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Posts Tagged ‘Journal of the National Cancer Institute’

Rewriting the Mathematics of Tumor Growth; Teams Use Math Models to Sort Drivers from Passengers

Posted in Biological Networks, Gene Regulation and Evolution, CANCER BIOLOGY & Innovations in Cancer Therapy, Cell Biology, Signaling & Cell Circuits, Chemical Biology and its relations to Metabolic Disease, Computational Biology/Systems and Bioinformatics, Genome Biology, Genomic Testing: Methodology for Diagnosis, Health Economics and Outcomes Research, Interviews with Scientific Leaders, Medical and Population Genetics, Molecular Genetics & Pharmaceutical, Personalized and Precision Medicine & Genomic Research, Pharmacogenomics, Statistical Methods for Research Evaluation, tagged , , , , , , , , , , , , , , , , , , , , , , , , , on February 10, 2013| 1 Comment »

Rewriting the Mathematics of Tumor Growth[1]; Teams Use Math Models to Sort Drivers from Passengers[2]:  Two JNCI Reviews by Mike Martin Regarding Genomics, Cancer, and Mutation

Curator: Stephen J. Williams, Ph.D.

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Recently, there has been extensive interest in the cancer research and oncology community on detecting those mutations responsible for the initiation and propagation of a neoplastic cell (driver mutations) versus those mutations that are randomly (or by selective pressures) acquired due to the genetic instability of the transformed cell.  The impact of either type of mutation has been a topic for debate, with a recent article showing that some passenger mutations may actually be responsible for tumor survival.  In addition many articles, highlighted on this site (and referenced below) in recent years have described the importance of classifying driver and passenger mutations for the purposes of more effective personalized medicine strategies directed against tumors. Two review articles by Mike Martin in the Journal of the National Cancer Institute (JCNI) shed light on the current efforts and successes to discriminate between these passenger and driver mutations and determine impact of each type of mutation to tumor growth.  However, as described in the associated article, the picture is not as clear cut as previously thought and highlights some revolutionary findings. In Rewriting the Mathematics of Tumor Growth, researchers discovered that driver mutations may confer such a small growth advantage that, multiple mutations, including the so called passenger mutations are necessary in order to sustain tumor growth. In fact, much experimental evidence has suggested at least six defined genetic events may be necessary for the in-vitro transformation of human cells.  The following table shows some of the genetic events required for in-vitro transformation in cell culture systems.

Genetic events required for transformation

 Species  Cell type  # of genes required for tumor formation*  Genes used  Reference Events required for priming
Human FibroblastsEmbryonic kidney 3 hTERTH-rasLarge T (a)Hahn(Weinberg) 2LT+hTERT
Mammary epithelialMyoblastsEmbryonic kidney 6 hTERTH-rasP53DDc-myc

cyclin D1CDK4

 (b)Kendall(Counter) Hras required for tumorigenesis so probably 5 events needed
Fibroblasts 4 Large TSmall TH-rashTERT (c)Sun(Hornsby) 2Large T + H-ras
Fibroblasts 4 Large TSmall ThTERTRas (d)Rangarajan(Weinberg) 3hTERT, Ras and either small or largeT
Keratinocytes 4 CyclinD1

dnp53

EGFR

c-myc

 (e)Goessel(Opitz) 3 for anchorage independence (cyclin D1, dnp53, EGFR),Cyclin D1+dnp53 for immortalization
HOSE 6 CDK4, cyclin D, hTERT plus combination of either P53DD, myrAkt, and H-ras or P53DD, H-ras, c-myc Bcl2 (f)Sasaki(Kiyono) 5
HOSE 3 hTERTSV40 earlyH-ras orK-ras (g)Liu(Bast) 2hTERT+ SV40 early
HOSE 3 Large ThTERTH-ras orc-erB-2 (h)Kusakari(Fujii) 2hTERT+large T
Rat Fibroblasts 2 Large TH-ras (i)Hirakawa Did not analyze
Fibroblasts 2 Large TH-ras (d)Rangarajan(Weinberg) Large T
Mouse MOSEIn p53-/- background 3 c-mycK-rasAkt (j)Orsulic
Pig Fibroblasts 6 p53DDhTERT

