Breast Cancer Genetics

September 7, 2006 Conference CoverageINTERNATIONAL FEDERATION of GYNECOLOGY & OBSTETRICS: Washington DC, USA

Courtesy of FIGO

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Dr. Mattias W. Beckmann: “Ladies and gentlemen, Mr. Chairman, thank you very much for the invitation. The problem that I have now is that I’ve been given twenty minutes to explain to you one of the things in the field which I’ve been working in for twelve years now, and it’s hard to understand what is going on so you’ll understand the difficulty I have in telling you about breast cancer genetics in about twenty minutes of time. So what I am going to do is give you some major hints in which direction breast cancer genetics is going to develop and what we can use in the daily practice. So what is breast cancer? Breast cancer is an accumulation of mutations in genes, which on two sides control either cell proliferation or cell death. How does it go? You have either genetic instability, which means that during development the accumulation of multiple mutations in the end will cause breast cancer or you have the physiological mutation rates and those mutations cannot be repaired and, therefore, you will get the development of breast cancer. There are various levels at which genetics can interfere with the development of breast cancer. The first level is on the nucleotide basis to basis level. Then the second level is on the level of a gene, which is like an alteration of a mixed matched repair gene, which is normally repairing defects in the cell. The third level is on the level of the mitotic spindle checkpoint, which means that there is accumulation on alteration in the number of chromosomes while the cells get divided and, therefore, you have additional information. What kind of genetic alterations of breast cancer do we have? We have small nucleotide alterations, chromosomal translocation, variation of the chromosome number, and we have gene amplification. With these four genetic alterations you can explain most of what we have seen and what is detected in the life of breast cancer genetics. What is chromosomal instability? That is the major thing that people working in breast cancer genetics see every day and that is that most tumors have either a gain or a loss of chromosomes or chromosomal pieces and, therefore, either gain or lose genes. 

There’s also genetic information and genetic functions, and the gain and loss of chromosomes is ten to a hundred times more abundant in the un-deployed cancer cells than in the normal cells or the deployed cancer cells. So what is it going to come up? We have a karyotype chromosome level, a genotype, and a genetic heterogeneity in a single cell and in every cell in the tumor. People who treat breast cancer know that breast cancer is a heterogenesis tumor and after a certain time if you do chemotherapy or antihormonal therapy, the woman can get a recurrence even though you’ve done everything that you could do. The reason for this is because from 100 cells, 80 cells are different and you cannot treat all cells with the same method. How does breast cancer genetics work? On the first basis you have the DNA, which is the mother of everything and from the DNA you have a regulatory network, and that network controls how the gene is transcribed. You have gene transcription on the irony (RNA) level and on the protein level and, therefore, every gene has a function in the cell and, therefore, either is leading to promotion to the cancer or it is inhibiting promotion to the cancer. We have three classes of tumor genes. This is G-oncogenes and these genes stimulate cell proliferation. The epidermal growth factor receptor belongs to this class but this is physiologically promoting growth. 

The second one is a tumor suppressor gene, which is inhibiting cell proliferation and growth. The third one is the mutated genes, which actually control the genetic stability of the cells and only indirectly if they’re routed you have the problem. I’m going through the classes so we understand in which way they have a function in the cell. We aren’t going into all of that but you can see there are tons of proto-oncogenes, which are published and compared in breast cancer genetics. But if you go and see which regions are altered and in which regions you see amplification of oncogenes, the only three genes, the c-Myc, the N-2, and the COP-2 which have a function in breast cancer genetics. So we have over the whole genome large areas, which are amplified but only three genes show the function relevant. How are proto-oncogenes altered? There is one proto-oncogene, which is due to a new concept of therapy and antibody therapy in breast cancer, this is the OP2 oncogene, which can either be detected by amplification like FSH or the quantity of RTPCR, or you can use immunochemistry and by this you see on the surface the alteration of the copies. 

If we go to the tumor suppressor genes, the second largest group, you have gatekeepers and caretakers. What is a gatekeeper? A gatekeeper gives a direct regulation of tumor growth by either growth division or cell death. On the other hand, you have the caretakers, which offer incubation and indirectly promote tumor initiation by genetic instability or increased numbers of other mutational genes. How are the tumor suppressor genes working? It’s a very simple way, and if we think of a bicycle, everybody knows that normally a bicycle has a front brake and rear brake. If you have a heredity mutation, you’re born with only one brake either in the front or in the rear. If both of those brakes - the front and the rear - are gone, then you have no function of the gene. On the other hand, you have an alteration which is causing cancer and that is how a tumor suppressor gene works. We know from the heredity background that in obstetrics and gynecology there are five large areas and the main genes are the BRCA-1 and the BRCA-2 as we talked about yesterday. For those you have sequence and techniques to detect those mutations, and you see it on the lower right side here. This is how a normal sequence should look like. Here you see an alteration, which is a polymorphism and here you see a mutation. So you have the two things either loss of heterozygosity - you lose part of it or you have a mutation, and both are possible to alter the gene. You can see again if you go over the whole genome here, you see that these alterations peak up to 70% or up to 25% over the whole genome so we have a huge area of loss of genetic information, and we have a huge area of gain of genetic information and all this leads to breast cancer. Sometimes there’s also a complete loss of a chromosome as you see here in the detection of LOH for BRCA-1, which is located here and other genes. This is an LOH, you lose the information and you can see the whole chromosome actually got stripped and areas are gone by the LOH analysis. But the problem which we have working in the area is that, as I showed you, we have a huge number of losses but there’s only one tumor suppressor gene mutated in breast cancer and that is P53. All the other genes are not mutated and that makes it very difficult to understand how an oncogene and how, in this case, a tumor suppressor gene is working because it is not, as I told you, you lose one break or the way it got lost is not the way we think it has. So we see genetic variations but we cannot interrupt those genetic variations and there are tons of mechanisms that may inactivate tumor suppressor genes. 

