Psychosocial factors predicting BRCA1/BRCA2 testing decisions in members of hereditary breast and ovarian cancer families.

Although BRCA1/2 testing has increasingly entered clinical practice, much is to be learned about the most effective ways to provide counseling to persons potentially interested in receiving test results. The purpose of this study was to identify factors affecting genetic testing decisions in a cohort of hereditary breast and ovarian cancer (HBOC) families presented with the choice to undergo testing. Relatives in these families are known to carry BRCA1 or BRCA2 mutations. Sociodemographics, personality traits, and family functioning were self-assessed using validated psychometric instruments at baseline. Among 172 individuals who participated in pretest education and counseling, 135 (78%) chose to undergo genetic testing and 37 (22%) chose not to be tested. Individuals who chose to undergo genetic testing were more likely to be older (> or =40 years), to have lower levels of optimism, and to report higher levels of cohesiveness in their families. A better understanding of factors that influence interest in predictive testing may help to inform the counseling that occurs prior to genetic testing.

Nevoid basal cell carcinoma syndrome with medulloblastoma in an African-American boy: a rare case illustrating gene-environment interaction.

We present an 8-year-old African-American boy with medulloblastoma and nevoid basal cell carcinoma syndrome (NBCCS) who exhibited the radiosensitive response of basal cell carcinoma (BCC) formation in the area irradiated for medulloblastoma. Such a response is well-documented in Caucasian NBCCS patients with medulloblastoma. The propositus was diagnosed with medulloblastoma at the age of 2 years and underwent surgery, chemotherapy, and craniospinal irradiation. At the age of 6 years, he was diagnosed with NBCCS following his presentation with a large odontogenic keratocyst of the mandible, pits of the palms and soles and numerous BCCs in the area of the back and neck that had been irradiated previously for medulloblastoma. Examination of other relatives showed that the propositus' mother also had NBCCS but was more mildly affected; in particular, she had no BCCs. This case illustrates complex gene-environment interaction, in that increased skin pigmentation in African-Americans is presumably protective against ultraviolet, but not ionizing, radiation. This case and other similar cases in the literature show the importance of considering NBCCS in the differential diagnosis of any patient who presents with a medulloblastoma, especially before the age of 5 years, and of examining other close relatives for signs of NBCCS to determine the patient's at-risk status. Finally, for individuals who are radiosensitive, protocols that utilize chemotherapy in lieu of radiotherapy should be considered.

Detection of eight BRCA1 mutations in 10 breast/ovarian cancer families, including 1 family with male breast cancer.

Genetic epidemiological evidence suggests that mutations in BRCA1 may be responsible for approximately one half of early onset familial breast cancer and the majority of familial breast/ovarian cancer. The recent cloning of BRCA1 allows for the direct detection of mutations, but the feasibility of presymptomatic screening for cancer susceptibility is unknown. We analyzed genomic DNA from one affected individual from each of 24 families with at least three cases of ovarian or breast cancer, using SSCP assays. Variant SSCP bands were subcloned and sequenced. Allele-specific oligonucleotide hybridization was used to verify sequence changes and to screen DNA from control individuals. Six frameshift and two missense mutations were detected in 10 different families. A frameshift mutation was detected in a male proband affected with both breast and prostate cancer. A 40-bp deletion was detected in a patient who developed intra-abdominal carcinomatosis 1 year after prophylactic oophorectomy. Mutations were detected throughout the gene, and only one was detected in more than a single family. These results provide further evidence that inherited breast and ovarian cancer can occur as a consequence of a wide array of BRCA1 mutations. These results suggests that development of a screening test for BRCA1 mutations will be technically challenging. The finding of a mutation in a family with male breast cancer, not previously thought to be related to BRCA1, also illustrates the potential difficulties of genetic counseling for individuals known to carry mutations.

Anticipated uptake and impact of genetic testing in hereditary breast and ovarian cancer families.

