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Put Your Tumor On Ice!
Why You Should Consider Freezing Your Tumor

Tumors On Ice

Tumors can be preserved at very low temperature by freezing in liquid nitrogen. This preserves the internal and molecular structure of the cells for years. It may even be possible to retrieve viable cells when the tumor is thawed. Freezing your tumor is definitely not standard practice, and if you want to do it you'll probably have to arrange it yourself with cooperation from your doctors, but I am recommending it because I think there are likely to be major benefits in the foreseeable future.

Why Freeze Your Tumor?

Some years ago the Kidney Cancer Association advocated freezing your tumor in case a vaccine was developed that could be made from the frozen tumor in the future. I was never enthusiastic about this approach because all the vaccine protocols I knew of required fresh tissue, and no vaccines were close to being commercially available.

But a talk at the 2003 Kidney Cancer Association Convention by Dr. Bin Teh of the Van Andel Research Institute on gene expression profiling of kidney cancer convinced me that it is well worth consider arranging to have your tumor preserved but the reason is quite different from saving it for a vaccine.

Gene Chips and Gene Expression Profiling

It turns out that a revolution in "Genomics" is making it possible to profile the gene expression of tumors. This means finding out which genes are active in the tumor compared to normal cells and which genes are not. The character of a cell is largely determined by what genes are turned on.

The technique for determining your tumor's gene expression profile involves what are known as "gene chips" or more formally "DNA Microarrays". Gene chips are clever marriage between microelectronics and molecular biology which permit one to determine the amount of Messenger RNA (mRNA) for tens of thousands of genes at once in a single experiment. mRNA is produced when a gene is turned on. mRNA codes for and specifies the amino acids that make the protein specified by that gene and allows the gene's DNA to be translated into its protein.

What Gene Expression Profiling Might Be Able Do For You

  • Help determine what Sub-Type of RCC you have: Dr Bin Teh presented research data showing that each of the known RCC sub-types has a different and identifiable pattern of gene expression - a different set of genes which are turned on or off compared to normal kidney cells. In the future this may be validated as a better way to understand what kind of RCC you have, especially in difficult to classify cases.

  • Give you a more accurate prognosis: Dr. Bin Teh presented preliminary data showing that gene expression patterns predicted which patients would survive five years and which would not, and a recent paper from the Urologic Oncology Branch of the NCI [Vasselli 2003] reported the discovery of two different patterns of gene expression in RCC primary tumors associated with different prognosis in patients who had metastatic disease.

  • Guide your treatment: Knowing which genes are activated (or turned off) may allow doctors to craft individualized therapies tailored to specific abnormalities in a tumor. For instance, it might be possible to choose anti-angiogenic drugs based on the particular factors driving angiogenesis in a non-clear cell tumor. Dr. Bin Teh didn't address this in his talk, but it's obviously a goal.

What You Can Do Today

Gene expression profiling isn't available now...

Right now, this is strictly a research technique, not a standard test, and it isn't available. Also, research on gene expression profiling for kidney cancer is only in its infancy and it's too early to reliably fulfill any of the promises of this technique.

...but I predict it will be in the not too distant future

A tremendous amount of effort is being put into this area in cancer research because of its huge potential. In addition, the cost of gene chips is constantly falling. At the meeting the cost of a gene chip was said to be about $1000.00. Although this doesn't include the costs related to setting up a lab, quality control and running and interpreting the test, it's clear to me that with falling prices, increased automation, and increased knowledge of what gene expression profiles tell us, these tests will probably become both economical and useful some time in the next several years. I do have to tell you that most of the doctors at the conference were skeptical due to the costs and the difficulty of convincing insurance companies to pay, but anyone who's had a CT scan, an MRI, or a PET scan knows that several thousand dollars for an important test is far from out of the question.

I predict that gene expression analysis will first be available from small "boutique" labs and may not be routinely paid for by insurance companies. If your case has difficult to understand pathology, or if early information from gene expression analysis research begins to show how it can guide treatment decisions, you may find it useful even before it is in general use.

... and it can be done with frozen tissue

Gene Profiling With Formaldehyde Preserved Tissue

At the 2004 ASCO meeting I learned that a technique called RT-PCR allows molecular profiling even with paraffin embedded formaldehyde preserved tissue. This is the paraffin block which is prepared from a sample of your tumor as part of the standard pathology examination. These blocks are often retained by the hospital for years or even indefinitely. You can check on the status of yours and even collect it if it's in danger of being tossed.

Even though the RNA (which is the result of gene activity and is what gene expression profiling measures) in paraffin blocks is degraded, RT-PCR is extremely sensitive and able detect small fragments of the original RNA transcripts. The main disadvantage is that a much smaller number of genes can be profiled compared to DNA microarrays which can profile tens of thousands of genes at once but require fresh or frozen tissue. Fortunately, it seems likely that a few dozen or so carefully selected genes should be able to serve to distinguish sub-types and prognosis. If this is correct, then you may someday be able to get useful information from your tumor even if you don't have frozen tissue available. In breast cancer there is already a test called OncoType DX which uses RT-PCR to profile the activity of 21 genes to determine prognosis (the test is valid only in limited clinical situations). Despite all of this I still think it would be better to have frozen tissue available just in case. There is another genetic profiling test for breast cancer called MammoPrint which does require frozen tissue.

