung cancer mutational hotspots in the tumor suppressor protein p53 amounts to "a direct etiological link between a defined chemical carcinogen and human cancer."

Preferential formation of benzo[a]pyrene adducts at lung cancer mutational hotspots in p53. MF Denissenko, A Pao, M-S Tang, GP Pfeifer. Science 1996 Oct 18;274(5286):430-432. "Cigarette smoke carcinogens such as benzo[a]pyrene are implicated in the development of lung cancer. The distribution of benzo[a]pyrene diol epoxide (BPDE) adducts along exons of the P53 gene in BPDE-treated HeLa cells and bronchial epithelial cells was mapped at nucleofide resolution. Strong and selective adduct formation occurred at guanine positions in codons 157, 248, and 273. These same positions are the major mutational hotspots in human lung cancers. Thus, targeted adduct formation rather than phenotypic selection appears to shape the P53 mutational spectrum in lung cancer. These results provide a direct etiological link between a defined chemical carcinogen and human cancer."

The first molecular evidence linking cigarette smoke to lung cancer. Doctor's Guide 1996 Oct 17. The admission here that "researchers had not yet determined which specific carcinogen, or combination of carcinogens, participate in the development of lung cancer" directly contradicts the act they've put on for decades for public consumption, of course.

Direct Link Found Between Smoking and Lung Cancer. By David Stout. New York Times, Oct. 18, 1996: "experts say findings provide long-missing link because they go beyond statistical association, shortfall that has allowed tobacco industry to deny that cigarettes cause cancer;" Study Isolates Chemical That Makes Smoking A Fatal Pursuit. By Nigel Hawkes. Times of London Oct. 18, 1996. The New York Times also quoted Dr. John Minna, a researcher at the University of Texas Southwestern Medical Center, who claimed that ''This paper absolutely pinpoints that mutations in lung cancer are caused by a carcinogen in cigarette smoke,'' and ''It is the smoking gun that makes the connection;'' and anti-smoker lawyer John F. Banzhaf boasted that the study would be a powerful weapon for eliminating smoking from those public places that still allow it. "We're moving to ban smoking even in bars, the last bastion," he gloated.

A week later, the New York Times featured Banzhaf as a supposed scientific expert, who ridiculously claimed that scientists are easier to convince than ordinary people, supposedly because the latter are not intelligent enough to understand statistics. (So, Smoking Causes Cancer: This Is News? By Denise Grady. New York Times, Oct. 27, 1996.)

A Newsweek cover story spread lies about p53, cancer and smoking: "It's a cell's most elegant defender, a gene called p53. It stops tumors before they grow. But if damaged, it is involved in 60 percent of cancers." This is misleading. In the first place, the protein made by the p53 gene doesn't "stop tumors," it arrests a cell during its cycle of division, so that dna damage can be repaired. If the damage has been repaired, p53 protein levels decline, and cell division continues. If it has not been repaired, the p53 protein causes the cell to die. Most important, the p53 gene does NOT have to be mutated in order for it to fail to work. The action of its protein is blocked if cells contain the polyoma virus large T antigen, human papillomavirus E6 protein, adenovirus E1B 55KD protein, or hepatitis B X protein. Newsweek then spread hysteria about benzopyrene in order to blame smoking: "Most p53 mutations, though, are not inherited. Instead, they arise from a copying error or an attack by a carcinogen. Bulky chemicals, such as the benzopyrene in cigarette smoke, change G to T and C to A, for instance." "Cancer-causing benzopyrene in cigarette smoke primarily changes just one letter, at one spot, on the p53 gene: a G becomes T. Other compounds in smoke change C to A. In October, Texas researchers detected benzopyrene clinging right to the mutational 'hot spot' that is mutated in lung cancer. 'This is the closest to a smoking gun linking smoking to cancer that people have gotten,' says molecular biologist Stephen Friend of the Fred Hutchinson Cancer Center in Seattle." In fact, exposure to benzo[a]pyrene from ordinary food is far greater than from cigarette smoke, including among active smokers. (The Cancer Killer. By Sharon Begley. Newsweek, Dec. 23, 1996. On the website of Dr. Dan DiResta, Introduction to Biological Science, University of Miami Department of Biology.)

The Australian Minister of Federal Health and Family Services, Dr Michael Wooldridge, took the lead in false pretenses by launching a television propaganda campaign purporting to show "a tumour growing in a smoker's airway which has taken hold because benzopyrene, a carcinogen found in high concentrations in cigarette smoke, directly damages a gene called p53." Wooldridge called it a "proven link" and lied that it proved "conclusively how smoking causes lung cancer." (New advertising exposes smoking and lung cancer link. Australian Government, Department of Health and Ageing, July 16, 1997.)

