Genes' Role in Cancer May Be Overestimated

[Petr]

http://news.yahoo.com/s/hsn/20060511/hl_hsn/genesroleincancermaybeoverestimated


Genes' Role in Cancer May Be Overestimated

By Steven Reinberg
HealthDay Reporter
Thu May 11, 7:08 PM ET


THURSDAY, May 11 (HealthDay News) -- Looking for genes that could boost a person's general risk for cancer is not likely to reap great rewards, new research concludes.

While vast sums of money and resources are being invested in the search for common, inherited genetic variants that increase susceptibility to cancer, that search faces big roadblocks.

The biggest one: Such genes probably don't exist, scientists now say. And if they do, they probably won't have much effect on the incidence of cancer.

"Enthusiasm for this new field of research should not precipitate unwarranted expectations," wrote experts Dr. Stuart Baker, from the U.S.
National Cancer Institute, and Dr. Jaakko Kaprio, from the University of Helsinki, Finland.

Their report appears in the May 13 issue of the British Medical Journal.

They pointed to studies that suggest that environmental, dietary or lifestyle changes have a much larger effect on the incidence of cancer than genetics do. Those studies find changes in the incidence of cancer within one generation or two generations, which is just too quick to be related to the introduction of new genes, Baker and Kaprio noted.

A pivotal study of cancer in twins also suggests genes aren't the key culprits in cancer. Looking at that data from identical and non-identical twins, that study found that genetic susceptibility had only a small-to-moderate effect on the incidence of cancer.

Baker and Kaprio believe that studies that have shown a strong association between specific genes and a higher risk for cancers may be biased.

"The search for common cancer susceptibility genes faces important methodological and practical challenges for cancer prevention, given the small chance that such genetic variants exist and the difficulty and expense of proving substantial clinical benefit if they do exist," Baker and Kaprio wrote.

The researchers noted that certain genes may enhance risks for very specific types of cancer -- for example, the BRCA1 and BRCA2 genes that doctors know are strongly linked to breast cancer. But genes that encourage cancer generally are less likely, they said.

One expert agreed that genetics can only go so far in determining anyone's risk for cancer.

"The age of the human genome is here," said Dr. Michael Thun, vice president of epidemiology and surveillance research at the
American Cancer Society. "The understanding of genes will transform the way we think about many diseases and is already transforming the way we understand cancers."

But the idea that that your genetic makeup is going to be the main factor that determines your susceptibility to cancer has been oversold, Thun added. "The things we know that are bad for you are bad for you in so many different ways that they won't become OK just because you're less susceptible to one or another disease," he said.

Genetics isn't going to transform efforts to prevent cancer, Thun added. "The most successful efforts to prevent cancer are going to come from public policies that make it easier to maintain a healthy body weight and make it easier to get kids not to smoke," he said.

Most of the genetic changes that cause cancer happen during your lifetime, not at birth, Thun said. Still, "research on what the genetic changes are that give rise to a cancer is already profoundly important," he said.

[Petr]

Craig Venter, who played leading part in charting human genome, seems to largely agree with the findings of this study:

http://www.edge.org/3rd_culture/highfield06/highfield06_index.html


So what does his code tell him, other than that he does indeed have blue eyes? For one thing, he is now taking a statin drug, after finding a variant of a gene that puts him at risk of heart disease. But the big picture is mind-bogglingly complex. 'There are more than 300 genes that contribute to blood pressure regulation alone,' Venter tells me.

'People say there are things like "colon cancer genes". There are not. We all have the same genes, but with variation in their spelling.' As he puts it, 'It is perfectly clear that it is not clear.' And even if we understood it all, he admits, there is still the influence of the environment to reckon with. 'I don't worry about what people will find in my genome because it is so hard to interpret.'


Petr

[wintermute]

With some respect due to Craig Ventner, who is after all in the cutthroat world of looking looking for venture capital and grants, this just isn't correct.

And it's not even wrong in the right way.

Gene expression and cancer are linked, not partiular genes. There is no colon cancer gene, but there are genes, when activated, deactivated, or deformed either are strongly associated with cancer risk or strongly associated with protection against cancer.

I can agree that the search for inherited 'cancer' genes may be be a boondoggle, but neither the author of the first study nor Ventner seems familiar with the latest research that shows that genes work with other genes that influence which proteins they're going to build.

Secondly, it's hardly as if this is a Manhattan style program. It is an inexpensive (relatively) research intitiative, much of which is already complete!

http://cancerquest.org/index.cfm?page=261

The cell division process is dependent on a tightly controlled sequence of events. These events are dependent on the proper levels of transcription and translation of certain genes. When this process does not occur properly, unregulated cell growth may be the end result. Of the 30,000 or so genes that are currently thought to exist in the human genome, there is a small subset that seems to be particularly important in the prevention, development, and progression of cancer. These genes have been found to be either malfunctioning or non-functioning in many different kinds of cancer.

