Genetic testing may prevent hereditary nonpolyposis colorectal cancer ...

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Hamilton Fairley Lecture, held at the ESMO Congress, Vienna, November 2-5, 1996. A. de la ..... professors are responsible for the planning and execu-.
Annals of Oncology 7: 883-885, 1996. © 1996 Kluwer Academic Publishers. Printed in the Netherlands.

Special article Genetic testing may prevent hereditary nonpolyposis colorectal cancer Hamilton Fairley Lecture, held at the ESMO Congress, Vienna, November 2-5, 1996

A. de la Chapelle Department of Medical Genetics, University of Helsinki, Helsinki, Finland

Key words: counseling, genetic testing, hereditary colon cancer, prevention

Introduction

A breakthrough in colorectal cancer

The media and the medical literature are bursting with A real breakthrough has taken place in the identinew research achievements. The present time is the fication, prevention and treatment of hereditary cologolden age of genetic research and new disease causing rectal cancer. There are two main types of susceptibility genes are cloned almost every week. Understandably, to hereditary colon cancer, polypotic and non-polypothe new discoveries are evoking hopes for new methods tic. The former is known as Familial Adenomatous Poof treatment and prevention - preferably very rapidly. lyposis (FAP) with an incidence of about 1:10,000 and Many papers about new disease genes end with the for which traditional prevention methods exist. Since phrase that the discovery is the first step towards an gene diagnostics have not brought anything radically efficient treatment and prevention of the disease. Is the new to the treatment of FAP, it will not be discussed reality actually that bright? further in this paper. The most common name of the The expectations have not been fulfilled. With a few non-polypotic form of the disease is Hereditary Nonrare exceptions, the cloning and identification of dis- polyposis Colorectal Cancer or HNPCC. For a review, ease genes has not yet led to the development of spe- see [1]. The name is misleading because only about cific drugs. However, this is not particularly surprising two-thirds of the tumors of the susceptible patients are because it is a well-known fact that the development of colorectal; the other organs with cancer susceptibility a new drug, to a marketable product, will take at least are e.g., the endometrium, ovaries, stomach and small 8-10 years even after the basic concept is laid down. intestine. A better name for the disease might be Lynch Fortunately, the development is faster in the case of syndrome after the American cancer researcher Henry diagnostics. Usually the cloning of a disease gene Lynch. Finland, with a population of 5 million, has a quickly leads to more accurate diagnostics. In diseases relatively low incidence of colorectal cancer. In this with Mendelian inheritance, the gene tests are accurate population more than 1800 people are diagnosed yearand reliable, can be made before the appearance of ly with colorectal cancer. The greater part of the cases symptoms, and even allow the screening of large num- are 'sporadic' but some are hereditary. According to an bers of people. Clearly, there is one group of individ- unconfirmed estimate, approximately 5% (90 cases) uals that immediately benefit from genetic testing: are caused by hereditary gene mutations. Many other those who are found not to carry the defect. Regret- western countries have higher incidences of colorectal tably, the detection of a gene defect often does not cancer. For example, in the United States some bring immediate benefit, at least not in a way that 160,000 new cases of colorectal cancer are diagnosed would affect the prognosis of the patient. This is the annually. If 5% were found to be HNPCC, then an case in Huntington disease which is often given as an astounding 8000 new HNPCC families could be diagexample; a disease with adult age onset and for which nosed each year. no cure or prevention methods are currently available. In contrast, cancer patients have immediate benefits because the cancer can be more effectively treated, Susceptibility genes even after onset, and the earlier the treatment is started the better the prognosis. For example, in retinoblas- How would gene testing facilitate the treatment and toma families prenatal or early postnatal genetic testing prevention of HNPCC? The hereditary susceptibility is can provide a tool for well-focused clinical surveillance caused by mutations in genes belonging to the mutator gene family [2]. Under normal conditions the proteins of infants at high risk.

