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DERT Papers of the Month

By Jerry Phelps
June 2006

Gene Variation Predicts Survival in Brain Cancer Patients

Researchers at the M.D. Anderson Cancer Center in Houston, Texas discovered a genetic variation that predicts survival in patients with an aggressive form of central nervous system tumor, glioblastoma multiforme (GBM). GBM and other gliomas arise from glial cells, which provide protection for neurons in the central nervous system and supply them with nutrients. The cause of GBM is unknown but it accounts for more than half of all primary brain tumor cases. The study appeared in the April 1 issue of the Journal of Clinical Oncology. It suggests that human telomerase (hTERT) is a possible target for therapeutic agents to combat cancer and it shows that molecular differences that relate to gene length can be predictive of treatment outcome.

The researchers caution that larger studies are necessary to verify these findings.

hTERT is an enzyme that adds specific DNA sequence repeats to the ends of DNA strands in the telomere regions of the chromosomes. The level of hTERT expression has been shown to be a good outcome predictor for many cancers including cancer of the lung, breast, cervix, stomach, and colon. The development of biomarkers for GBM could be useful to modify treatments and improve outcomes of patients with GBM.

In previous research, the team found variations, or alleles, of the gene. These alleles were deemed either short (S) or long (L) based on the length of the DNA sequences. In the current study, median survival for patients with two short alleles (SS genotype) was about 11 months longer than those with either one or two long alleles (SL or LL genotypes).

Citation: Wang L, Wei Q, Wang LE, Aldape KD, Cao Y, Okcu MF, Hess KR, El-Zein R, Gilbert MR, Woo SY, Prabhu SS, Fuller GN, Bondy ML. Survival prediction in patients with glioblastoma multiforme by human telomerase genetic variation. J Clin Oncol. 2006 Apr 1;24(10):1627-32.

Genes Regulated by Estrogen Predict Survival in Hormone-Positive Breast Cancers

Charles Perou at the Lineberger Comprehensive Cancer Center at the University of North Carolina found that differential expression of estrogen-regulated genes is useful in predicting patient outcome in breast cancer.

This study shows that a selected set of estrogen-regulated genes may be useful in predicting the survival outcome and recurrence of cancer in hormone-receptor positive breast cancer patients treated with tamoxifen.

Breast cancers are classified as hormone receptor positive or negative depending upon whether cell surfaces contain significant levels of estrogen or progesterone receptors. Doctors use this information to determine whether women with breast cancer should be given anti-estrogen therapies such as tamoxifen or aromatase inhibitors.

The NIEHS-supported team first identified estrogen-regulated genes by treating an estrogen receptor-positive breast cancer cell line with estradiol and performing microarray analysis. The researchers then applied this gene-set to 65 primary breast cancer tumors. Further analyses refined the gene-set to 822 genes that optimally defined two groups based on the genes activated in the tumors. The poor-prognosis group showed high expression of cell proliferation and antiapoptosis genes, while the good-prognosis group showed high expression of estrogen and GATA3-regulated genes.

The researchers suggest additional studies are necessary focusing on whether the two groups gain similar benefits from chemotherapy and whether the poor-prognosis group might do better with alternative therapies.

Citation: Oh DS, Troester MA, Usary J, Hu Z, He X, Fan C, Wu J, Carey LA, Perou CM. Estrogen-regulated genes predict survival in hormone receptor-positive breast cancers. J Clin Oncol. 2006 Apr 10;2(11):1656-6.

A Mutation Linked with Autism Causes Cholinesterase Retention in the Endoplasmic Reticulum

NIEHS-supported investigators at the University of California San Diego determined that homologous arginine to cysteine mutations in butyrylcholinesterase and acetylcholinesterase result in endoplasmic reticulum (ER) retention. This mutation in butyrylcholinesterase is one that is found to give rise to succinylcholine apnea in patients with plasma butyrylcholinesterase deficiency.

The researchers propose that the mutation impairs processing through the ER and the Golgi apparatus of the cell because of misfolding of the proteins. Accumulation in the ER causes the protein to be more susceptible to proteosomal degradation. The authors speculate that altering intracellular oxidation/reduction parameters may assist in the proper folding of these proteins and their export. This finding could shed light on the molecular causes of autism and other neurological disorders associated with misfolding of proteins.

Neuroligin, butyrylcholinesterase, and acetylcholinesterase are members of the a, ß-hydrolase fold family of proteins. Previous research has implicated a mutation in neuroligin 3, one of the five genes encoding the neuroligin family of proteins, in autism spectrum disorders. The mutation, an arginine to cysteine substitution, was identified in a set of twins and has been shown to result in the protein being retained within the ER with very little reaching the cell membrane. Misfolded proteins are known to cause ER stress, which has been implicated in a diverse group of human diseases including viral infections, diabetes, and neurodegeneration.

Citation: De Jaco A, Comoletti D, Kovarik Z, Gaietta G, Radic Z, Lockridge O, Ellisman MH, Taylor P. A mutation linked with autism reveals a common mechanism of endoplasmic reticulum retention for the alpha, beta-hydrolase fold protein family. J Biol Chem. 2006 Apr 7;281(14):9667-76.

Urine Biomarkers of Benzene Metabolism: An Example of "Exposure Biology"

Martyn Smith at the University of California Berkeley and Stephen Rappaport at the University of North Carolina Chapel Hill identified specific urinary metabolites of benzene as biomarkers of exposure in the April issue of the journal Carcinogenesis. They are conducting additional analyses to examine the dose-related metabolism of benzene and explore factors that might influence metabolism and risk of disease.

The researchers' goal was to see if differences in dose led to differences in the pattern of metabolite levels. In a population of occupationally exposed Chinese-workers and controls, they found that at lower exposures (less than 1 part per million [ppm]), the metabolism of benzene shifted towards its more toxic metabolites, hydroquinone and muconic acid.

Benzene is a highly used and important industrial solvent and precursor in the production of plastics, synthetic rubber, dyes, drugs, etc. It is a natural constituent of crude oil, is highly volatile and is a known carcinogen. Benzene is highly toxic to organs and systems involved in the production of blood and is a known cause of leukemia. Occupational exposures to benzene at air levels greater than 10 ppm have been linked to toxicity, but recent reports have raised concerns about the health effects at levels below 1 ppm.

The recently released strategic plan for NIEHS entitled "New Frontiers in Environmental Sciences and Human Health" describes the need for an initiative on Exposure Biology that will "Develop sensitive markers of environmental exposure, early (pre-clinical) biological response, and genetic susceptibility." This research is a clear example of work that may lead to the ability to quantify individual exposures and to identify features that account for differing responses to the same exposure.

Citation: Kim S, Vermeulen R, Waidyanatha S, Johnson BA, Lan Q, Rothman N, Smith MT, Zhang L, Li G, Shen M, Yin S, Rappaport SM. Using urinary biomarkers to elucidate dose-related patterns of human benzene metabolism. Carcinogenesis. 2006 Apr;27(4):772-81.

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