CDK4H-ras c-myc

cyclin D1

 (k)Adam(Counter) 5 need all butp53DD

Note: priming means events required to immortalize but not fully transform.  * Note that both ability to form colonies in soft agarose and subsequently tested for tumor formation in immunocompromised mice.

a.         Hahn, W. C., Counter, C. M., Lundberg, A. S., Beijersbergen, R. L., Brooks, M. W., and Weinberg, R. A. (1999) Creation of human tumour cells with defined genetic elements, Nature 400, 464-468.

b.         Kendall, S. D., Linardic, C. M., Adam, S. J., and Counter, C. M. (2005) A network of genetic events sufficient to convert normal human cells to a tumorigenic state, Cancer Res 65, 9824-9828.

c.         Sun, B., Chen, M., Hawks, C. L., Pereira-Smith, O. M., and Hornsby, P. J. (2005) The minimal set of genetic alterations required for conversion of primary human fibroblasts to cancer cells in the subrenal capsule assay, Neoplasia 7, 585-593.

d.         Rangarajan, A., Hong, S. J., Gifford, A., and Weinberg, R. A. (2004) Species- and cell type-specific requirements for cellular transformation, Cancer Cell 6, 171-183.

e.         Goessel, G., Quante, M., Hahn, W. C., Harada, H., Heeg, S., Suliman, Y., Doebele, M., von Werder, A., Fulda, C., Nakagawa, H., Rustgi, A. K., Blum, H. E., and Opitz, O. G. (2005) Creating oral squamous cancer cells: a cellular model of oral-esophageal carcinogenesis, Proc Natl Acad Sci U S A 102, 15599-15604.

f.          Sasaki, R., Narisawa-Saito, M., Yugawa, T., Fujita, M., Tashiro, H., Katabuchi, H., and Kiyono, T. (2009) Oncogenic transformation of human ovarian surface epithelial cells with defined cellular oncogenes, Carcinogenesis 30, 423-431.

g.         Liu, J., Yang, G., Thompson-Lanza, J. A., Glassman, A., Hayes, K., Patterson, A., Marquez, R. T., Auersperg, N., Yu, Y., Hahn, W. C., Mills, G. B., and Bast, R. C., Jr. (2004) A genetically defined model for human ovarian cancer, Cancer Res 64, 1655-1663.

h.         Kusakari, T., Kariya, M., Mandai, M., Tsuruta, Y., Hamid, A. A., Fukuhara, K., Nanbu, K., Takakura, K., and Fujii, S. (2003) C-erbB-2 or mutant Ha-ras induced malignant transformation of immortalized human ovarian surface epithelial cells in vitro, Br J Cancer 89, 2293-2298.

i.          Hirakawa, T., and Ruley, H. E. (1988) Rescue of cells from ras oncogene-induced growth arrest by a second, complementing, oncogene, Proc Natl Acad Sci U S A 85, 1519-1523.

j.          Orsulic, S., Li, Y., Soslow, R. A., Vitale-Cross, L. A., Gutkind, J. S., and Varmus, H. E. (2002) Induction of ovarian cancer by defined multiple genetic changes in a mouse model system, Cancer Cell 1, 53-62.

k.         Adam, S. J., Rund, L. A., Kuzmuk, K. N., Zachary, J. F., Schook, L. B., and Counter, C. M. (2007) Genetic induction of tumorigenesis in swine, Oncogene 26, 1038-1045.

However it may be argued that the aforementioned experimental examples were produced in cell lines with a more stable genome than that which is seen in most tumors and had used traditional assays of transformation, such as growth in soft agarose and tumorigenicity in immunocompromised mice, as endpoints of transformation, and not representative of the tumor growth seen in the clinical setting.

