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2001 Meet the Expert: The Human Genome and Its Implications for Cancer
Introduction
All diseases, including cancer, have a genetic component that is either inherited or results from the body's response to environmental stresses like smoking, radiation, viruses, or toxins. The Human Genome Project (HGP) is enabling researchers to pinpoint mutations in genes that cause or contribute to disease, and search for new genes involved in disease.
The ultimate goal is to use this information to develop new ways to treat, cure or prevent disease. The main focus of the HGP is to identify all of the genes in human DNA and determine the sequence of the entire human genome (the genetic blueprint of all human beings).
Understanding the human genome promises to revolutionize the practice of medicine. Many questions are being raised about the impact it will have on people with cancer, as well as those at high risk for the disease. Will this breakthrough lead to new approaches in the diagnosis and treatment of cancer? How will cancer researchers use this information? What are the legal and ethical issues that arise from obtaining genetic information?
To answer these questions, the American Society of Clinical Oncology (ASCO) gathered some of the country's leading experts in cancer genetics together for a Meet the Expert session on cancer and genetics. The session, held in November 2000 in New York, covered topics ranging from how knowledge of the human genome is changing the scope of cancer care and research to ethical, legal, and social implications surrounding this issue.
This issue of Cancer Advances presents highlights from the session.
For more information on the Genetics and Cancer event, see the following original fact sheets.
Speakers
Larry Norton, MD,
ASCO President
Ken Offit, MD, MPH
Michel Sadelain, MD, PhD
Memorial Sloan-Kettering Cancer Center
Olufunmilayo Olopade, MBBS
Melody White, MS
University of Chicago
Sridhar Ramaswamy, MD, PhD
Whitehead Institute/MIT Center for Genomic Research
Judy Garber, MD, MPH
Dana Farber Cancer Center
Jeffrey Weitzel, MD
City of Hope Comprehensive Cancer Center
Frank Haluska, MD, PhD
Massachusetts General Hospital
Kathy Hudson, PhD
National Human Genome Research Institute
Susan Scherr
National Coalition for Cancer Survivorship
Lawrence Einhorn, MD
ASCO Immediate Past President
Indiana University Medical Center
William Gradishar, MD
Chair, ASCO Cancer Communications Committee
Northwestern University Medical Center
The Magnitude of the Human Genome
Cancer Genetics
"Cancer arises from genetic alterations, it doesn't start overnight, and it's a multi-step process," said Olufunmilayo Olopade, MBBS, Associate Professor of Medicine and Director of the Center for Clinical Cancer Genetics at the University of Chicago Medical Center.
"We know that about five to 10 percent of cancers are hereditary, and we can identify those individuals with a predisposition. What we hope will come out of the genome project is predictive tests to identify cancer, diagnostic tests to detect cancer in its earliest stages, prognostic tests to determine course of disease, and therapies that target gene abnormalities in cancer cells."
Inheritance can also contribute to the development of cancer, even when a singular inherited genetic mutation is not present. For example, certain inherited characteristics that are controlled by multiple genes such as light skin and red hair, may put an individual at increased risk for developing skin cancer. These polymorphisms (the difference in DNA sequence among individuals) can contribute to an individual's or family's risk for developing cancer.
Environmental influences still account for the majority of cancers and may influence whether or not someone with an inherited predisposition actually develops cancer. As scientists continue to decode the human genome, researchers hope to learn more about the roles singular and multiple genes, and inheritance, play in cancer.
"We have an opportunity to make a difference, because if you could just identify those individuals who are born predisposed and learn the pathway that's going to get them to developing cancer, we might, in fact, be able to cure these individuals of their predisposition to cancer," said Dr.Olopade.
"We have to use the technology very carefully, and we should not make recommendations that are irreversible based on gene changes," she cautioned. She added that educating physicians and patients about what genetics can and cannot tell them is vitally important.
The Benefits of Genetic Analysis
According to Sridhar Ramaswamy, MD, PhD, a Research Fellow at the Whitehead Institute of Biomedical Research, the work being done today in cancer genetics is leading to a molecular understanding of predisposition. "If mutations drive the cancer process, then looking at those mutations at the DNA level would be very useful for talking about things like predisposition and, in addition, might be very useful in individuals who develop cancer for determining exactly what those changes are and maybe directing therapies to those changes."
