Evolving perspectives on genetic discrimination in health insurance among health care providers.

Previous studies have documented that concerns about genetic discrimination (GD) may influence access to and participation in medically necessary care. We sought to characterize how GD issues influence current cancer genetics professional (CGP) practice, determine if their attitudes regarding GD have changed over time, and compare their knowledge and attitudes regarding laws prohibiting GD to a contemporary cohort of non-genetics clinicians. Members of the National Society of Genetic Counselors Familial Cancer Special Interest Group were invited to complete a 39 item online survey, adapted from previously published instruments. The resulting data were compared to a survey of CGPs published in 2000 and to a contemporary cohort of non-genetics clinicians (n = 1,181). There were 153 qualified respondents. Compared to the historical CGP cohort (n = 163), a significantly greater proportion said they would bill insurance for the cost of genetic testing for themselves (P < 0.0001). Most CGPs (94%) considered the risk of GD to be low to theoretical, concordant with 64% who expressed confidence in existing federal laws prohibiting GD. The mean knowledge score of CGPs regarding GD protective laws was significantly greater than that of non-genetics clinicians (P < 0.001). As barometers of change, CGPs show a migration in opinion over the past 8 years, with decreased fear of GD and greater knowledge of laws prohibiting GD compared to non-genetics clinicians. Better knowledge of GD and protective legislation, may facilitate non-genetics clinician utilization of genetics and personalized medicine.

Contralateral risk-reducing mastectomy in young breast cancer patients with and without genetic cancer risk assessment.

BACKGROUND: Decisions regarding contralateral risk-reducing mastectomy (CRRM) among women diagnosed with unilateral breast cancer can potentially be influenced by age at diagnosis and other factors. In this study, we examined the use of CRRM before versus after genetic cancer risk assessment (GCRA) in women diagnosed with breast cancer before age 50. METHODS: We conducted a retrospective analysis of women with invasive breast cancer diagnosed before age 50 who were seen for GCRA between October 1996 and March 2005. Associations between the presence of generally accepted indications for risk-reducing surgery among women who had CRRM and the timing of GCRA were examined. RESULTS: The cohort included 378 women, of whom 57 had CRRM pre-GCRA and 45 had CRRM post-GCRA after a median follow-up of 26 months. Women who had CRRM pre-GCRA were more likely to not have a generally accepted indication for the procedure than those who did after GCRA (odds ratio [OR] 5.3, 95% confidence interval [95% CI] 1.6-17.8, P = .007). Women diagnosed with breast cancer before BRCA genetic testing became clinically available (1997) were more likely to have had CRRM pre-GCRA than those who were diagnosed more recently (OR 2.9, 95% CI 1.6-5.2, P = .0003). CONCLUSION: When personal and family history was carefully examined, a substantial proportion of women seen in our clinic did not have a clear indication for CRRM. Decreased use of empiric CRRM among women diagnosed after 1997 may indicate increased awareness and use of GCRA. Thus, judicious application of GCRA may help focus use of surgical risk reduction measures to the most risk-appropriate patients.

Social-cognitive aspects of underserved Latinas preparing to undergo genetic cancer risk assessment for hereditary breast and ovarian cancer.

OBJECTIVES: As Latinos are a growing ethnic group in the United States, it is important to understand the socio-cultural factors that may be associated with cancer screening and prevention in this population. The socio-cultural factors that may affect preparedness to undergo genetic cancer risk assessment (GCRA) deserve particular attention. The pre-GCRA period can provide insight into variables that may influence how medically underserved Latinas, with limited health resources and access, understand hereditary cancer information and subsequently implement cancer risk management recommendations. This study explores social, cognitive and cultural variables in Latinas prior to undergoing GCRA. METHODS: The study sample consisted of low-income, underserved Latinas referred for GCRA because of a personal and/or family history of breast or ovarian cancer. Acculturation, cancer-specific fatalism, self-efficacy and social support were assessed prior to GCRA. RESULTS: Fifty Latinas (mean age=40.1+/-7.7) completed instruments; 86% had invasive cancer, 78% spoke primarily Spanish and 61% were of Mexican ancestry. Low levels of acculturation (n=50, mean=9.0+/-5.8) and cancer-specific fatalism (n=43, mean=5.6+/-3.2), but relatively high self-efficacy (n=49, mean=40.9+/-7.8) and social support (n=49, mean=37.3+/-8.7) were reported. Cancer-specific fatalism and self-efficacy were inversely correlated (r=-0.47, p=0.002). Those over age 38 at the time of cancer diagnosis reported higher acculturation (mean=11.4+/-7.2, p=0.02) and social support (mean=40.5+/-1.2, p=0.05). CONCLUSIONS: These findings suggest that medically underserved Latinas may already possess some of the necessary skills to successfully approach the GCRA process, but that special attention should be given to cultural factors.