Therefore Bert Vogelstein, M.D., along with collaborators around the world developed a model they termed the “sequential driver mutation theory”, in which they describe that driver mutations multiply over time with each mutation “slightly increasing the tumor growth rate through a process that depends on three factors”:

  1. Driver mutation rate
  2. The 0.4% selective growth advantage
  3. Cell division time

This model was based on a combination of experimental data and computer simulations of gliobastoma multiforme and pancreatic adenocarcinoma.  Most tumor models follow a Gompertz kinetics, which show how tumor growth is exponential but eventually levels off over time.

This new theory shows though that a tumor cell with only one driver mutation can only grow so much, until a second driver mutation is required.  Using data for the COSMIC database (Catalog of Somatic Mutations in Cancer) together with analysis software CHASM (Cancer-specific High-throughput Annotation of Somatic Mutations) the researchers analyzed 713 mutations sequenced from 14 glioma patients and 562 mutations in nine pancreatic adenocarcinomas, revealing at least 100 tumor suppressor genes and 100 oncogenes altered.  Therefore, the authors suggested these may be possible driver mutations, or at least mutations required for the sustained growth of these tumors.  Applying this new model to data obtained from Dr. Giardiello’s publication concerning familial adenopolypsis in New England Journal of medicine in 19993 and 2000, the sequential driver mutation model predicted age distribution of FAP patients, number and size of polyps, and polyp growth rate than previous models.  This surprising number of required driver mutations for full transformation was also verified in a study led by University of Texas Southwestern Medical Center biologist Jerry Shay, Ph.D., who noted “this team’s surprise nearly 45% of all colorectal candidate oncogenes (65 mutations) drove malignant proliferation”[3].

However, some investigators do not believe the model is complex enough to account for other factors involved in oncogenesis, such as epigenetic factors like methylation and acetylation.  In addition the review also discusses host and tissue factors which may complicate the models, such as location where a tumor develops.  However, most of the investigators interviewed for this review agreed that focusing on this long-term progression of the disease may give us clues to other potential druggable targets.

Teams Use Math Models to Sort Drivers From Passengers

A related review from Mike Martin in JNCI [2] describes a statistical method, published in 2009 Cancer Informatics[4], which distinguishes chromosomal abnormalities that can drive oncogenesis from passenger abnormalities.  Chromosomal abnormalities, such as deletions, additions, and translocations are common in cancer.  For instance, the well-known Philadelphia chromosome, a translocation between chromosome 9 and 22 which results in the BCR-ABL tyrosine kinase fusion protein is the molecular basis of chronic myelogenous leukemia.

In the report, Eytan Domany, Ph.D., from Weizmann Institute and several colleagues from University of Lausanne, University of Haifa and the Broad Institute were analyzing chromosomal aberrations in a subset of medulloblastoma, which had more gain and losses in chromosomes than had been attributed to the disease.  Using a statistical method they termed a “volumetric sieve”, the investigators were able to identify driver versus passenger aberrations based on three filters:

  • Fraction of patients with the abnormality
  • Length of DNA involved in the aberrant chromosome
  • Abnormality’s copy number

Another method to sort the most “important” chromosomal aberrations from less relevant alterations is termed GISTIC[5], as the website describes is: a tool to identify genes targeted by somatic copy-number alterations (SCNAs) that drive cancer growth (at the Broad Institute website http://www.broadinstitute.org/software/cprg/?q=node/31).  The method allows for comparison across multiple tumors so noise is eliminated and improves consistency of analysis.  This method had been successfully used to determine driver aberrations is mesotheliomas, leukemias, and identify new oncogenes in adenocarcinomas of the lung and squamous cell carcinoma of the esophagus.

Main references for the two Mike Martin articles are as follows:

1.         Martin M: Rewriting the mathematics of tumor growth. Journal of the National Cancer Institute 2011, 103(21):1564-1565.