He noted that the production of so-called DNA chips has revolutionized the analysis of gene expression in cancer; current technology allows researchers to measure up to 60,000 genes simultaneously from a given tumor. He added that another study that might be done, in addition to classical pathological analysis, is a DNA chip analysis using the computation tools that he and others are developing. This would enable physicians to determine the exact entity they're dealing with and to devise a treatment plan based not only on a gross subjective type of analysis but, rather, on the genetics of the actual cancer that a person has.
"That's a very exciting prospect, because it allows us to make some analyses and interpretations of what is happening once one accumulates these genetic alterations at a DNA level, what is happening at the RNA level, and points us towards both potential diagnostic, as well as therapeutic, targets," said Dr. Ramaswamy.
The analysis of such massive amounts of information is quite daunting, he added. "The challenge for us has been to work at the interface of biology, medicine, and computer science, and to try to use the tools that are available in computer science to analyze large amounts of data from biological experiments and medical samples, and hopefully arrive at some treatments.
Treatment Strategies
Researchers are optimistic that an increased understanding of the human genome will help enhance the effectiveness of current treatment strategies and eventually lead to the development of new treatment options. However, these treatments could take years or even decades to develop.
One such option is gene therapy, according to Michel Sadelain, MD, PhD, Head of the Gene Transfer and Gene Expression Laboratory and Director of the Gene Transfer and Somatic Cell Engineering Facility at Memorial Sloan-Kettering Cancer Center. "Gene therapy enjoys a very unique relationship to the Human Genome Project because, whereas in most forms of therapies, gene products, may they be RNA or the proteins that are coded by the gene, are the targets for therapy. In gene therapy, the gene itself may be a drug," he said.
The key to successful therapies is to have an approach that is effective and yet not toxic, noted Dr. Sadelain. "Genetic approaches hold that promise in delivering a specific gene, either the normal gene or a modified gene, to cells," he said.
A number of strategies are under consideration today. Some of them make use of gene transfer in the tumor cells themselves, and other approaches are based on transfer into a patient's normal cells. Dr. Sadelain said genetic approaches could also be used to introduce genes into normal cells to protect them from the side effects of chemotherapy.
QUICK FACTS
Gene Therapy - Gene therapy seeks to stop cancer growth through a number of different strategies. Some of these strategies aim to eliminate tumor cells either by enhancing targeted delivery of toxic drugs or by partially correcting the genetic defects that characterize a given tumor. Other strategies aim to genetically alter cells other than the tumor cells in order to promote tumor destruction by the immune system (immunotherapy), prevent tumor progression (antiangiogenic therapy) or limit toxic side effects caused by conventional therapies (chemoprevention using drug resistance genes).
- To initiate gene therapy, physicians must deliver healthy genes to either cancer cells or patient cells that play a role in tumor progression or tumor rejection. Modified (or recombinant) viruses, such as retroviruses and adenoviruses, are commonly used as delivery systems or vectors. Plasmid (non-viral) DNA is used in some applications.
- Finding successful delivery systems for introducing enough modified genes into the body to stop the spread of cancer, without affecting healthy cells, is the biggest challenge facing researchers in the field of gene therapy.
- Researchers are currently working to identify genes that interact with nontoxic antiviral drugs and become highly targeted to kill only cancer cells.
Targeted Therapies - Pharmacogenomics holds the promise that drugs may one day be tailor-made and adapted to each person's genetic makeup, ensuring that individuals receive the most effective treatment. For example, cancer patients facing chemotherapy could receive a genetic fingerprint of their tumor that would predict which drugs are most likely to be effective, leading to fewer treatment-related side effects and improved prognoses.
- In a step towards tailoring treatments based on genetic analysis, scientists recently discovered a gene that, when active, prevents some patients with brain cancer from responding to certain cancer drugs. The gene, MGMT, is a DNA repair gene. Normally, it would function to prevent the DNA damage which causes cancer—but when it remains active in tumors, the MGMT gene seems to repair drug-induced DNA damage in cancer cells, preventing effective treatment. MGMT is active in over half of brain cancer patients, and this gene alteration has been detected in other tumors such as lung, colon and tumors that originate from lymph nodes.