The Australian broadcasting network ABC outdid the rest of the media with this succession of gigantic whoppers: "Summary: Researchers have discovered that the genetic damage from tobacco smoke is so specific it's almost a fingerprint for the toxic effects of cigarettes... Norman Swan: Is it a specific that if somebody wanted to have a court case about smoking-related cancer they could say 'Look, my p53 shows this damage, it has to have been the passive smoking in the pub.' John Kovach [of the Beckman Institute]: The particular sign the p53 gene is called position 157; it's found really almost only in lung cancers, and now that benzopyrene has been found to target that spot, it's pretty strong evidence." (The Health Report. Lung Cancer and Smoking. Broadcast Monday 21 July 1997.)

Others have taken issue with this claim of a supposed "direct etiological link." Rodin and Rodin likewise found a difference between smokers and nonsmokers in the percentage of lung cancers with p53 mutations. However, according to them, this is merely the result of physiological selection for tumor cells with p53 mutations. They point out that the within-strand p53 mutational patterns of smokers and nonsmokers is the same; that the distribution of G-->T transversions is the same as in cancers of other, smoke-inaccessible tissues; and that the frequency of tumors with silent p53 mutations is the same in smokers and nonsmokers. (Human lung cancer and p53: The interplay between mutagenesis and selection. SN Rodin, AS Rodin. Proc Natl Acad Sci USA 2000 Oct 24;97(22):12244-12249.)

In the mass media, United Press International was beside itself with outrage to this challenge to dogma, rushing to get dismissive quotes from Lasker Syndicate pooh-bahs at the mentally ossified National Cancer Institute, and homages to their sacred orthodoxy that mutations caused by chemical carcinogens in cigarette smoke alone are to blame (Analysis: Lung cancer cause blows more smoke than facts. Damaris Christensen, UPI Science News 2000 Oct 18). Interestingly, one of Sergei Rodin's positions was at the Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia, where they are evidently more comfortable with the existence of dissent than is the Prussianized health establishment of the United States.

The professionally-oriented Reuters Health was less hysterical but no less orthodox (Physiologic, not genetic, factors dominate in p53-associated lung cancer. Reuters Health 2000 Oct 16).

The Bottom Line: BPDE Adducts Are Unrelated to Lung Cancer Risk

Prospective analysis of DNA damage and repair markers of lung cancer risk from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. AJ Sigurdson, IM Jones, Q Wei, X Wu, MR Spitz, DA Stram, MD Gross, WY Huang, LE Wang, J Gu, CB Thomas, DJ Reding, RB Hayes, NE Caporaso. Carcinogenesis 2011 Jan;32(1):69-73. In Epstein-Barr virus-transformed lymphoblastoid cell lines established from prospectively collected peripheral blood samples of 117 lung cancer patients with 117 matched controls, the alkaline Comet assay and the host cell reactivation (HCR) assay with the mutagen benzo[a]pyrene diol epoxide were unrelated to lung cancer risk. In the bleomycin mutagen sensitivity assay, "statistically significantly increased lung cancer odds ratios (OR(adjusted)) were observed for bleomycin mutagen sensitivity as quartiles of chromatid breaks/cell [relative to the lowest quartile, OR = 1.2, 95% confidence interval (CI): 0.5-2.5; OR = 1.4, 95% CI: 0.7-3.1; OR = 2.1, 95% CI: 1.0-4.4, respectively, P(trend) = 0.04]. The magnitude of the association between the bleomycin assay and lung cancer risk was modest compared with those reported in previous lung cancer studies but was strengthened when we included only incident cases diagnosed more than a year after blood collection (P(trend) = 0.02), supporting the notion the assay may be a measure of cancer susceptibility." [However, infections by both Epstein-Barr virus and cytomegalovirus make cells more susceptible to damage by bleomycin - cast]

Evidence supports the selection hypothesis

In fact, there is experimental evidence that polycyclic organic hydrocarbons and physiological conditions such as hypoxia select for cells with mutated p53. Polycyclic aromatic hydrocarbons inhibited growth of normal cells more than those whose p53 has been previously inactivated either by mutations or by HPV E6, the oncogenic protein of human papillomavirus. (Polycyclic aromatic hydrocarbons enhance terminal cell death of human ectocervical cells. EA Rorke, N Sizemore, H Mukhtar, LH Couch, PC Howard. Int J Oncol 1998 Sep;13(3):557-563) And, immortalized cells are not killed as readily as normal cells. (Hypoxia-mediated selection of cells with diminished apoptotic potential in solid tumours. TG Graeber, C Osmanian, T Jacks, DE Housman, CJ Koch, SW Lowe, AJ Giaccia. Nature 1996 Jan 4;379(6560):88-91).