2.         Martin M: Aberrant chromosomes: teams use math models to sort drivers from passengers. Journal of the National Cancer Institute 2010, 102(6):369-371.

3.         Eskiocak U, Kim SB, Ly P, Roig AI, Biglione S, Komurov K, Cornelius C, Wright WE, White MA, Shay JW: Functional parsing of driver mutations in the colorectal cancer genome reveals numerous suppressors of anchorage-independent growth. Cancer research 2011, 71(13):4359-4365.

4.         Shay T, Lambiv WL, Reiner-Benaim A, Hegi ME, Domany E: Combining chromosomal arm status and significantly aberrant genomic locations reveals new cancer subtypes. Cancer informatics 2009, 7:91-104.

5.         Beroukhim R, Getz G, Nghiemphu L, Barretina J, Hsueh T, Linhart D, Vivanco I, Lee JC, Huang JH, Alexander S et al: Assessing the significance of chromosomal aberrations in cancer: methodology and application to glioma. Proceedings of the National Academy of Sciences of the United States of America 2007, 104(50):20007-20012.

Further posts on CANCER and GENOMICS and Sequencing published on the site include:

The Initiation and Growth of Molecular Biology and Genomics

Inaugural Genomics in Medicine – The Conference Program, 2/11-12/2013, San Francisco, CA

LEADERS in Genome Sequencing of Genetic Mutations for Therapeutic Drug Selection in Cancer Personalized Treatment: Part 2

Paradigm Shift in Human Genomics – Predictive Biomarkers and Personalized Medicine – Part 1

Breast Cancer: Genomic profiling to predict Survival: Combination of Histopathology and Gene Expression Analysis

Computational Genomics Center: New Unification of Computational Technologies at Stanford

GSK for Personalized Medicine using Cancer Drugs needs Alacris systems biology model to determine the in silico effect of the inhibitor in its “virtual clinical trial”

arrayMap: Genomic Feature Mining of Cancer Entities of Copy Number Abnormalities (CNAs) Data

Comprehensive Genomic Characterization of Squamous Cell Lung Cancers

Mosaicism’ is Associated with Aging and Chronic Diseases like Cancer: detection of genetic mosaicism could be an early marker for detecting cancer.

http://onlinelibrary.wiley.com/doi/10.1111/j.1755-148X.2011.00905.x/full

http://pharmaceuticalintelligence.com/2013/02/05/winning-over-cancer-progression-new-oncology-drugs-to-suppress-driver-mutations-vs-passengers-mutations/

Additional references:

[1] Michor F, Iwasa Y, and Nowak MA (2004) Dynamics of cancer

progression. Nature Reviews Cancer 4, 197-205.

[2] Crespi B and Summers K (2005) Evolutionary biology of cancer.

Trends in Ecology and Evolution 20, 545-552.

[3] Merlo LMF, et al. (2006) Cancer as an evolutionary and ecological

process. Nature Reviews Cancer 6, 924-935.

[4] McFarland C, et al. “Accumulation of deleterious passenger mutations

in cancer,” in preparation.

[5] Birkbak NJ, et al. (2011) Paradoxical relationship between

chromosomal instability and survival outcome in cancer. Cancer

Research 71,3447-3452.

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Aspirin a Day Tied to Lower Cancer Mortality

Posted in CANCER BIOLOGY & Innovations in Cancer Therapy, Cell Biology, Signaling & Cell Circuits, Chemical Biology and its relations to Metabolic Disease, tagged , , , , , , on August 11, 2012| 3 Comments »

Aspirin a Day Tied to Lower Cancer Mortality

Reporter: Aviva Lev-Ari, PhD, RN

Aspirin a Day Tied to Lower Cancer Mortality

Download Complimentary Source PDF 

Daily aspirin use is associated with a modest decrease in mortality from cancer, particularly for malignancies of the gastrointestinal tract, a large retrospective study confirmed.

