Gene Variant May Make Some Men Prone to Cancer-Causing Pollutants

Oct 17 2003 /Wake Forest/ — Some men may be more susceptible to cancer because they carry a variant of a gene, CYP1B1, sensitive to cancer-causing pollutants that interact with hormones, Wake Forest and Johns Hopkins scientists report.

In the first-ever such study of human patients, geneticists at Wake Forest looked for clues to understanding what environmental factors trigger prostate cancer's development.

They examined a gene that controls the body's response to cancer triggers both inside and outside of the body. They found men with the disease were more likely to carry a variant which seems to increase vulnerability to environmental chemicals.

CYP1B1 has been under study since the early 1990s. CYP1B1 is thought to play an important role in the development of cancer. It is classified as "dioxin-induced."

Some men may be more prone to prostate cancer because a variation in this specific gene makes them more susceptible to the harmful effects of cancer-causing agents, the researchers found.

The results of the study led by researcher Jianfeng Xu, Ph.D. will be published today in the British Journal of Cancer.

Xu and his team, together with researchers at Johns Hopkins University, looked at variations in a gene that controls the body’s response to carcinogens in the environment as well as hormones natural to the body. They found men with prostate cancer often had a different version of the gene than men who were not affected by the disease.

Scientists believe their findings may hold important clues in understanding what environmental factors may trigger the development of prostate cancer.

"Previous research suggests prostate cancer arises in certain individuals due to a combination of genetic and environmental factors," said Xu. "Our study suggests that the genetic make-up of some men leaves them more susceptible to potential carcinogens in the environment or hormones in the body that could trigger the disease."

CYP1B1 normally plays a dual role in the body and therefore has been suggested to both cause and prevent cancer. It helps the body eliminate environmental chemicals that can cause cancer but also can activate some hormones, turning them into cancer-causing agents.

Tiny variations in the gene may alter its function, say the researchers, with some increasing the cancer-causing effects of the gene and others enhancing its ability to prevent cancer.

The team looked separately at 13 variations in CYP1B1 and clusters of these variations, called polymorphisms, commonly found in Caucasian male populations. They found that one cluster of variations was more common in men with prostate cancer who had no family history of the disease, while another combination appeared more frequently in men who did not have the disease.

The study suggests men with a particular gene variant have an increased risk of prostate cancer. “It’s an exciting finding because we know the gene interacts with certain cancer-causing chemicals,” said Xu. “Studying this more closely will bring us closer to finding out what factors in the environment or within the body may trigger the disease.”

This information will help scientists better understand how changes in the gene alter its dual functions in the body, and allow them to identify people at high risk and advise them on ways to prevent the disease.

Source, Wake Forest University. This story edited by J. Strax. Page updated Oct 16, 2003.

ABSTRACT

British Journal of Cancer (2003) 89, 1524-1529.

Polymorphisms in the CYP1B1 gene are associated with increased risk of prostate cancer

B L Chang and team, Center for Human Genomics, Wake Forest University School of Medicine and Department of Urology, Johns Hopkins Medical Institutions, Baltimore.

CYP1B1 has been evaluated as a candidate gene for various cancers because of its function in activating environmental procarcinogens and catalysing the conversion of oestrogens to genotoxic catechol oestrogens. To test the hypothesis that genetic polymorphisms in the CYP1B1 gene may associate with the risk for prostate cancer (CaP), we compared the allele, genotype, and haplotype frequencies of 13 single nucleotide polymorphisms (SNPs) of CYP1B1 among 159 hereditary prostate cancer (HPC) probands, 245 sporadic CaP cases, and 222 unaffected men. When each of the SNPs was analysed separately, marginally significant differences were observed for allele frequencies between sporadic cases and controls for three consecutive SNPs (-1001C/T, -263G/A, and -13C/T, P=0.04-0.07). Similarly, marginally significant differences between sporadic cases and controls in the frequency of variant allele carriers were observed for five consecutive SNPs (-1001C/T, -263G/A, -13C/T, +142C/G, and +355G/T, P=0.02-0.08). Interestingly, when the combination of these five SNPs was analysed using a haplotype approach, a larger difference was found (P=0.009). One frequent haplotype (C-G-C-C-G of -1001C/T, -263G/A, -13C/T, +142C/G, and +355G/T) was associated with an increased risk for CaP, while the other frequent haplotype (T-A-T-G-T) was associated with a decreased risk for CaP. These findings suggest that genetic polymorphisms in CYP1B1 may modify the risk for CaP.

