Peter T. Rowley

Sequence analysis of BRCA1 and BRCA2: correlation of mutations with family history and ovarian cancer risk.

PURPOSE Previous studies of mutations in BRCA1 or BRCA2 have used detection methods that may underestimate the actual frequency of mutations and have analyzed women using heterogeneous criteria for risk of hereditary cancer. PATIENTS AND METHODS A total of 238 women with breast cancer before age 50 or ovarian cancer at any age and at least one first- or second-degree relative with either diagnosis underwent sequence analysis of BRCA1 followed by analysis of BRCA2 (except for 27 women who declined analysis of BRCA2 after a deleterious mutation was discovered in BRCA1). Results were correlated with personal and family history of malignancy. RESULTS Deleterious mutations were identified in 94 (39%) women, including 59 of 117 (50%) from families with ovarian cancer and 35 of 121 (29%) from families without ovarian cancer. Mutations were identified in 14 of 70 (20%) women with just one other relative who developed breast cancer before age 50. In women with breast cancer, mutations in BRCA1 and BRCA2 were associated with a 10-fold increased risk of subsequent ovarian carcinoma (P = .005). CONCLUSION Because mutations in BRCA1 and BRCA2 in women with breast cancer are associated with an increased risk of ovarian cancer, analysis of these genes should be considered for women diagnosed with breast cancer who have a high probability of carrying a mutation according to the statistical model developed with these data.

Prenatal screening for cystic fibrosis carriers: an economic evaluation.

The cloning of the CFTR gene has made it technically possible to avert the unwanted birth of a child with cystic fibrosis (CF). Several large trials offering prenatal CF carrier screening suggest that such screening is practical and that identified carriers generally use the information obtained. Therefore, a critical question is whether the cost of such screening is justified. Decision analysis was performed that used information about choices that pregnant women were observed to make at each stage in the Rochester prenatal carrier-screening trial. The cost of screening per CF birth voluntarily averted was estimated to be

Carrier screening for cystic fibrosis : Test acceptance and one year follow-up

1,320,000-

Impact of genetic testing for breast-ovarian cancer susceptibility.

1,400,000. However, the lifetime medical cost of the care of a CF child in todays dollars was estimated to be slightly>

Alveolar Cell Carcinoma in Identical Twins: Similarity in Time of Onset, Histochemistry, and Site of Metastasis

1,000,000. Therefore, despite both the high cost of carrier testing and the relative infrequency of CF conceptions in the general population, the averted medical-care cost resulting from choices freely made are estimated to offset approximately 74%-78% of the costs of a screening program. At present, if it is assumed that a pregnancy terminated because of CF is replaced, the marginal cost for prenatal CF carrier screening is estimated to be

Human lymphocyte telomerase is genetically regulated

8,290 per quality-adjusted life-year. This value compares favorably with that of many accepted medical services. The cost of prenatal CF carrier screening could fall to equal the averted costs of CF patient care if the cost of carrier testing were to fall to

Attitudes of obstetrician-gynecologists toward DNA testing for a genetic susceptibility to breast cancer

100.

High resolution analysis of hemoglobins: polyacrylamide isoelectric focusing.

We identified 124 carriers among 4,879 patients of prenatal care providers in the Rochester region. Six factors were identified that together permitted a correct classification regarding test acceptance for 77.5% of all subjects. For those pregnant, the most influential of these factors was a more accepting attitude toward abortion. As an indication for abortion, cystic fibrosis (CF) ranked between mild and moderate mental retardation. Of the 124 carrier women identified, we obtained 1-year follow-up information on 100. Mean score for CF knowledge at 1 year (77.4 +/- 13.2%), although significantly lower than immediately after counseling (84 +/- 12.4%), was still significantly higher than after detection but before counseling (51.1% +/- 20.7%). Anxiety about having a child with CF significantly declined from 25.8 +/- 8.0 SD immediately after counseling to 18.9 +/- 7.8 at 1 year (Spielberger State Anxiety Scale). Although 15 carriers regretted having been tested, 83% believed that they benefited from testing, 83% would make the same decision to be tested over again, and 79% would recommend testing to a friend. We conclude that, for most women, CF carrier screening accomplished its purpose: most carriers detected came for counseling, had their partners tested, and, if their partners were also carriers, had prenatal diagnosis. The major undesirable outcomes were that many women testing negative did not understand that a negative result did not exclude being a carrier and that three women found to be carriers did not have their partners tested because of anxiety or the unacceptability of pregnancy termination and therefore may not have carefully considered their decision to be tested. Both of these undesirable outcomes could have been avoided by greater attention to pretest patient education by the primary care provider.

Anhidrotic Ectodermal Dysplasia: Predisposition to Bronchial Disease

Previously, we have reported a clinical trial in which any woman in a defined geographic region who had a qualifying family history and who was referred by her physician or who was identified through a regional cancer registry was offered free genetic counseling, BRCA testing, and recommendations based on test results. Each family was represented by one affected and one unaffected person. Of the 87 families actually tested, 13 were found to have deleterious mutations. To assess the impact of the counseling and testing process, we contacted the tested individuals 1 month and 1 year after receiving the test result and those with an abnormal test result after 4 years. Index subjects, we found, differed significantly from relatives. Before coming for counseling, index subjects perceived both their general health and emotional health as worse than did their relatives. After counseling and testing, index subjects continue to worry more about breast cancer than do relatives. Affected subjects, we found, differed significantly from unaffected subjects. Before counseling, affected subjects knew more about breast cancer, perceived their general health as poorer, and reported greater adherence to recommended breast cancer surveillance than did unaffected subjects. After counseling and testing, affected subjects were less satisfied than unaffected subjects with having been tested. This study indicates that the group most prone to distress by cancer risk genetic counseling and testing is not the recruited relatives, nor even those affected with cancer, but rather the index patients themselves. The index patients, i.e., the ones who want the risk information most, appear to undergo the most stress in obtaining it.

Issues in implementing prenatal screening for cystic fibrosis: Results of a working conference

Identical male twins had alveolar cell carcinoma with nearly synchronous onset and similar histopathologic features, both metastatic to the brain. The hypothesis is advanced that there are genes shared by these twins that determine not only the susceptibility of pulmonary cells to malignant transformation but also the character of the resultant neoplasm, including its histologic features and metastatic behavior.