The genes that have been identified to date have been categorized into two broad categories, depending on their normal functions in the cell.

Genes whose protein products stimulate or enhance the division and viability of cells. This first category also includes genes that contribute to tumor growth by inhibiting cell death.

Genes whose protein products can directly or indirectly prevent cell division or lead to cell death.

The normal versions of genes in the first group are called proto-oncogenes. The mutated or otherwise damaged versions of these genes are called oncogenes.

The genes in the second group are called tumor suppressors.

Note that by convention gene names are italicized and the proteins they make are not. As an example p53 refers to the gene and p53 refers to the protein.

Thirdly, the reduction of cancer incidence among people who consume large amounts of Green Tea, as well as those who eat cruciferous vegetables (especially broccoli) has been definitively linked to gene expression. Note: not inherited genes.

Here, some brave scientists save our littlest friends, the rats, by giving them some broccoli for their cancer and then taking notes:

http://jpet.aspetjournals.org/cgi/content/full/310/1/263

Sulforaphane (SUL) belongs to the isothiocyanate (ITC) class of chemopreventive compounds and is found abundantly in many cruciferous vegetables such as broccoli and cauliflower (Zhang et al., 1992). This class of compounds has been shown to be effective in blocking initiation as well as progression of various chemically induced carcinogenesis models in anim[/B]als (Hecht, 1995, 1999; Fahey et al., 1997). Previously, many studies have shown that SUL and other ITCs can induce phase II drug-metabolizing enzymes or detoxifying enzymes in in vitro cell lines as well as in animals (Guo et al., 1992; Zhang et al., 1992, 1994; Prestera and Talalay, 1995; Thimmulappa et al., 2002). The induction of phase II detoxifying enzymes includes glutathione S-transferases (GSTs) and NADPH:quinone oxidoreductase as well as cellular defensive enzymes such as heme-oxygenase-1) by ITC, commonly occurred via the activation of a basic leucine zipper Nrf2 transcription factor (Venugopal and Jaiswal, 1996; Itoh et al., 1997) acting on the antioxidant response element (ARE) or electrophile response element located in the 5'-flanking region of these genes (Nguyen et al., 1994, 2000; Kensler, 1997). The induction of these detoxifying enzymes would result in the detoxification and clearance of potential carcinogens as well as endogenous reactive oxygen species, consequently leading to protection of these cells against DNA or other cellular damage and thereby blocking the initiation of carcinogenesis. It seems that in general, many of the naturally occurring chemopreventive compounds possess this mechanism of action via the induction of detoxifying enzymes and cellular defensive enzymes (Kensler, 1997). In addition, the ITCs can also induce apoptotic cell death (Kirlin et al., 1999; Gamet-Payrastre et al., 2000) either via the caspase pathway (Yu et al., 1998) or the p53-dependent pathway (Huang et al., 1998). Furthermore, the ITC can also induce cell cycle arrest (Chiao et al., 2000; Gamet-Payrastre et al., 2000) and/or potentially induce cell death genes, leading to apoptosis.

To further understand the in vivo mechanisms of cancer preventive action of ITC such as SUL, we have conducted a study in the F344 rats to elucidate its in vivo pharmacokinetics and to ascertain what other genes are modulated in normal rat livers after oral administration of SUL. An additional objective was to examine the in vivo activation of the mitogen-activated protein kinase (MAPK) in rat liver after SUL administration. Because previously we as well as others have found that the ITC, including SUL, can modulate MAPKs in different mammalian cell lines, and one of the biological consequences of modulation of MAPKs would lead to changes in gene expression (Patten and DeLong, 1999; Yu et al., 1999). In this study, we also investigated the time course (kinetics) of the gene expression profiles elicited by SUL using the rat oligonucleotide-based DNA microarray. The dose chosen has been shown to be effective against azoxymethane-induced rat intestinal cancer model (Chung et al., 2000). We found that in this in vivo study, it provided the first clue as to the plasma concentrations of SUL, in vivo MAPK activations in rat livers, as well as what other genes are modulated in addition to phase II detoxifying genes by SUL. The results from this study would yield better insights for the chemopreventive functions of SUL and other ITCs. [/B]
Regarding Tea:

SUL Induces MAPK Activation in Rat Liver in Vivo. MAPKs characterized as proline-directed serine/threonine [ProXSer/ThrPro; [Gonzalez, 1991 #935; Alvarez, 1991 #936]] kinases (Marshall, 1994) are important cellular signaling components, which convert various extracellular signals into intracellular responses through serial phosphorylation cascades (Cobb and Goldsmith, 1995). Several laboratories, including ours, have found that other chemopreventive agents such as tea polyphenols can modulate MAPK signaling pathways (Dong et al., 1997; Yu et al., 1997). In terms of the ITCs, we and others have also shown that phenethyl isothiocyanate, SUL, and benzylisothiocyanate can activate MAPK, resulting in gene expression and apoptosis in many mammalian cell lines (Yu et al., 1996, 1998; Samaha et al., 1997; Huang et al., 1998; Kirlin et al., 1999; Patten and DeLong, 1999; Chiao et al., 2000; Gamet-Payrastre et al., 2000; Xu and Thornalley, 2000; Yang et al., 2002b). However, it is not clear regarding the roles of MAPK in the in vivo situation. As shown in Fig. 2, the maximum activation of ERK1/2 occurred at 2 h (and again at 36 and 48 h; due to second dose); however, very little JNK or p38 MAPK activation was observed. This result suggests that in the in vivo rat liver, the ERK pathway may play an important role in the early signal transduction event leading to the transcriptional activation of ARE-mediated genes expression, analogous to the in vitro cell lines situation (Yu et al., 1999).

And did the Broccoli cause a change in the gene expression of the rats?

Gene Expression Profiles Induced by SUL in Rat Liver in Vivo. DNA microarrays are a powerful tool to assess simultaneously the expression profile of tens or thousands of genes in one experiment. The data were obtained after two oral doses of 50 µmol of SUL given at 0 and 24 h. Three animals per time point were obtained at 0, 2, 4, 12, 24, and 48 h to show the kinetics profile of gene expression. The data were normalized and the average of three animals per time point and the standard errors were obtained. The Student's t test, p < 0.05, filter was used to select data reproducibly different from control. From the Genespring analysis, 562 genes were found to be either 2-fold up- or down-regulated in at least one of the five time points compared with control. The genes represented in Table 1 have been generated from these 562 genes with specific importance in the regulation of the stress response, homeostasis, cell cycle, phase I and II drug metabolizing enzymes, transcription factors, kinases, phosphatases, as well as others. As shown in Table 1, very robust induction of certain genes, up to 30-fold as early of 2 to 4 h after SUL administration, was observed. Similarly, inhibition of certain genes down to 0.1-fold of the controls was observed as early as 2 to 4 h. Figure 3 shows the up-regulation of metallothionein (MT-2/1 and -1a). MT-2/1 was induced as early as 2 h up to 37-fold, decreased slightly at 4 h, and then peaked at 24 h up to 43-fold induction over control RNA. Similarly pattern was observed for MT-1a, although with less induction.

Did the wee little rats live? No, they were all ruthlessly sacrificed by scientists. However, we did learn a bit more about the effects of SUL (the chemical in Broccoli) in gene expression:


In summary, this microarray study of SUL in in vivo rat livers provided the first clue as to what genes are modulated in addition to phase II detoxifying genes such as GST and UGT. The induction of MT genes by SUL is somewhat surprising and has not been reported before. The down modulation of cell cycle and cell death genes suggest that SUL may have biological effects in preinitiated or tumor cells, and future studies would be needed to confirm this phenomenon. The elucidation of this global gene expression profile elicited by isothiocyanates such as SUL may yield further insights for their chemopreventive functions. Future studies focusing on potential cell signaling and biological significance of isothiocyanate-induced gene expression would greatly extend our understanding of the mechanisms of chemopreventive functions of isothiocyanates.

So, listen to your mother and not Craig Ventner. Eat your broccoli and drink Green (or better, White) tea or else you'll get cancer!

Best,

Wintermute

[Petr]

Do you have a degree in natural sciences, Winnie?


Petr

[il ragno]

I love it when the not-a-scientist questyions the other guy's Official Scientist Credentials.

And I can assure you, with still-fresh grief, that genetics play a role in cancer.

[Petr]

I love it when the not-a-scientist questyions the other guy's Official Scientist Credentials.
You are as paranoid as ever.

That was an honest question, not a scoffing remark.


Petr

[Helios Panoptes]

I also have an honest question. I've been wondering, what are your scientific credentials, Petr?

[Petr]

I also have an honest question. I've been wondering, what are your scientific credentials, Petr?
Although my paternal grandfather was a physicist and my father is a biologist, I myself have pursued more humanistic endeavors. My major is English language, and I partly finance my studies with translation jobs.

Arguing on forums such as this also keeps my language skills ready and intact, so it a serves a purpose of its own. :)


Petr