Individuals who were current daily users for 5 years or more at baseline had an 8% decrease in cancer mortality compared with non-users (RR 0.92, 95% CI 0.83 to 1.02), according to Eric J. Jacobs, PhD, and colleagues from the American Cancer Society in Atlanta.

The association was stronger, with a 16% decrease for those with daily use for 5 years or more, when the analysis included data collected periodically during 2 decades of follow-up (RR 0.84, 95% CI 0.75 to 0.95), the researchers reported in the Journal of the National Cancer Institute.

A recent pooled analysis of more than 50 trials involving aspirin use for cardioprotection found a 37% reduction in deaths from cancer among users, which was considerably greater than in observational studies and trials of alternate-day aspirin.

To clarify the magnitude of the association between aspirin use and overall cancer mortality, Jacobs and colleagues analyzed data from the Cancer Prevention Study II, which began in 1992 and included 100,139 participants who completed questionnaires with information on demographics, medical history, and behavioral influences.

Beginning in 1997, participants also provided information about aspirin use, and continued to provide updates every 2 years.

The 1997 questionnaire was considered the baseline for the analysis, at which time 23.8% of participants were using either low-dose or adult-strength aspirin.

More than half of participants were older than 60 and female, and almost all were white.

During the 20 years of follow-up, there were 5,138 deaths from cancer.

Among those who reported aspirin use in 1997, three-quarters said they were still taking it in 2003, while among those who were non-users at baseline, 25% had begun doing so.

Baseline aspirin users tended to be more educated, former smokers, and obese, as well as to have a history of cardiovascular disease and diabetes.

Male users also were more likely to have a history of prostate specific antigen (PSA) testing, and women users were more likely to have a history of mammography.

Overall mortality was slightly lower even for individuals who had been users for less than 5 years (RR 0.84, 95% CI 0.76 to 0.94).

Relative risks were similar for users of low-dose and full-strength aspirin, and for those with and without a history of cardiovascular disease, ranging from 0.82 (95% CI 0.72 to 0.91) to 0.95 (95% CI 0.86 to 1.04).

Current users who had never smoked had considerably lower mortality (RR 0.68, 95% CI 0.57 to 0.81), a reduction that was not seen for former smokers (RR 0.92, 95% CI 0.82 to 1.04) or those currently smoking (RR 0.91, 95% CI 0.70 to 1.19).

Even after discounting lung cancer deaths, the only lower mortality among aspirin users was for never-smokers (RR 0.67, 95% CI 0.56 to 0.81).

A possible explanation for the lack of effect on cancers other than those in the lung among ever-smokers is that smoking may attenuate the antiplatelet activity of aspirin, and activated platelets are thought to promote tumor metastases, the researchers explained.

Aspirin use at the 1997 baseline was not significantly associated with mortality from specific cancers, but differences were seen when data through 2008 were included in the analysis:

  • Cancers within the gastrointestinal tract, RR 0.61 (95% CI 0.44 to 0.84)
  • Cancers outside the gastrointestinal tract, RR 0.88 (95% CI 0.78 to 1)
  • Colorectal cancer, OR 0.64 (95% CI 0.42 to 0.98)
  • Esophageal and stomach cancer, RR 0.56 (95% CI 0.37 to 0.86)

“The reduction in overall cancer mortality was driven by both a substantial reduction in mortality from gastrointestinal tract cancers and a small, but statistically significant, reduction in mortality from cancers outside the gastrointestinal tract,” they stated.

They noted that their study was observational, which was an important limitation, in that confounding factors could have resulted in either an underestimate or an overestimate of the effects of aspirin on mortality.

Also, the absolute risk for cancer mortality between non-users and daily long-term aspirin users — approximately 100 per 100,000 person-years for men and about 40 per 100,000 person-years for women — would represent an important benefit of aspirin use if it were causal, the authors stated.