884 produced by these genes identify and repair short mismatch defects during DNA replication. When the repair function is deficient, the cell accumulates numerous defects. As a result many functions of the cell are affected when the respective genes are either inactivated or hyperactive. This is precisely the way cancer arises. Inherited ('germline') defects of imitator or DNA mismatch repair genes cause the HNPCC syndrome, i.e., susceptibility to colon and other types of cancer. The susceptibility penetrance is very strong because cancer occurs in some 90% of the carriers of these gene defects. The age at diagnosis of the first cancer is approximately 42 years (in sporadic colon cancer it is approximately 70 years). The adult onset of the disease indicates how long it takes before multiple mutations accumulate in the developing clone. Among the mutator genes so far identified, two are more important than the others for cancer susceptibility. Defects in either MLH1 or MSH2 are found in at least 70% of the typical HNPCC-families [3]. The gene test In practice the procedure is as follows: A search for mutations of the MLH1 and MSH2 genes is performed when there is a reason to suspect HNPCC on the basis of the patient's family history, age, or the location or behavior of the tumor or for other reasons. This is the most demanding part of the laboratory work because the mutation can occur in any part of the gene and there is no easy way to determine in which one of the genes the defect is located. However, to develop a diagnostic method for the patients and family members, the gene defect must be unequivocally identified on the DNA level in at least one member of the family. After this demanding phase, it is usually possible to design a simple PCR-based test to detect the same mutation in other members of the family.

Legal and ethical issues

The predictive gene testing generates a number of ethical-moral-economic questions. Do people want to know whether they possess a gene defect causing a predisiposition to a severe disease? In Huntington disease, for which no prevention or cure is available, testing may create more problems than advantages [4] and many people do not wish to take the test. In contrast, an overwhelming majority of the Finnish HNPCC family members want diagnostics apparently because the disease can be prevented and treated (as mentioned later). Do parents have the right to request the test for their child? Should the diagnostics requested by an individual be done if it would indirectly also reveal the situation of a relative who himself would not like to know? These kinds of problems have been known in connection with Huntington disease. However, it has been empirically established that most members of HNPCC families at least in Finland, USA and New Zealand wish to have diagnostics. They also usually request the testing of children (which is not recommended). Could gene testing lead to discrimination in work life or cause insurance problems? These risks exist but should be avoidable by legislation. Dr. Risto Pelkonen, a prominent Finnish academic and insurance physician has proposed that the Finnish insurance companies should not ask their clients for the results of gene diagnostics. Nowhere in the world have insurance companies demanded DNA-analyses as a condition for granting insurance but in some countries the insurance companies can demand the results of gene diagnostics if the client knows about them and the amount of the insurance is high. The situation can deteriorate if gene testing becomes common, commercialized and available to everyone. Counseling

Scope In the Finnish population about 100 HNPCC-families are presently known, comprising 300 living cancer patients and more than 1000 healthy adults whose calculatory risk to be a carrier of the gene defect is 50%. In addition, there are many family members whose calculatory risk is smaller than this, e.g., 25% as well as more than 1000 children who have similar risk figures. If the share of HNPCC of all colorectal cancers is about 5%, then approximately 90 of the annual 1800 new colorectal cancer patients have HNPCC and part of these represent new, not previously identified cancer families. If the diagnostics were 100% accurate then this would mean that every year tens of new HNPCC families would be diagnosed, so theoretically, in Finland after five years several thousand healthy people, whose risk to be a gene carrier is 50%, would be identified. These people should be offered access to gene testing.

Counseling and information are essential in gene diagnostics. Counseling starts with a discussion of basic facts so that the client is able to rationally decide the meaning and necessity of gene diagnostics and whether he/she wants it or not After a test has been performed and the results disclosed, the client needs more counseling help and support. In specific counseling sessions, directed only to identified gene carriers, prevention and treatment must be discussed and planned and additional psychological support given. At least one counseling session must be with an MD clinical geneticist, and one with a gastroenterologist. In most countries there is a lack of genetic counselors and these professionals will soon be in great demand. However, on-the-job training of counselors has been successfully practised.