Metastasis Occurs Before Mutations

And, there is additional evidence that p53-inactivating mutations are a late event, occurring after a cancer has already been established and has spread to the bone marrow (p53 gene mutations are not required for early dissemination of cancer cells. S Offner, W Schmaus, K Witter, GB Baretton, G Schlimok, B Passlick, G Riethmuller, K Pantel. Proc Natl Acad Sci USA 1999 Jun;96(12):6942-6946). The authors compared the p53 status of primary and micrometastatic tumor cells, and found no correlation. Also, they found that "the disseminated carcinoma cells rarely accumulate mutated p53 protein and that 10 cell lines derived thereof did not harbor p53 mutations even in the presence of such mutations in the autologous primary tumors." They believe that "malignant cells may leave the primary carcinoma at an early stage of its development when p53 is not mutated yet." This also indicates that p53 mutations are irrelevant to the etiology of cancer and not the initiating event as the health establishment pretends.

Furthermore, because these micrometastases are predictive of patient survival, they cannot simply be dismissed (Isolated tumor cells in bone marrow predict reduced survival in node-negative non-small cell lung cancer. B Passlick, B Kubuschok, JR Izbicki, O Thetter, K Pantel. Ann Thorac Surg 1999 Dec;68(6):2053-2058).

Anti-smokers and their media accomplices continue to lie about p53 mutations

Despite these facts, the well-funded and intellectually corrupt old war-horses of the health establishment continue to use this specious theory, including to manufacture bogus "evidence" that passive smoking causes lung cancer (p53 mutations and exposure to environmental tobacco smoke in a multicenter study on lung cancer. K Husgafvel-Pursiainen, P Boffetta, A Kannio, F Nyberg, G Pershagen, A Mukeria, V Constantinescu, C Fortes, S Benhamou. Cancer Res 2000 Jun 1;60(11):2906-2911; The TP53 gene, tobacco exposure, and lung cancer.).

Toyooka S, Tsuda T, Gazdar AF. Hum Mutat. 2003 Mar;21(3):229-39. Review. Authors admit that previous claims of "tobacco-related hotspots" were inflated: "We also examined the seven codons which have been previously identified as hot spots, that is, the sites of frequent G:C to T:A transversions in smoking-related lung cancers. However, there was no specific codon which was strongly related to smoke exposure despite a moderate relationship. We considered the term "warmspot" may be more appropriate." But they still don't address the "after the fact" issue, or the role of infection.

The psychopathic anti-smoker fraud, Stanton Glantz, grandly proclaimed that "The 1996 study was the first to prove the actual molecular mechanism by which cigarette smoke caused cells to grow into tumors. The finding offered a powerful tool that could be used in litigation and regulation of tobacco use, to connect a patient's disease to its specific cause. The industry would be left with little defense." Except that his claim is a lie on both counts: It is not true that p53 mutations are causal, nor has the tobacco industry ever attempted a genuine defense. Like the crackpot Nazi inquisitor that he is, Glantz pretends that any challenge to the anti-smokers' propaganda-oriented claims are automatically improper. He accuses two researchers, who merely disagreed about the prevalence of the mutations and didn't even raise the after-the-fact issue, and the editor of Mutagenesis, who published their papers, of being corrupted by tobacco industry money, whose receipt they supposedly concealed - when the real corruption issue is the flagrant funding of lying frauds such as Glantz himself, with public tax dollars. (How big tobacco reneged on pledge. Industry tried to subvert study, UCSF report finds. By Alex Barnum, Chronicle Staff Writer. San Francisco Chronicle, Jan. 14, 2004.)

Stanton Glantz's specious and lengthy tome, The p53 tumour suppressor gene and the tobacco industry: research, debate, and conflict of interest. A Bitton, MD Neuman, J Barnoya, SA Glantz. UCSF.

Most importantly -- this lie serves as a rationalization for the anti-smokers to ignore the role of infection, and thus to condone the deaths of nonsmokers as well as smokers. Denissenko's co-author Gerd Pfeifer has received three grants totalling $1,172,866 from the so-called Tobacco-Related Disease Research Program, which is funded with smokers' money stolen via California's Proposition 99 cigarette tax. Pfeifer's theory of "How Does Cigarette Smoke Induce Cancer?" continues to ignore the known role of infection in inactivating p53, and the observation that p53 mutations are not the initiating event in cancer.

