Years of intensive research have enhanced our understanding of how tumors develop. First and foremost, we have learned that cancer is a genetic disease. Mutations in our own genes drive the development of cancer. These mutations alter the normal processes that help a cell regulate its fate. When these processes are disrupted, control is lost and tumor development is promoted. Second, we now understand that a cancer will arise only after several mutations occur in the same cell. One mutation is never sufficient, and multiple mutations are required to generate the full set of changes that make tumors aggressive. Third, we have learned that the number of different genes that can be mutated and contribute to all types of cancer is large. Certainly the number of genes involved in cancer overall will be in the hundreds; our current knowledge suggests that the number will not reach 1,000. These numbers are large, daunting perhaps, but not impossible to handle.
These three major discoveries explain the fundamental genetic basis of tumor development. Cancer is a disease caused by mutations in key target genes that give selective advantage to the growth of the tumor cell. The accumulated mutations allow the cells to grow out of control. They divide, obstruct, invade, and destroy normal tissue architecture. Through the accumulation of genetic changes, these cells acquire properties that allow them to escape the normal biological defenses and controls and, in turn, pose a life-threatening problem to the individual in whom they live.
The most direct and ultimately the most effective approach to preventing, detecting, diagnosing, and treating cancer is to learn the properties of the responsible genes. Recent advances in our understanding of human genetics have provided an important new opportunity to identify cancer genes through studies of cancer-prone families. This approach unlocks vast potential to expand our knowledge of the origins of cancer, to develop new ways to detect a tumor in an early stage, and to identify new targets for cancer therapies. With this opportunity, however, comes an important social responsibility to provide effective and helpful genetic counseling. Our plan to develop cancer genetics opens this area to scientific discovery, medical application, and social responsibility.
1. Identify every major human gene that predisposes people to cancer.
2. Use this information to transform medical practice.
3. Identify and solve psychosocial, ethical, and legal issues associated with cancer genetics.
Recent discoveries have ushered in a new era in cancer research. We have long known that it is important to identify risks that predict an individual's likelihood of developing a particular cancer and have even longer recognized that cancer may "run in families." Now we are at the threshold of being able to identify in cancer-prone families the specific genes that predict an individual's risk of cancer.
The scientific literature demonstrates that the most successful approach to identifying human "cancer genes" (genes whose alterations predispose to cancer) has been to use the tools of human genetics. Even the earliest writings of the Greeks and Romans contain clear references to families in which the chance of developing cancer is passed from one generation to the next. The modern day outcome of this early realization is becoming one of the most important weapons in our arsenal to attack human cancer. On the order of 5 to 10 percent of all cancers in the United States occur in individuals who have inherited a mutation that predisposes to cancer. Thus, several million Americans carry such inherited predispositions. The likelihood that a tumor will develop can be predicted by the rules of heredity. Just as eye color is determined by genes inherited from one's parents, in cancer-prone families the chance of developing a tumor is passed from one generation to the next.
Tracing these patterns of inheritance has provided an important method for studying cancer. The patterns of inheritance have given scientists the molecular signposts that identify where to look for cancer genes. Although still in its early stages, this approach has allowed us to identify approximately 20 new cancer genes. Even with this small number, it is clear that this is a powerful approach. By studying families at risk, we can gather the clues that will lead to identification of the culprit gene.
Identifying the first few inherited cancer genes produced an unexpected finding that promises an even broader and deeper impact. Surprisingly, these genes also have been remarkably informative about cancers that appear in individuals with no family history. Scientists have learned that the same genes that predispose members of cancer-prone families to disease quite often also contribute to the development of cancers in individuals with no family history. We now realize that there aren't two different sets of cancer genes, one group for inherited predisposition and one for sporadic tumor development. The mutations that drive inherited predisposition are at least a subset of the ones that spur all human tumor development.
These revelations in cancer genetics have convinced us that this area is an under-explored gold mine. They also have provided an important lesson: Use the rare predisposition genes to learn more about common cancers. This lesson is a guidepost for future research, and the cancer genetics initiative proposes a plan to exploit this lesson.
The opportunities afforded by advances in cancer genetics also raise enormous challenges. What are the psychological, social, family, and medical consequences of being able to determine inherited susceptibility to cancer? The cancer genetics investment initiative must also address these issues to ensure that individuals are helped, not harmed, by personal genetic knowledge.
To capitalize on these unprecedented opportunities and to address the diverse challenges in cancer genetics, support is needed for new activities in five areas.
* We need to support the identification of high-risk families and the infrastructure required to identify and characterize cancer predisposition genes.
* We need to support the development of accessible and reliable diagnostic tests for alterations in these genes.
* We need to provide greatly increased resources to support clinical research and trials to answer the key questions about inherited mutations in these genes, including:
* The enormous impact of genetics in oncology requires support for education and training. Educational materials aimed at the public, physicians and other health care providers and payers are needed. A new medical work force with expertise in genetics and counseling is required.
* Successfully dealing with these challenges will involve generating and analyzing enormous amounts of data about dozens of genes and hundreds of alterations in each gene plus correlating each of these alterations with clinical outcomes. Therefore, the fifth area of the cancer genetics initiative is to develop an informatics system to collect, store, analyze, and integrate molecular data with epidemiologic and clinical data. Only a usable informatics infrastructure will allow progress to affect all aspects of cancer research. For example, as new families that suffer a predisposition to cancer are identified, the properties of their disease need to be passed to the researchers who will map the gene. Basic researchers' discoveries about how a tumor develops must be passed on to those who treat and counsel cancer-prone families. The latest developments in genetic mapping need to be converted into useful genetic tests. These critical information needs demand a new level of exchange that can only be achieved through coordinated efforts.
Together, these five areas of the cancer
genetics initiative provide a unique opportunity to attack the cancer problem
at its core with speed, coordinated effort, and insight. Without a national
effort in this area, opportunities for key scientific advances will be lost,
cancer care advances will be slowed, and critical attention to difficult
psychosocial and societal issues will be delayed.
Unquestionably, the era of genetic medicine is upon us. The plan outlined above is designed to complete the identification of all major cancer susceptibility genes within five years and to prepare our Nation and its health system to deal with the challenges of this new aspect of medicine. The consequences of not establishing a national cancer genetics plan are dire. In the absence of this investment, we will not be able to respond to the desire of individuals to know whether they are at increased risk for cancer due to an inherited predisposition. Without this investment, we may be unprepared for the ethical, legal, and other challenges associated with testing. Without this investment, we will be unable to rapidly answer the questions health care providers and individuals will have about what to do with this potent information. Without this added investment, we will be unable to offer the opportunity to participate in important clinical trials and to offer careful counseling to millions of Americans who will seek counseling and answers. Finally, without this added investment, we will not be able to utilize fully and rapidly the advances in cancer genetics to improve our understanding of and approach to all cancers.
Missing this opportunity will slow the pace of basic and clinical research, and many patients who could have been helped will not be. Ultimately, we will have missed opportunities for prevention and treatment. We will have lost the opportunity to provide leadership in addressing the fundamental societal issues that accompany genetic testing. We are quickly approaching an era when genetic testing will be available. By establishing a clear, integrated plan, we will be able to prepare for its arrival and manage its growth and development responsibly and ethically. The cancer genetics initiative provides a plan to capture the advantages of this new opportunity.
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