Development, implementation and evaluation of clinical and genetic screening programs for hereditary tumour syndromes

Green, Jane Stuart (1995) Development, implementation and evaluation of clinical and genetic screening programs for hereditary tumour syndromes. Doctoral (PhD) thesis, Memorial University of Newfoundland.

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Abstract

Families with an autosomal dominant predisposition to benign or malignant tumours were identified in Newfoundland in the 1980s, including families with von Hippel-Lindau disease (VHL), the multiple endocrine neoplasias, type 1 (MEN-1), and type 2 (MEN-2), and the hereditary colon cancers, familial adenomatous polyposis (FAP), and hereditary non-polyposis colon cancer (HNPCC). Each family was identified because of an excess of early deaths and disabilities in family members who had presented with symptomatic disease, and an increased anxiety in affected and unaffected family members. -- The medical team recognized that a multidisciplinary approach to the disease in each family was necessary to improve the prognosis, and that a screening program might be central to this type of care. -- Successful genetic screening programs had been developed since the 1960s for severe or lethal hereditary diseases with neonatal or early childhood onset: for early identification and treatment of affected infants, or for identification of those at risk of having an affected child with provision of counselling to allow informed reproductive decisions. Subsequently predictive testing for incurable late-onset diseases, such as Huntington disease, was introduced to reduce uncertainty. Many lessons were learned from these early screening programs, about the ethical requirements of screening for hereditary disease, and the need for coordination with pre-screening and post-screening education, counselling, and follow-up. -- In the 1980s there were recommendations for screening programs for hereditary tumour syndromes, for early identification of gene carriers to provide reproductive counselling, and for early identification and treatment of tumours to improve the prognosis. At the same time there were concerns that more harm than good might result from this type of program. The large Newfoundland families with VHL, MEN-1, MEN-2, FAP and HNPCC provided an opportunity to develop, implement, and then evaluate clinical and genetic screening programs for these hereditary tumour syndromes. -- For each "hereditary cancer" an extended pedigree was documented and medical records reviewed. A clinical screening protocol was developed based on the type of tumours and ages at which they occurred. Educational materials were prepared, counselling was provided, and clinical screening was offered to affected and at-risk family members. Medical and psychosocial results of screening were documented. Genetic testing by linkage analysis or mutation detection was developed in collaboration with molecular geneticists in Newfoundland and elsewhere, and predictive testing was offered to at-risk family members. Affected and unaffected members of the VHL family were interviewed to assess the psychosocial implications of the disease and the screening program, and a formal health care evaluation was completed for the VHL screening program, including a cost-benefit analysis. -- For VHL, an earlier age at diagnosis, an improved prognosis (reduced morbidity and mortality), and a better quality of life (reduced anxiety, and more informed reproductive decisions) were demonstrated for those identified by screening, compared with those presenting symptomatically. The overall cost to society of screening and management of presymptomatic disease was less than the combined costs of treatment of symptomatic disease and the costs related to early deaths and disabilities. Screening programs for the other hereditary tumour syndromes were less formally reviewed, but provided similar results. -- As a group these hereditary cancers differed from untreatable adult-onset disorders because the harmful effects of the disease genes could be mitigated. At the same time, important differences were identified within this group of diseases (the age at onset, severity of disease, the spectrum of disease expression, the potential for treatment, and the state of genetic knowledge) which influenced the development of specific screening programs, and the attitudes of family members towards participation in the clinical and genetic components of screening. -- It was concluded that screening programs combining clinical and genetic testing methods to identify and provide reproductive counselling for gene carriers, and to identify and treat presymptomatic tumours, provide appropriate management for hereditary tumour syndromes, and that this approach reduces monetary costs to the health care system, as well as monetary and psychosocial costs to individual family members.

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