More About p53

Tumor Suppressor Genes. By John W. Kimball. "John W. Kimball has retired from a lifetime of teaching biology. A graduate of Harvard College, he began his teaching career at the secondary level, teaching chemistry and biology to students at Phillips Academy, an independent school in Andover, Massachusetts. In 1969, he returned to Harvard to study immunology with the late Professor A. M. Pappenheimer. After receiving his Ph.D. there, he went on to teach introductory biology (in both majors and nonmajors courses) and immunology at Tufts University where he became a tenured professor. In 1982 he returned again to Harvard where he taught immunology and also participated in teaching the introductory course for majors. The first edition of Kimball's general biology text was published in 1965. Since that time it has gone through five revisions, the most recent being the sixth edition, which appeared in 1994... He has also published books on cell biology and a widely-used text on immunology. His biology books have also been published in Spanish, German, Japanese, Arabic, Polish, Korean and Bahasian (Indonesian) versions." (Kimball's Biology Pages. By John W. Kimball.)

The p53 Tumor Suppressor Gene: From Molecular Biology to Clinical Investigation. T Soussi. Ann NY Acad Sci 2000 Jun;910:121. "The most common changes of p53 in human cancers are point missense mutations within the coding sequences of the gene. Such mutations are found in all major histogenetic groups, including cancers of the colon (60%), stomach (60%), breast (20%), lung (70%), brain (40%), and esophagus (60%). It is estimated that p53 mutations are the most frequent genetic event in human cancers, accounting for more than 50% of cases."

Efficient repair of bulky anti-BPDE DNA adducts from non-transcribed DNA strand requires functional p53 but not p21(waf1/cip1) and pRb. MA Wani, MA El-Mahdy, FM Hamada, G Wani, Q Zhu, QE Wang, AA Wani. Mutat Res 2002 Aug 29;505(1-2):13-25. "[T]he removal of anti-BPDE DNA adducts from the genome overall and NTS by GGR was significantly reduced in HPV-16E6 protein expressing cells as compared to that in normal and HPV-16E7 protein expressing cells, indicating the role of p53 and not pRb in nucleotide excision repair (NER).... the modulation of NER by p53 may be independent of its function in the regulation of cell cycle arrest upon chemically induced DNA damage."

P53 TRANSFORMATION-RELATED PROTEIN 53; TRP53 COLON TUMORS, CONCURRENT MULTIPLE PRIMARY, INCLUDED. OMIM

More after-the-fact gene mutations

"Researchers uncover mutated genes involved in lung cancer; one affects nonsmokers." UT Southwestern Medical Center News Release, March 1, 2005. Contrary to the false impression they create, the mutations in EGFR, KRAS, and HER2 genes may turn out to be useful in the treatment of the disease, but provide no clues to the cause of lung cancer.

The Aneuploidy Theory of Carcinogenesis

Drug resistance argues against mutation theory of cancer. By Robert Sanders. Press Release, UC-Berkeley News, Jun. 26, 2007. Peter Duesberg, professor of molecular and cell biology at theUniversity of California, Berkeley: "'The mutation theory of cancer says that a limited number of genes causes cancer, so cancers should all be more or less the same,' Duesberg said. The chromosomal theory, which he laid out in an article in the May 2007 issue of Scientific American, implies instead that, 'even if cancers are from the same tissue, and are generated with the same carcinogen, they are never the same. There is always a cytogenetic and a biochemical individuality in every cancer.' ...Duesberg proposed in 2000 that the assumption underlying most cancer research today is wrong. That assumption, that cancer results from a handful of genetic mutations that drive a cell into uncontrolled growth, has failed to explain many aspects of cancer, he said, and has led researchers down the wrong path. His alternative theory is that cancer results from aneuploidy - that is, duplication or sometimes loss of one or more of our 46 chromosomes, which throws thousands of genes out of whack. This condition, generated by a defect in the mechanism that duplicates chromosomes during cell growth, leads to more and more chromosomal disorder as the cells divide and proliferate, disrupting even more genes and providing ample opportunity for the development of resistance to drugs being used to control the cancer. 'In this new study and in one published in 2005, we have proved that only chromosomal rearrangements, rather than mutations, can explain the high rates and wide ranges of drug resistance in cancer cells,' he said.... 'The fundamental problem these conventional theories don't address is why it (drug resistance) doesn't happen in normal cells," he said. "Why aren't we all getting resistant to any toxic drug we are exposed to? Why does it happen only in cancer cells? Why do cancer cells become resistant and the patients don't?... They see now, more and more, that aneuploidy cannot be ignored. It is a big elephant compared to their little mutations,' he said."

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cast 02-03-11