Evidence for common ancestral origin of a recurring BRCA1 genomic rearrangement identified in high-risk Hispanic families.

BACKGROUND: Large rearrangements account for 8% to 15% of deleterious BRCA mutations, although none have been characterized previously in individuals of Mexican ancestry. METHODS: DNA from 106 Hispanic patients without an identifiable BRCA mutation by exonic sequence analysis was subjected to multiplexed quantitative differential PCR. One case of Native American and African American ancestry was identified via multiplex ligation-dependent probe amplification. Long-range PCR was used to confirm deletion events and to clone and sequence genomic breakpoints. Splicing patterns were derived by sequencing cDNA from reverse transcription-PCR of lymphoblastoid cell line RNA. Haplotype analysis was conducted for recurrent mutations. RESULTS: The same deletion of BRCA1 exons 9 through 12 was identified in five unrelated families. Long-range PCR and sequencing indicated a deletion event of 14.7 kb. A 3-primer PCR assay was designed based on the deletion breakpoints, identified within an AluSp element in intron 8 and an AluSx element in intron 12. Haplotype analysis confirmed common ancestry. Analysis of cDNA showed direct splicing of exons 8 to 13, resulting in a frameshift mutation and predicted truncation of the BRCA1 protein. CONCLUSIONS: We identified and characterized a novel large BRCA1 deletion in five unrelated families-four of Mexican ancestry and one of African and Native American ancestry, suggesting the possibility of founder effect of Amerindian or Mestizo origin. This BRCA1 rearrangement was detected in 3.8% (4 of 106) of BRCA sequence-negative Hispanic families. An assay for this mutation should be considered for sequence-negative high-risk Hispanic patients.

Limited family structure and BRCA gene mutation status in single cases of breast cancer.

CONTEXT: An autosomal dominant pattern of hereditary breast cancer may be masked by small family size or transmission through males given sex-limited expression. OBJECTIVE: To determine if BRCA gene mutations are more prevalent among single cases of early onset breast cancer in families with limited vs adequate family structure than would be predicted by currently available probability models. DESIGN, SETTING, AND PARTICIPANTS: A total of 1543 women seen at US high-risk clinics for genetic cancer risk assessment and BRCA gene testing were enrolled in a prospective registry study between April 1997 and February 2007. Three hundred six of these women had breast cancer before age 50 years and no first- or second-degree relatives with breast or ovarian cancers. MAIN OUTCOME MEASURE: The main outcome measure was whether family structure, assessed from multigenerational pedigrees, predicts BRCA gene mutation status. Limited family structure was defined as fewer than 2 first- or second-degree female relatives surviving beyond age 45 years in either lineage. Family structure effect and mutation probability by the Couch, Myriad, and BRCAPRO models were assessed with stepwise multiple logistic regression. Model sensitivity and specificity were determined and receiver operating characteristic curves were generated. RESULTS: Family structure was limited in 153 cases (50%). BRCA gene mutations were detected in 13.7% of participants with limited vs 5.2% with adequate family structure. Family structure was a significant predictor of mutation status (odds ratio, 2.8; 95% confidence interval, 1.19-6.73; P = .02). Although none of the models performed well, receiver operating characteristic analysis indicated that modification of BRCAPRO output by a corrective probability index accounting for family structure was the most accurate BRCA gene mutation status predictor (area under the curve, 0.72; 95% confidence interval, 0.63-0.81; P<.001) for single cases of breast cancer. CONCLUSIONS: Family structure can affect the accuracy of mutation probability models. Genetic testing guidelines may need to be more inclusive for single cases of breast cancer when the family structure is limited and probability models need to be recreated using limited family history as an actual variable.

If we build it ... will they come?--establishing a cancer genetics services clinic for an underserved predominantly Latina cohort.