RELATED TOPICS

At least 15 genes including CYP1B1 are thought to be involved in prostate cancer. CYP1B1 is a gene subfamily of cytochrome P450, cytochrome P4501B1. It was first mapped by scientists at Johns Hopkins and Purdue Universities, Thomas Sutter et al, in 1991. A PDF file of their article is online (requires Acrobat reader).

CYP1B1 is associated with inherited glaucoma. It is also dioxin-inducible.

Scientists at the University of Michigan in 2001 reported finding CYP1B1 in prostate tissue along with 6 other genes not previously reported. That made a total of 15 genes then found in prostate tissue. They wrote: " These genes describe at least four metabolic and signaling pathways likely disrupted in human prostate tumorigenesis."

An article in J Pharmacol Exp Ther. 2001 Feb;296(2):537-41 examines how "The cytochrome P450 1B1 (CYP1B1) is involved in the metabolism of procarcinogens and xenobiotics." Since CYP1B1 protein" has been detected in a variety of tumors but is not detected in adjacent normal tissues or in liver," they suspected that " CYP1B1 could biotransform anticancer agents specifically in the target cells."

They looked at how CYP1B1 interacts with 12 commonly used anticancer drugs including flutamide, paclitaxel, mitoxantrone and docetaxel, all of which inhibited CYP1B1.Doxorubicin and daunomycin "were mixed inhibitors, while tamoxifen was a noncompetitive inhibitor..." Vinblastine, vincristine, 5-fluorouracil, etoposide, and cyclophosphamide did not inhibit CYP1B1 activity."

"In vitro incubations with flutamide and CYP1B1 produced a metabolite consistent with 2-hydroxyflutamide. Comparison of kinetic parameters (K(m), K(i), V(max)) for flutamide 2-hydroxylation by CYP1B1, CYP1A1, and CYP1A2 indicate that CYP1B1 could play a major role for flutamide biotransformation in tumors. The results obtained indicate that several anticancer agents inhibit CYP1B1 activity. Drug inactivation by CYP1B1 may represent a novel mechanism of resistance, influencing the clinical outcome of chemotherapy."

See the free, full text article for details. Human CYP1B1 and Anticancer Agent Metabolism: Mechanism for Tumor-Specific Drug Inactivation? Bertrand Rochat, Janine M. Morsman, Graeme I. Murray, William D. Figg and Howard L. McLeod, University of Aberdeen, National Cancer Institute, National Institutes of Health, Bethesda, Maryland

GeneCard for CPY1B1 from Bioinformatics at Weizmann Institute, Israel.

Several natural and synthetic compounds have been studied in an effort to find inhibitors of the CYP1 subfamily. Those studied include include soy genistein, resveratrol (from grape skins) and baicalin (skullcap) You will see some of these mentioned in abstracts and free, full text papers listed here:

Abstracts at PubMed about CPY1B1 and cancer

The above link calls up 20 pages of titles. Can't help but look at it as an uneven fight, especially in the bodies of genetically susceptible people, between "nutrients" and environmental pollutants. This is what the nutrients extracted from grape skins, red clover and so on are supposed to protect us from:

Polycyclic Aromatic Hydrocarbons (PAHs)

What are polycyclic aromatic hydrocarbons (PAHs)? Agency for Toxic Substances and Disease Registry says:

"Polycyclic aromatic hydrocarbons (PAHs) are a group of over 100 different chemicals that are formed during the incomplete burning of coal, oil and gas, garbage, or other organic substances like tobacco or charbroiled meat. PAHs are usually found as a mixture containing two or more of these compounds, such as soot."

"Some PAHs are manufactured. These pure PAHs usually exist as colorless, white, or pale yellow-green solids. PAHs are found in coal tar, crude oil, creosote, and roofing tar, but a few are used in medicines or to make dyes, plastics, and pesticides."

JOIN A DISCUSSION

at PSA Rising Forums -> Cancer Research News -> New Knowledge About Cancer