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Summary

Acceptance and compliance with screening and genetic programs for genetic illness depends crucially on the compatibility and fit of their design with the social, cultural and religious concerns and mores of target communities. As a case in point, genetic screening programs that are currently in use within Jewish populations are considered on the background of ethical and religious concerns. Implications to design of programs for surveillance and screening of hereditary cancer syndromes are discussed.

I. Introduction
The recently defined ability to identify patients and families genetically at increased risk for developing specific cancers has important ramification for ethnic and religious communities composed of individuals with higher risk of carrying the offending alleles. The effects on a community�s self-image, the potential for stigmatization of healthy disease carriers as unfit marriage prospects, and the impact on traditional patterns of behavior in the sphere of matchmaking and marriage are poorly understood but are of potentially great import to the design of screening and surveillance programs. The stresses will likely be accentuated as the genomic revolution makes personal genetic profiles commercially available in the near future. Regrettably, these issues have so far remained unexplored, yet they will affect acceptance of the scientific advances and the milieu in which medical treatment will be offered or provided. Self referral to screening, acceptance of early diagnosis and prevention programs, and maintaining communal and organizational support for population based genetic research is crucially dependent on exploring and defining these issues. What follows is an exploration of the impact of genetic knowledge in the sphere of hereditary cancer on the Jewish community, as a case in point. BRCA associated cancers represent an instructive example in-as-far as their impact on families and communities at risk. It is particularly important to bring together the scientific and social/ ethical issues and investigate how they interact and affect screening and surveillance for cancer. After all, a program rejected by the very community that it attempts to help will be of little practical use. The issues that concern us in this paper are especially those issues that would impact on the design and formulation of a surveillance and screening program that would be accepted and internalized by the communities that it would benefit. The hope is that the issues raised by this paper may serve to crystallize points of concern in other communities and groups at risk.

II. The Background: Genetics, genomics and the Jews
The �Jewish� genetic illnesses can be roughly divided or assigned into three groups. It is estimated that 1 in 4 Ashkenazi Jews carries one or another genetic mutation (Levin, 1999), In itself, this is not unusual in historically interbreeding populations; however, these facts interact poignantly and differently than they do, say in Iceland, with specific social, political and communal concerns.

First, the Jewish populations, especially those ofEastern European origin, carry genes for certain genetic diseases at a rate much higher than the general population. These include the recessive Canavan Disease, Gaucher Disease, Tay-Sachs, Familial Dysautonomia, Bloom�s Syndrome, Mucolipidosis IV, Torsion Dystonia, Fanconi Anemia and Nieman-Pick Syndrome. These diseases affect primarily children, can be diagnosed in the carrier state in the unaffected heterozygotes (who carry the gene and can pass it on to their children) and can be prevented through early detection of carriers and, in certain cases, via prenatal testing. The strategies for detection of these conditions have been uniformally supported and wellaccepted by the Jewish community and grass-roots screening programs have been designed and implemented.

The second group includes conditions equally common in Jews and non-Jews, such as Down�s Syndrome, Cystic Fibrosis, and those that represent common condition for which only probabilities of development can be currently predicted. As an example or the latter group, genetic make-up can predict whether an individual has a 5% or 40% risk of developing heart disease or diabetes. The interaction of poly-genic factors that determine such risk in populations is now popularly termed genomics.

The third group of illnesses includes those that increase the risk of serious conditions later in life but do not guarantee that illness will develop. Screening, surveillance and prevention strategies for this group are being refined but have already shown promise. BRCA associated cancers, while also affecting certain other ethnic groups, typify this kind of condition. The Jewish community is at a particular risk; it is estimated that some 2.5% of Jewish women of Ashkenazi (Eastern and Central European) origin carry one of the BRCA genes (Tonin et al, 1995; Moslehi et al, 2000), and one in ten Jewish women with breast cancers is a BRCA carrier while almost 40% of Jewish ovarian cancer victims carry this gene. (Tonin et al, 1996)