- Molecular analysis of tumors may lead to more reliable assessments about the course of a disease. By examining the genes in each tumor, physicians will be able to distinguish a patient with an aggressive type of cancer from one whose disease may progress more slowly.
- Patients who are given a more accurate disease prognosis will be able to make informed decisions about their treatment regimen. For example, a patient with a good prognosis early stage cancer might want to take a "wait and see" approach before undergoing aggressive therapies that may have significant side effects.
Ethical, Legal and Social Issues
A Patient's Perspective
Susan Scherr, Director of Programs for the National Coalition for Cancer Survivorship, is a cancer survivor and patient advocate who has undergone genetic testing. She related her experience at the Meet the Expert event.
There are over 700 genetic tests currently available. There will probably be thousands more very soon. You may be tested but there may be nothing that you can do for the disease. You may find out that you have a rare disease. What is that knowledge going to do to you, and how are you going to be told?
In an effort to learn more, I decided to take part in a genetic test and clinical trial. In my early 30s, I was diagnosed with breast cancer. I did everything I was supposed to do. I found out as much information as I possibly could, made my five-year anniversary, made my 10-year anniversary, thought, 'Wow, I'm home free, I don't have to deal with cancer anymore.' In my 11th year, at my office, I fainted, was taken to the hospital, was told that I had uterine sarcoma and very little chance of survival. That was 12 years ago.
I felt that I was probably a very good candidate to take part in clinical trial. I had had uterine cancer and a sarcoma. I had breast cancer at a very young age. My mother had been diagnosed in her late 70s. And maybe the most important, both my children are adopted. I felt that I would not be jeopardizing or putting them at risk in any way if I consulted to be tested. So I did. I took part in the clinical trial, did it as a professional, really didn't do it as the individual or as a member of my own immediate family. I did it so I would be better educated and better able to articulate what the problems were and what the process was.
But the reality was that I was absolutely shocked when I tested positive; when I heard what my risk was for still additional cancers, I was devastated. I was able to say there needs to be more counseling and support, and psychological handholding through this process, before, during and after.
It had a positive effect on me. It has a positive effect on a number of people. It's a personal choice for everyone. Women choose to have prophylactic mastectomies, they choose to have oophorectomies. I have lost a breast already. I've had a complete hysterectomy, so that doesn't apply to me. I chose not to have my other breast removed.
I informed all my doctors, and told my internist not to put it in my medical records. Instead of going once a year, now I see a doctor every three or four months.
One of the most important things to come out of this too is that if people can look at their family trees, whether they decide to be tested or not, they can make behavioral or preventive changes. What a marvelous and instructive and important and life-enhancing thing that would be.
Genetic Counseling
Genetic counseling helps an at-risk person or family understand the medical facts and available cancer risk management options. Genetic counselors are on the front lines in terms of explaining human genetics to individuals, often at the most difficult part of their lives, when they have to make actual decisions related to their own genes and their own health.
"Genetic counselors are advocates for genetic privacy, confidentiality and for legal protection against genetic discrimination," said Melody White, MS, a genetic counselor in the Cancer Risk Program at the University of Chicago Medical Center. "Genetic counseling is essential for appropriate and responsible dissemination of information available through the successful completion of the Human Genome Project."
The process begins with the construction of a three-generation family tree. "Based on assessing that family tree, we can provide an estimate of the risk for cancer for an individual, in addition to using the variety of risk assessment models," she explained.
Genetic counselors are trained to talk about complex psychosocial issues both before and after testing. They are also responsible for ordering and interpreting genetic tests, and helping eligible patients get into clinical trials. Before undergoing genetic testing, it's essential that patients undergo the informed consent process, a thorough discussion of the risks, benefits and limitations of genetic testing.
It is important to note that a genetic test result does not always provide new information or information a patient can utilize. "This is especially true if we don't have a previously identified mutation in the family and an individual tests negative," White said. "It's also possible to identify a mutation of unknown clinical significance, which means that it could be a normal variation in the family, or it could be associated with the disease in question."