885 Prevention by clinical screening

How does the person with an elevated cancer risk benefit from gene testing? In 1995 an important first study was published presenting the results of a 10year colography-sigmoidoscopy-colonoscopy screening project [5]. Approximately half of the 251 people having a 50% calculatory risk to be carriers of HNPCC gene defects, wanted to take part in the screening, whereas the other half refused. The results were interesting because six of the clients that refused testing, but none of the screened patients, died of colorectal cancer. This result supports the hypothesis that an early diagnosis and removal of adenomas can prevent cancer deaths in HNPCC families. The results of gene diagnostics mean that (1) if there is no mutation then the cancer risk is equal to the risk of average people or (2) if the gene defect is found then the risk of cancer is very high (more than 90%) but with clinical screening the cancer can be prevented by early removal of the tumor or can be successfully treated after an early diagnosis. The other organs with high susceptibility to cancer are a challenge for prevention and treatment. The most common of these is cancer of the endometrium. The cancer of the ovaries, pancreas or biliary ducts cannot easily be detected by screening tests. Fortunately, the risk is minor compared to colon cancer and the onset of these cancers often takes place at a relatively old age.

Availability of services and funding

Are most public or private health services prepared to offer the citizens gene diagnostics and the possibilities to prevent cancer by clinical screening? Regrettably the answer is negative. A project has been started in Finland trying to offer the services described in this presentation to the members of some HNPCC families. The gene defect has been identified in more than 30 families and more than 400 presently healthy at-risk persons have been offered gene testing. Approximately 70% of those counseled have requested to have the test performed and about 100 people have already been tested. At present the only funding for this project is from grants appropriated for research. One physician and one specially trained nurse are taking care of the counseling of the patients. The gene tests are made by one senior scientist, one graduate student and one laboratory technician. One professor and four assistant professors are responsible for the planning and execution of the project. Clinical screening is offered to the individuals who are found to be mutation carriers; this is mainly accomplished at general hospitals.

The grants appropriated to research are objectively not misused in this way because research is an essential part of the project. The scientific aspects of the project are, however, soon accomplished which means that the funding from grants will come to an end. At the same time the need of the patients and the public to have access to gene diagnostics, counseling, and cancer screening increases. A solution must be found for this dilemma. In principle, the university departments of clinical genetics should take care of this activity. However, these departments have to be provided with adequate resources; clinical genetics is traditionally concerned with numerous diseases that are fairly rare. HNPCC has introduced a more common disease that may suddenly double the number of patients needing counseling. Moreover, the resources for the laboratory testing in gene diagnostics must be found. And finally hospitals and pension systems should adopt a more positive attitude than before towards healthy people that are gene carriers or are at risk. These clients are as important as the patients that are already diagnosed with the disease.

Acknowledgements

I thank Lauri Aaltonen, Helena Kaariainen, JukkaPekka Mecklin, Risto Pelkonen and Paivi Peltomaki for constructive comments on the manuscript. References 1. Lynch HT, Smyrk TC, Watson P et al. Genetics, natural history, tumor spectrum, and pathology of hereditary nonpolyposis colorectal cancer An updated review. Gastroenterology 1993; 104: 1535-49. 2. de la Chapelle A, Peltomaki P. Genetics of hereditary colon cancer. Annu Rev Genet 1995; 29: 329-48 3. Peltomaki P, de la Chapelle A. Mutations predisposing to hereditary nonpolyposis colorectal cancer. Adv Cancer Res; in press. 4. Harper PS. Research samples from families with genetic diseases: A proposed code of conduct BMJ 1993; 306:1391-4. 5. Jarvinen HJ, Mecklin J-P, Sistonen P. Screening reduces colorectal cancer rate in families with hereditary nonpolyposis colorectal cancer. Gastroenterology 1995; 108:1405-11. Received 2 August 1996; accepted 14 August 1996. Correspondence to: Albert de la Chapelle, MD, PhD Department of Medical Genetics Haartman Institute University of Helsinki P.O. Box 21 FIN-00014 Helsinki Finland