“However, even if causal, differences in absolute rates are likely to differ between our predominantly elderly population and younger populations at much lower risk of cancer mortality,” they warned.

They concluded that the “relatively modest benefit” seen in their analysis could “meaningfully influence the balances of risks and benefits of prophylactic aspirin use.”

In an accompanying editorial, John Baron, MD, of the University of North Carolina in Chapel Hill, offered a word of caution. Baron was the lead author of the meta-analysis on aspirin use and cancer risk.

“Just because aspirin is effective does not mean it necessarily should be used,” he argued.

“Aspirin is a real drug, with definite toxicity. As for any preventative intervention, the benefits must be balanced against the risks, particularly when the benefits are delayed whereas the risks are not,” Baron stated.

The American Cancer Society funds the Cancer Prevention Study II cohort.

The authors are employees of the American Cancer Society.

Editorialist Baron has been a consultant for Bayer, and holds a use patent for aspirin chemoprevention.

Primary source: Journal of the National Cancer Institute
Source reference:
Jacobs E, et al “Daily aspirin use and cancer mortality in a large US cohort” JNCI 2012; DOI: 10.1093/jnci/djs318.

Additional source: Journal of the National Cancer Institute
Source reference:
Baron JA, et al “Aspirin and cancer: trials and observational studies” JNCI 2012; DOI: 10.1093/jnci/djs318.

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High Doses of Certain Dietary Supplements Increase Cancer Risk

Posted in CANCER BIOLOGY & Innovations in Cancer Therapy, Chemical Biology and its relations to Metabolic Disease, tagged , , , , , , on May 17, 2012| 2 Comments »

Reporter: Prabodh Kandala, PhD

Beta-carotene, selenium and folic acid — taken up to three times their recommended daily allowance, these supplements are probably harmless. But taken at much higher levels as some supplement manufacturers suggest, these three supplements have now been shown to increase the risk of developing a host of cancers.

“It’s not that these nutrients are toxic — they’re essential and we need them, but we need them in a certain balance,” says Tim Byers, MD, MPH, professor of epidemiology at the Colorado School of Public Health and associate director for prevention and control at the University of Colorado Cancer Center.

Byers is senior author of a commentary recently published in the Journal of the National Cancer Institute that discusses the clinical and policy implications of the increased cancer risk from high dose dietary supplements.

“We have a window into less than half of the biology of what these nutrients are doing,” Byers says. “We say generalized things about them, calling them an antioxidant or an essential mineral, but true biology turns out to be more complex than that. The effects of these supplements are certainly not limited to the label we give them. And, as we’ve seen, sometimes the unintended effects include increased cancer risk.”

Currently the FDA regulates dietary supplements as food, but, as Byers and colleagues suggest, supplements, especially at high doses, are more accurately described as inhabiting a mid-ground between food and drugs. Like drugs, supplement ingredients are biologically active — sometimes for better and sometimes for worse

“We need to do a better job as a society in ensuring that the messages people get about value versus risk is accurate for nutritional supplements,” Byers says. “My conclusion is that taking high doses of any particular nutrient is more likely to be a bad thing than a good thing.”

Abstract:

Abstract

Nutritional supplementation is now a multibillion-dollar industry, and about half of all US adults take supplements. Supplement use is fueled in part by the belief that nutritional supplements can ward off chronic disease, including cancer, although several expert committees and organizations have concluded that there is little to no scientific evidence that supplements reduce cancer risk. To the contrary, there is now evidence that high doses of some supplements increase cancer risk. Despite this evidence, marketing claims by the supplement industry continue to imply anticancer benefits. Insufficient government regulation of the marketing of dietary supplement products may continue to result in unsound advice to consumers. Both the scientific community and government regulators need to provide clear guidance to the public about the use of dietary supplements to lower cancer risk.

http://www.sciencedaily.com/releases/2012/05/120515151034.htm

http://jnci.oxfordjournals.org/content/104/10/732

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