Because tests are not 100 percent able to detect some genetic changes, genetic counselors also explore the accuracy of the tests with patients. "There are definitely effects of even having a negative test result that need to be explored with patients, especially in light of potential for other family members to be tested positive," she added. Genetic counselors also address the psychological consequences of a positive or negative test result and how that may affect family dynamics.
Predictive testing offers individuals an opportunity for intervention and prevention, basically to improve upon their cancer risk management, White said. "We can make lifestyle recommendations with regard to diet and exercise. Certainly this can be done anyway, but it may propel them to make some changes."
Test results can relieve uncertainty and anxiety, whether the result is positive or negative, because if patients are having genetic testing, many times they're concerned and have been anxious about their cancer risk for a long time.
It's important to remember that genetic susceptibility testing is not a screening test meant for the general population. "Only 10 percent of all cancer is due to a hereditary susceptibility, so it's really not appropriate to be offering this type of screening to the general population," said White. "It's potentially a very important component, but it's one component of a comprehensive cancer risk management plan."
Protecting Medical Privacy
As genetic research continues to unearth new information and knowledge about disease, many ethical, legal and social issues have surfaced. These issues are complex, and span many areas, including genetic testing, privacy and confidentiality, discrimination, public and physician education, access to genetic testing, genetic information legislation, and the psychological and social distress that patients may experience after learning their genetic makeup.
According to Kathy Hudson, PhD, Director of Policy and Public Affairs at the National Human Genome Research Institute, one reason people decide not to participate in genetic research testing is because of their concern about who will have access to their genetic information and how that information will be used. "Our goal is that in the very short term, we can enable genetic counselors and physicians to be able to tell their patients unequivocally that there is no risk that their insurers or employers will be able to use their genetic information to deny them insurance coverage or a job."
In 1996,Congress took an important step to prohibit genetic discrimination in health insurance in the form of a law called the Health Insurance Portability and Accountability Act (HIPAA). The law prohibits insurers in the group health insurance market from using health-related factors, including genetic information, to deny coverage or make enrollment decisions. It also specifically addresses genetics in stating that genetic information without a diagnosis may not be considered a pre-existing condition.
Dr. Hudson noted that HIPAA does not cover the individual health insurance market, and it places no protections on the collection or disclosure of genetic information. There are movements in Congress and also at the state level to fill these gaps in the law.
The definition that has been proposed for genetic information is that protected genetic information should include information from genetic tests, information about family members' genetic tests, and information about the occurrence of a disease or a disorder in family members.
Dr. Hudson addressed the issue of workplace discrimination. "Our basic principles of fairness dictate that decisions about a person's ability to do a job should be based on just that—the person's ability to do the job," she said. "This principle is embodied in a federal law called the Americans with Disabilities Act (ADA), which says that employers may not discriminate against people even if they are disabled, so long as they are able to do the job."
People are legitimately concerned that even if genetic information will not be used for social or economic harm, they're still interested in controlling access to their genetic information, she said. A key issue is whether genetic information should be afforded a higher standard of privacy than other health information. "The precedent here is that a number of states have special statutes that protect HIV information, mental health information, and drug abuse information. Those states perceive that this information is potentially more sensitive and more stigmatizing than other kinds of health information."
Dr. Hudson believes genetic information and all health information should be afforded the same very high levels of privacy protection; it would be unworkable and unwise, she said, to have different levels of privacy protections for different kinds of health information.
Ethical and Legal Questions
"In our field, we get very close to the families, not only the patients, because of this extraordinary endeavor," said Ken Offit, MD, MPH, Chief of the Clinical Genetics Service at Memorial Sloan-Kettering Cancer Center. "I've spent a lot of time going out into the community to try to make the point that this is an extraordinary opportunity for cancer prevention that we have in front of us."
Dr. Offit noted that there has been an explosion of information since the 1990s. "We're beginning now to actually believe that we may be showing some first evidence of lives saved because of the genetic testing that we’re doing," he said. "The translation of 21st century genetics and old-fashioned surgery is the first application of this genetics revolution."
Dr. Offit discussed the issue of an individual's right to know his or her genotype. "One of the basic rules of bioethics is that the individual decides whether he or she wants to know this information," he said. "When you get into testing, you can have situations which may not always be simple to sort out."