Women with the BRCA I and II mutations are thought to have a lifetime risk of developing breast cancer of up to 85%. The incidence risk rises after age 50, with BRCA II carriers lagging a few years behind in age as compared to BRCA I carriers. Those with BRCA I have an approximately 49% lifetime risk of developing ovarian cancer with risk beginning in lower 30s and rising thereafter. For BRCA II mutation the lifetime risk is approximately 20%, with incidence mostly after age 40 and rising sharply after age 50; incidence rates of both ovarian and breast cancer do vary in different reports (Thompson and Easton, 2001). Parity appears to increase breast cancer risk in mutation carriers, at least in some surveillance studies, inverse to the usual relation of parity and risk in the general population. Similarly use of oral contraceptive use increases risk in some reports among women at high risk but may decrease it in BRCA carriers (Narod et al, 1998; Warner, 2003).

As in general, hereditary cancers ultimately affect a large proportion of affected individuals and include familial breast, prostate and ovarian cancer and a type of colon cancer. These cancers tend to occur at earlier ages and strike multiple members of families. These devastating effects on individuals and families can be prevented or at least ameliorated through surveillance or prevention strategies. Unlike the previously discussed groups of disorders, these conditions present unique and specific challenges. This paper will specifically focus on this group of conditions.

Traditionally, the Jewish community has supported and encouraged premarital genetic testing for the conditions in the first group; however, it realized more than 20 years ago that the existing screening programs, though ultimately screening more than a million people (Kaback et al, 1992), did not address some important communal and religious concerns. Foremost among these were concern for privacy, confidentiality and the impact on the traditional courting and marriage patterns in the

Orthodox communities. Rabbi M. Feinstein, the leading expert on religious law in the United States, laid the following guidelines in a 1974 responsum: �it is advisable for one preparing to be married, to have himself tested. It is also proper to publicize the fact�that such a test is available. It is clear that absolute secrecy must be maintained to prevent anyone form learning the results of such a test performed on another. The physician must not reveal these to anyone�these tests should be performed in private�. Encouraged by these guidelines, a grass root organization was formed in 1974; by 1997, it has screened 80.000.00 individuals for Tay-Sachs, Canavan and Cystic fibrosis. Currently, anonymous screening for 10 conditions, most recently including familial dysautonomia is available. The program has been immensely successful essentially wiping out Tay-Sachs disease in the New York metropolitan area. The details of this program and its design have been well described 1. One must, however, realize that this program was designed for recessive conditions, ones that can be easily identified, with risk well quantified and with the goal of preventing marriage between carriers. As designed, it is not suitable for BRCA related cancers or other variable penetrance inherited cancer syndromes that remain a significant challenge for organized Jewish communities. The very anonymity of this program makes it a poor vehicle for screening for complex conditions with possible but not certain onset of symptoms at a far-removed future date and for which a variety of interventions is available.

III. Approach to woman with a diagnosed BRCA mutation
The options for a woman with a diagnosed BRCA mutation include five potential courses of action:

  1. Doing nothing. This course of action has in the past been advocated by some community activists, primarily for its purported benefits in allaying individual and group anxiety. However, as new options for early detection and potential curative intervention have developed, this option has become much less attractive.
  2. Surveillance. To better define terms that are used in this field � screening refers to low or average risk population while surveillance is the term applied to high risk groups.

For ovarian cancer, we know little securely about screening in high risk populations because screening has not yet been proven to reduce mortality in the general population. Two randomized studies that utilized CA125 screening in combination with trans-vaginal ultrasound failed to show benefit in the general population (Rosenthal and Jacobs, 1998), In addition, there are no randomized studies in BRCA carriers. Unlike the situation in breast cancer screening, where an over aggressive screeningstrategy leads to more unnecessary biopsies, . . . Continue to article and footnotes (PDF)

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Dr. Mark Levin is an Academic Physician with a wide range of experience in various practice settings, including academia, teaching hospital and private practice settings. He is first author of over thirty academic articles, chapters and several books.

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