Hereditary breast/ovarian cancer : Implementation of BRCA1 & BRCA2 testing

Sammanfattning: Breast cancer is the most common malignancy among women in the western world. Most cases are sporadic but in 5 to 10 % an inherited genetic mutation is the main cause of the disease. Families with inherited breast cancer are characterized by multiple breast cancer cases, early age of onset, frequently occurring bilaterality and in many families women affected by ovarian cancer are found. Two important genes involved in hereditary breast or breast/ovarian cancer have been identified, BRCA1 on chromosome 17q and BRCA2 on chromosome 13q The genes are suppose to be tumor suppressor genes and both are suggested to participate in DNA repair. The entire function of the two genes is not yet fully known. Families in which a mutated BRCA 1 or BRCA2 gene can be suspected are offered genetic screening. If a mutation is revealed, predictive testing in healthy family members is a possibility. Identified mutation carriers have a greatly increased risk of breast and ovarian cancer and are offered regular surveillance and preventive measures. Family members without the mutation can be relieved from substantial cancer worries for themselves and for their offspring. In order to estimate the contribution of BRCA1 and BRCA2 germ line mutations in different breast or breast/ovarian cancer families from the Stockholm region, three screening studies were performed. Initially no restriction with respect to age at onset was made, but when in 1997 the procedure was implemented into clinical practice age-related screening criteria were employed in families with breast cancer only in order to optimize the outcome. Different mutation screening methods were used and successively evaluated. Healthy members of families with a revealed mutation in a breast/ovarian or a hereditary colon cancer gene were offered genetic predictive testing. The Psycho-social consequences of pre-symptomatic testing were evaluated in a 15 month follow-up study. BRCA1 mutations were consistently found in one third of the breast/ovarian cancer families (Paper 1, 11 IV). In breast cancer-only families BRCA1 mutations were found 1-2 % (Paper I and II). When age- related screening criteria were introduced this figure increased to 7% and the criteria could be further limited in the breast cancer-only families without loss of sensitivity (Paper IV). More than 50% of the BRCA1 aberrations detected were one of three founder mutations, 2594deIC, 3166insTGAGA or 3745delT (Paper 1, 11 and IV). Tumors other than breast and ovarian cancers were not overrepresented in the BRCA1 families (Paper IV). BRCA2 mutations were found to be rare in the Stockholm region and consistently found in 1-2 % of the families despite limited screening criteria (Paper III and IV). No family with the common Icelandic BRCA2 founder mutation was found (Paper 111). In many breast-cancer-only families no mutations were found, and other genes than BRCA1 and BRCA2 are likely to segregate in the breast cancer families in the Stockholm region (Paper 1, 11, 11, and IV). Independent of the screening methods used in paper 1, 11, 111 and IV, the frequency of disease causing mutations were approximately identical. Toward the end of the project when the entire genes were sequenced automatically, only an expected moderately increased number of BRCA2 missense mutations were found (Paper IV). Predictive genetic testing for germ I ine mutations in the BRCA1, BRCA2 hMLH1 or hMSH2 genes, preceded by extensive information and surveillance did not impair mental health of the people at risk. The individual's response to the test result was not predicted by the presence or absence of a mutation. Non carriers may also benefit from follow-ups (Paper V).