More Than You Want To Know: RT-PCR stands for "Reverse Transcriptase - Polymerase Chain Reaction." The Polymerase Chain Reaction is an amazing trick which allows one to make a huge number of copies of any piece of DNA in a sample matching a predetermined sequence (simplifying a bit ;-)). Reverse Transcriptase is an enzyme which translates RNA into matching DNA. Actually reverse transcriptase is an evil trick used by RNA viruses (like the AIDS virus) to infect cells, that scientists have turned to good use. Combining this with PCR allows detection of small amounts of RNA even from degraded samples by first translating the RNA to DNA with Reverse Transcriptase and then doing PCR against that DNA.

One of the other patients at the KCA conference (a physician) asked Dr. Bin Teh some very smart questions and we all learned that although this test can't be done with pathology slides or paraffin blocks (the standard method of preserving your pathology), it can be done with frozen tissue. And it turns out it's possible to have your surgical specimen frozen if you arrange it before surgery. If you have your tumor preserved today, then when the technology becomes available your tumor can be tested. From the discussion at the conference, it sounded as though freezing can preserve the tissue for many years.

Which Tumors Can Be Preserved?

The most common surgery for kidney cancer patients is a nephrectomy and the primary tumor is usually the biggest tumor mass. This then is the obvious choice. But patients having surgery for metastatic tumors might also be able to have the tumor preserved if the tumors are big enough.

Cost

The initial cost to have your tumor preserved will probably be in the range of a few hundred to a few thousand dollars. After an initial storage period, there may be a yearly storage charge which should be reasonable. The cost won't be covered by insurance and you should inquire carefully before signing up for anything.

How To Get Your Tumor Preserved

Important: You must arrange for tumor preservation before your surgery!

I am not yet sure of the best way to have your tumor frozen. Since the diagnostics I am talking about aren't yet standard, and there are different ways to handle and freeze tissue it's hard to know which is best. I am still looking into it.

  • Your local hospital's pathology department may be able to freeze a sample of your tumor: If this is an option, you need to ensure that they will not discard the sample without your permission (I recently talked to a patient whose sample was discarded without either permission or notice), that they will release it as you direct, and that their freezer system is fully protected against power and mechanical failures.

  • I have found two different commercial services which offer tumor cryopreservation. I would be sure to discuss both the cost of initial preservation and ongoing maintenance as well as how much will be stored and whether the samples would be suitable for future gene chip analysis. Preserving cell viability is not a requirement but ensuring that cellular RNA and DNA will be preserved is.

  • I do not specifically endorse either of these commercial services. They are the only two I have found:


  • The Future: "Biorepositories" At a clinical trials meeting I attended in October 2003 tissue preservation was one of the hot topics and I think its very likely that in the future many patients will be asked to donate their tissue for research purposes. If you are asked, I hope you are willing to donate tissue, but I also advise you make sure some tissue will be preserved for your use. In an ideal world this would be automatic with donation. In the real world, you need to make sure your interests are respected. Recent plans I have seen (January 2004) for a US national biorepository, explicitly and intentionally leave out making a sample from your donated tumor available to you - ever. The same for information on research that was done with it. This isn't written in stone - yet.

Some References on Gene Expression Profiling in Renal Cell Cancer

Boer JM, Huber WK, Sultmann H, Wilmer F, von Heydebreck A, Haas S, Korn B, Gunawan B, Vente A, Fuzesi L, Vingron M, Poustka A.
Identification and classification of differentially expressed genes in renal cell carcinoma by expression profiling on a global human 31,500-element cDNA array.
Genome Res. 2001 Nov;11(11):1861-70. [Free Full Text (will open in new window)]
Higgins JP, Shinghal R, Gill H, Reese JH, Terris M, Cohen RJ, Fero M, Pollack JR, van de Rijn M, Brooks JD.
Gene expression patterns in renal cell carcinoma assessed by complementary DNA microarray.
Am J Pathol. 2003 Mar;162(3):925-32. [PubMed Abstract (will open in new window)]
Huber W, Boer JM, von Heydebreck A, Gunawan B, Vingron M, Fuzesi L, Poustka A, Sultmann H.
Transcription profiling of renal cell carcinoma.
Verh Dtsch Ges Pathol. 2002 ;86:153-64. [PubMed Abstract (will open in new window)]
Skubitz KM, Skubitz AP.
Differential gene expression in renal-cell cancer.
J Lab Clin Med. 2002 Jul;140(1):52-64. [PubMed Abstract (will open in new window)]
Takahashi M, Rhodes DR, Furge KA, Kanayama H, Kagawa S, Haab BB, Teh BT.
Gene expression profiling of clear cell renal cell carcinoma: gene identification and prognostic classification.
Proc Natl Acad Sci U S A. 2001 Aug 14;98(17):9754-9. [Free Full Text (will open in new window)]
Vasselli JR, Shih JH, Iyengar SR, Maranchie J, Riss J, Worrell R, Torres-Cabala C, Tabios R, Mariotti A, Stearman R, Merino M, Walther MM, Simon R, Klausner RD, Linehan WM.
Predicting survival in patients with metastatic kidney cancer by gene-expression profiling in the primary tumor.
Proc Natl Acad Sci U S A. 2003 Jun 10;100(12):6958-63. [PubMed Abstract (will open in new window)]


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This CancerGuide Page By Steve Dunn. © Steve Dunn
Page Created: August 6, 2003, Last Updated: June 12, 2004