He raised a number of important questions surrounding this issue. "What happens when you've actually gone ahead and tested an individual and you don't have contact with all of the family members? What are the obligations now that you have? Do you respect autonomy of these individuals, of family members who may be in the position of guardianship of next of kin, or do you actually have a duty to break into the family relationship and to warn individuals? The duty to warn is one of the challenges in front of us."
QUICK FACTS
Genetic Testing- Genetic testing is the analysis of human DNA, RNA, chromosomes, and proteins to predict risk of disease, identify carriers of disease, and establish clinical diagnosis or prognosis.
- Genetic testing for cancer risk is "predictive testing" — the probability that an individual will develop the disease in their lifetime. For example, a woman with a 75 percent chance of developing a breast cancer may remain healthy throughout her life, while a woman with only 25 percent probability of breast cancer may develop the disease.
- Oncologists recommend genetic testing only to individuals who are at high risk of carrying an inherited genetic mutation. Factors that signal that a person may be at risk include:
- family history of cancer — three or more relatives on the same side of the family with the same or related forms of cancer
- early onset — two or more relatives diagnosed with cancer at early age
- multiple sites — two or more cancers occurring in the same relative
From Research to Treatment — How the Human Genome is Changing the Scope of Cancer Care
Colorectal Cancer
"Focusing on the family history element of this, if you have no family member with colon cancer, everybody still has some risks," said Jeffrey Weitzel, MD, Director of the Department of Clinical Cancer Genetics at City of Hope Comprehensive Cancer Center.
"There are the environmental elements. But, if you have one first degree and two second degree relatives, or ever-earlier age multiple family members, your risk for colon cancer is elevated," he said. "When you get to the syndromes, the risk is dramatic. The point is that family history matters."
Inherited mutations may contribute to a third of all colon cancer cases, according to Dr. Weitzel. There are two forms of inherited colon cancer that account for some, but not all, of thosecases: familial adenomatous polyposis (FAP) and hereditary non-polyposis colon cancer (HNPCC), also known as Lynch Syndrome.
"From the molecular standpoint, it wasn't until 1985 that we had our first clue where the gene for familial polyposis resided," he noted. "One of the first genes of the tumor suppressor era to be cloned was the adenomatous polyposis coli gene, sequenced in 1990." This meant that researchers could start identifying people who carried the genes. "It's gone on to show us multiple other important things," he said. "As we could identify the carriers by virtue of their genetics, we could identify that there were different phenotypes, different pictures associated with different mutations in the same gene."
With FAP, the risk for colon cancer is virtually 100 percent if the condition is not treated, said Dr. Weitzel. Genetic testing can identify most carriers, and endoscopic surveillance and prophylactic colectomy can improve survival in at-risk patients.
"Probably just as importantly, and this is where genetic counseling and testing comes in too, is that whereas before we've always recognized the syndrome, we can now identify who is actually at risk and spare them from further scrutiny."
The other syndrome relevant in colon cancer genetics today is HNPCC. When there is strong suspicion of HNPCC, mutation analysis is the next step. "If mutation analysis is positive, it tells us to do colon surveillance, at the least. If it's negative, we go back to other techniques to try and see if we should still do colon surveillance, even though we couldn't find the mutation," Dr. Weitzel said.
He added that physicians pay close attention to these individuals, and begin screening at a much earlier age. With close surveillance, there is less cancer in these families, because polyps are removed before they have the chance to become cancerous.
Melanoma
The role of genetics in the development of melanoma is prominent, but still being explored. There are several types of inherited predisposition. First, people with certain inherited traits, including those with fair skin, who burn but do not tan, and have freckles, blue eyes and red hair, are all at increased risk for developing melanoma. Although this predisposition is genetically controlled, it is not fully understood. Second, there is a syndrome of inherited dysplastic (clinically abnormal) moles that also predispose individuals to a very high risk of melanoma. This, too, is a genetic disease, but the genes controlling it have yet to be identified.
Several genes that do cause inherited melanoma have been identified. These genetic conditions clearly interact with the environment, and in particular with sunlight exposure, to cause melanoma.