BACKGROUND: Cancer genetic counseling and testing is a standard of care option for appropriate families and can identify individuals at increased risk prior to diagnosis, when prevention or detection strategies are most effective. Despite documented efficacy of cancer risk reduction in high-risk individuals, underserved and minority individuals have a disproportionate cancer burden and limited access to genetic counseling. METHODS: A needs assessment survey documented gaps in knowledge and interest in prevention. Satellite clinics were established at two indigent healthcare systems. Cancer genetics CME lectures were conducted and referral guidelines disseminated to clinicians who referred patients for counseling. RESULTS: An increase in clinician knowledge was demonstrated post-CME and reflected by quality referrals. Eighty-eight percent of patients kept their appointments. In the predominantly Latina(6) (n=77) clinic population, 71.4% were affected with cancer, and 17 mutation positive families were identified. Preliminary data shows a positive impact on patients' motivation and behavior. The majority has expressed satisfaction and reduction in anxiety. CONCLUSIONS: This study demonstrates feasibility and acceptability of cancer genetics services in this population, suggesting the potential to reduce cancer morbidity in underserved, high-risk families.

Prevalence of BRCA mutations and founder effect in high-risk Hispanic families.

UNLABELLED: Approximately 12% of the U.S. population is Hispanic, with the majority residing in urban centers such as Los Angeles. The prevalence of BRCA mutations among high-risk Hispanic families is unknown. METHODS: One hundred and ten unrelated probands of Hispanic origin, with a personal or family history of breast and/or ovarian cancer, presented for genetic cancer risk assessment, were enrolled in an Institutional Review Board-approved registry and underwent BRCA testing. Haplotype analyses were done if BRCA mutations were observed in two or more unrelated probands. RESULTS: Mean age at diagnosis was 37 years (range = 23-59) for the 89 (81%) probands with invasive breast cancer. Overall, 34 (30.9%) had deleterious mutations (25 in BRCA1, 9 in BRCA2), 25 (22.7%) had one or more unclassified variants, and 51 (46.4%) had negative results. The mean pretest mutation probability using the Couch model, Myriad model, and BRCAPro was 19.6% (range = 4-77%). The combined average mutation probability was 32.8% for carriers, 15.5% for noncarriers, and 12.9% for variant carriers (P < 0.0001). The most common deleterious mutation was 185delAG (4 of 34, 11.8%). The Hispanic 185delAG carrier families share the same haplotype from D17s1320 through BRCA1, as do two reference Ashkenazi Jewish families. Haplotype analyses of additional recurrent BRCA1 mutations [IVS5+1G>A (n=2),S955X (n = 3), R1443X (n = 3), and 2552delC (n = 2)] also suggest founder effects, with four of six mutations seen almost exclusively in families with Latin American/Caribbean or Spanish ancestry. CONCLUSION: This is the largest study to date of high-risk Hispanic families in the United States. Six recurrent mutations accounted for 47% (16 of 34) of the deleterious mutations in this cohort. The BRCA1185delAG mutation was prevalent (3.6%) in this clinic-based cohort of predominantly Mexican descent, and shared the Ashkenazi Jewish founder haplotype.

Depolarization-induced ERK phosphorylation depends on the cytosolic Ca2+ level rather than on the Ca2+ channel subtype of chromaffin cells.

The contribution of Ca2+ entry through different voltage-activated Ca2+ channel (VACC) subtypes to the phosphorylation of extracellular signal regulated kinase (ERK) was examined in bovine adrenal-medullary chromaffin cells. High K+ depolarization (40 mM, 3 min) induced ERK phosphorylation, an effect that was inhibited by specific mitogen-activated protein kinase kinase inhibitors. By using selective inhibitors, we observed that depolarization-induced ERK phosphorylation completely depended on protein kinase C-alpha (PKC-alpha), but not on Ca2+/calmodulin-dependent protein kinase nor cyclic AMP-dependent protein kinase. Blockade of L-type Ca2+ channels by 3 microm furnidipine, or blockade of N channels by 1 micromomega-conotoxin GVIA reduced ERK phosphorylation by 70%, while the inhibition of P/Q channels by 1 micromomega-agatoxin IVA only caused a 40% reduction. The simultaneous blockade of L and N, or P/Q and N channels completely abolished this response, yet 23% ERK phosphorylation remained when L and P/Q channels were simultaneously blocked. Confocal imaging of cytosolic Ca2+ elevations elicited by 40 mm K+, showed that Ca2+ levels increased throughout the entire cytosol, both in the presence and the absence of Ca2+ channel blockers. Fifty-eight percent of the fluorescence rise depended on Ca2+ entering through N channels. Thus, ERK phosphorylation seems to depend on a critical level of Ca2+ in the cytosol rather than on activation of a given Ca2+ channel subtype.