We’re not going to get into this but you can see that the picture is very complex. That’s what we come up with at the end if you have worked for a long time; you have the normal epithelium, the cell proliferation, carcinoma in situ, the invasive carcinoma, and distant metastases. You see there are a lot of things working at different time points in the development of the invasive cancer, and as we heard from the previous talk about the hormone replacement therapy, and I’m always grateful when we talk on it prior to this talk, you see hormones and receptors only play a marginal role in the development of breast cancer. It’s actually all the others that also have the same importance as the hormones do. So how can we use what I’ve shown you now in a very brief way - the clinical use of breast cancer genetics? We use it in predictive genetic testing with high and low penetrant genes, we use it in selection of disease markers, which actually are used for making a decision for therapy and for specific disease related therapies. Predictive genetic testing is if a woman with 36 years comes with a mother with 39 years and a sister who died already with 61 years of breast cancer and arfs cannot get genetic testing. What is my lifetime breast cancer risk? You have to talk with her about prevention, early detection, and therapy. On the other hand, she asked for the invitation and you have to offer her genetic predictive testing. For low penetrance genes and that is the hardest thing which we have and this is we know some genes influence the development of breast cancer but not as a mutation BRCA-1 which have a lifetime risk of 80% for getting breast cancer which is tremendously high. We have some genetic polymorphisms which alter the lifetime risk only marginally but that makes the life even worse because we have it in a few areas like the sara-toma (serotonin) receptor area, carcinogenic areas, and other genes. If you go over the summary, you will see that there are five genes which have shown to alter the lifetime risk but the alterations, and as we heard about the interpretation of relative risk, is not that high but the question is if you have five or six of those low penetrant genes, what kind of risk do they bring at the end on the lifetime risk of the woman carrying those polymorphisms? For the prognostic factors, and that is the woman has breast cancer, what kind of factors can we detect in the cancer and what kind of conclusions can we take from those? You can see there’s a list, and when I went over it in MEDLINE in the Pub-MED, there were more than 260 different factors categorized but if we go to the International Meeting for ?Oncology for example, or the San Antonio Breast Conference, which will be next March in 2001, none of those prognostic factors has been included in the treatment of breast cancer. 

It remains with the old one like age, estrogen-progestin receptor, tumor size, lymph node status, and those things so they give us information but actually the information cannot be transmitted at present. The same thing is true for the predictor factors - factors that predict the outcome of a therapy, which we are applying to a patient with breast cancers. There’s a tremendous amount of markers for various therapeutic regiments but you see at present they’re not in the daily life of a physician treating a woman with breast cancer. If you come to the therapeutics, and you’ll see the slope gets even slower, there’s only one specific therapeutic agent at present and that is the new COP2 antibody which has been tested in women with metastatic breast cancer and an over expression, as I demonstrated earlier, of COP2. To my knowledge, this is the only specific breast cancer related therapy except for the antihormonal therapy. How can I summarize all of this, which is really a short ride through the breast cancer genetics that I told you? Breast cancer genetics started with Beatson in 1896, and from that time the development in scientific discoveries have tremendously been rising. You see this is the Roux Sarcoma virus, we have the oncogenes, tumor suppressor genes, strie-a-toma (serotonin?) receptors, and we go up BRCA-1, H&PCC’s, cell sac-ra-dition, and apoptosis. This is a scientific discovery but what do we have in the daily life in the clinics? You see the slope is much lower for the cancer diagnostics and prevention, and here you see we have the prognostic factors, I showed you already, not on the routine basis. We have the predictive factors and we have surrogate markers, which are used, for example, in mammography trials or other trials. If we come to the last point of cancer therapy, you see there are only two things - antihormones and the antibodies. So in summary, I think breast cancer genetics is a very complex system, a lot of factors have been influencing but I think in the end, if we meet here somewhere at 2030, probably these two slopes should be here and that slope should be on the same level. 

Thank you very much.”