"Inherited predisposition for melanoma accounts for approximately five percent of all melanoma," said Frank Haluska, MD, PhD, Director of Melanoma Research at Massachusetts General Hospital. "About 10 to 15 percent of patients with melanoma actually have a family history; a lot of this is from shared environmental risk."
Dr. Haluska said researchers have a very good model for how tumors respond to therapy. "Instead of doing largescale clinical trials on human beings with cancer agents, we can save a lot of time by treating colonies of mice, where we can model their cancers that have the exact same genetic alterations that the human cancers have. This is a direction that is going to be important, a clear-cut outflow of our genetic understanding of the basis of melanoma and other cancers."
There are other implications for genetic findings, including prognosis and treatment, and gene therapy. "Prognosis is very important for the melanoma patient," said Dr. Haluska. "We know a lot about how well a melanoma patient will do because of how thick their melanoma is. But we'd like to find genes that also control this."
Although scientists have some understanding of the genetic mutations in melanoma, they are just beginning to apply this understanding to determine prognosis. Researchers have found patterns of gene expression that distinguish aggressively malignant melanoma from tumors that are less likely to metastasize. Early studies of the Melastatin gene demonstrate that melanoma tumors that stop making Melastatin are more likely to spread. If these results are confirmed, Melastatin and similar genes may be used to predict which patients may benefit from aggressive early treatment.
Dr. Haluska noted that the immune system sometimes makes melanoma disappear. "Through genetic techniques, we've been able to identify what the targets are of the immune system when this happens," he said. "Some of them have been cloned out, put into viruses and used in genetic therapies. Two of these are proteins that are on melanoma and on melanocytic cells in normal skin. We know that we can immunize patients against this."
"Using genetic techniques and gene therapy approaches, we're beginning to be able to see evidence that we can help the immune system recognize melanoma, and hopefully this will have therapeutic, positive implications for the patient," he concluded.
Breast Cancer
Scientists believe that approximately five to 10 percent of all breast cancer cases are caused by inherited mutations in strong predisposition genes. The most common cancer susceptibility genes that have been identified are known as BRCA1 and BRCA2. Women with a BRCA1 or BRCA2 mutation have an estimated 50 to 85 percent lifetime risk of developing breast cancer, compared with a 12 percent lifetime risk for women in the general population. Scientists are continuing to search for other breast cancer susceptibility genes as well.
BRCA1 and BRCA2 genes are also linked to ovarian cancer. Women with these mutations have a 10 to 40 percent lifetime risk of developing ovarian cancer, compared to a 1.7 percent risk among other women. Men with BRCA1 mutations are at increased risk for developing prostate cancer and for passing the inherited mutation on to their children. Men with BRCA2 mutations are at risk for breast, prostate and other cancers.
"There is part of the paradigm that I think we'll see played out many times in thinking about hereditary diseases, which is it's not only the genes," said Judy Garber, MD, MPH, Attending Physician at the Breast Evaluation Center and Associate Physician at Brigham and Women's Hospital, and Associate Professor of Medicine at Harvard University.
"The main problem in breast cancer genetics is that even though we've spent almost the last 10 years—BRCA1 was mapped in 1990—we still are missing a huge group of genes," said Dr. Garber. "Unfortunately, we find many families who are not accounted for by just BRCA1 and BRCA2. It is not usually a good idea to test unaffected women when you don't know the mutation in the family—there are too many you can miss," she explained. "Once you know where the mutation is, you know where to look—it's either there or it's not."
Genetic testing can identify women who may have inherited mutations in BRCA1 and BRCA2 genes. The identification of these genes has made a real difference for patients; women who carry mutations may begin intensive surveillance programs, and may start getting clinical breast exams and mammograms earlier than women in the general population. Breast MRI and ultrasound are also being evaluated as possible screening methods because of concerns about decreased sensitivity of mammograms in young women.
For More Information
ASCO Informational Video: Cancer and Genetics
A 60-minute videotape featuring highlights from ASCO's Meet the Expert session is now available. To order a copy of "Cancer and Genetics," or for more information, please contact ASCO's Communications Department at 703-299-1014.
Also see our Genetic Testing section and original fact sheets for more information.
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