In anticipation of the identification of the BRCA1 gene, we studied the interest in and anticipated reaction to DNA testing for mutations in this gene in members of high-risk families. We surveyed 91 female and 49 male subjects using a structured interview by study nurses. All subjects were members of inherited breast-ovarian cancer families participating in a genetic linkage study at the National Cancer Institute. The main outcomes of the study were interest in genetic testing and anticipated impact of test results. Seventy nine % of subjects indicated that they would "definitely" want to be tested, and 16% would "probably" want to be tested for mutations in the BRCA1 gene. Subjects with a high self-perceived risk of having an altered BRCA1 gene were more likely to definitely want testing (P = 0.02), while estimated true genetic risk did not predict interest in the test. Females were significantly more likely to definitely want testing (P = 0.005) and had a significantly greater mean anticipated negative-impact score (2.3) compared to males (1.0) (P < 0.001). We found a high level of interest in genetic testing for BRCA1 among members of inherited breast-ovarian cancer families participating in a genetic linkage study. While utilization may fall below levels of interest reported in this and other preliminary surveys, given the potential for early detection and treatment of breast and ovarian cancer, interest in BRCA1 testing may translate into high rates of uptake. These results indicate that it will be critical to incorporate follow-up counseling and support into BRCA1 testing programs.

Problems ascertaining friend controls in a case-control study of lung cancer.

Willingness of newly diagnosed lung cancer patients to volunteer names of friends as potential control subjects was assessed from August through December 1988 in a case-control study at the National Cancer Institute and Naval Hospital, Bethesda, Maryland. Friend controls appeared ideal to examine a genetically determined metabolic characteristic and lung cancer risk, since potentially confounding characteristics could be matched and cooperation should be high. Only 11 of 23 cases named at least one friend. Cases interviewed during the second study month were most likely to volunteer names. Either the recency of the diagnosis of a highly fatal disease or the referral to a tertiary care research hospital may have contributed to the reluctance of cases to volunteer names. No characteristic was identified that might offer a means to increase referral of friend controls.

Decreased helper T lymphocytes in homosexual men. I. Sexual contact in high-incidence areas for the acquired immunodeficiency syndrome.

In June 1982, sexual and other behavioral patterns were examined in 245 homosexual men in relationship to T-lymphocyte phenotypes that are characteristic of the acquired immunodeficiency syndrome (AIDS). Mean helper T-cell counts in New York City (579 +/- 32 cells/mm3) and Washington, DC, homosexual men with sexual contacts in areas at high risk (endemic) for AIDS (567 +/- 24 cells/mm3) were significantly lower than in Washington, DC, residents without such contacts (672 +/- 36 cells/mm3, p = 0.04 by analysis of variance). Helper T-cell counts in the Washington men were inversely correlated with a greater number of endemic-area homosexual contacts (p = 0.005), even after adjustment for multiple confounding variables (p = 0.02). The 31 Washington men with more than 15 endemic-area partners had a mean helper T-cell count of 517 +/- 44 cells/mm3, and 12 of those 31 men had helper T-cell counts less than 400 cells/mm3. AIDS patients are known to have a marked reduction in the number and function of helper T-lymphocytes. The data suggest that deficits of helper T lymphocytes can be acquired by homosexual contact with men in cities where AIDS is common. This supports the hypotheses that low helper T-cell counts may be caused by a sexually transmissible agent and that frequent homosexual exposure to residents of high-risk areas for AIDS may be an important means of spread of this agent.

Decreased helper T lymphocytes in homosexual men. II. Sexual practices.

In June 1982, the sexual practices of 245 homosexual male outpatients of private physicians were evaluated in relationship to decreased numbers of helper T lymphocytes, an abnormality that is characteristic of the acquired immunodeficiency syndrome (AIDS). Three risk groups were defined a priori--85 high-risk men from central Manhattan ("New York"), 96 intermediate-risk men from Washington, DC, with AIDS-area homosexual contacts ("Washington-exposed"), and 64 low-risk Washington, DC, men without such contacts ("Washington-unexposed"). An increasing number of homosexual partners was correlated with decreasing helper T-cell counts (R = -0.29, p = 0.009) and decreasing helper:suppressor T-cell ratios (R = -0.32, p = 0.005) in the entire study group combined and in New York subjects separately. Suppressor T-cell counts were unrelated to the number of partners in all three groups. Increasingly frequent receptive anal intercourse correlated with decreasing helper T-cell counts most clearly in the New York City group (R = -0.23, p = 0.04), somewhat less so in the Washington-exposed group (R = -0.18, p = 0.07), and not at all in the Washington-unexposed group (R = -0.09, p = 0.48). This association persisted in the New York and Washington-exposed groups after adjusting for seven other sexual practices, the number of homosexual partners, and five other potentially confounding variables. A transmissible agent associated with receptive anal intercourse best explains these data. The cause of these low helper T-cell counts may also be the cause of AIDS.