From Probands to Relatives: Communication of Genetic Risk for Hereditary Breast-Ovarian Cancer and Its Influence on Subsequent Testing.

BACKGROUND: The genetic risk communication from proband to relatives varies from family to family, and patients often need support with the communication of genetic test results and making decisions to manage hereditary cancer risks. OBJECTIVE: The aim of this study was to characterize the communication of BRCA1 or BRCA2 (BRCA1/2) genetic risk from proband to first-degree relatives (FDRs) using a social network framework. METHODS: We characterized network and nonnetwork factors to explore their association with which FDRs were told about the genetic risk and whether or not relatives underwent genetic testing. Ninety-two female probands with hereditary breast and ovarian cancer who have confirmed BRCA1/2 mutations participated in the study. Communication of hereditary breast and ovarian cancer risk was assessed between 92 probands and their 417 FDRs. RESULTS: Of 92 probands, 94.5% (n = 87) communicated their genetic test result to at least one of their FDRs. Of FDRs older than 18 years, 19.9% (n = 72) have genetic testing. Emotional closeness, educational level of the proband, and relative's age were significantly associated with communicating test results with FDRs. CONCLUSION: Communication of genetic risk with the FDRs after having a BRCA1/2 gene-mutation-positive test result was high in this group of cancer patients. However, the rate of genetic testing among FDRs was low. IMPLICATIONS FOR PRACTICE: Probands' educational level and age of relatives for cascade genetic screening should be considered during counseling. Interventions to support women with BRCA1/2 mutations during the communication process and their family members' engagement in testing and risk-reducing strategies are needed.

Experiences of BRCA1/2 Gene Mutation-Positive Women With Cancer in Communicating Genetic Risk to Their Relatives.

BACKGROUND: When a woman is diagnosed with hereditary breast or ovarian cancer, family members may be at high risk of cancers associated with BRCA1/2 gene mutation and benefit from disclosure of the genetic test result. This duty of informing relatives may be distressing, or relatives may not be properly informed. OBJECTIVE: To qualitatively describe breast cancer patients' experiences communicating genetic risk of cancer to their relatives. METHODS: Probands with BRCA1/2 gene mutations were recruited from an oncology institute in Istanbul, Turkey, and interviewed by telephone. Qualitative content analysis was conducted to derive central elements of the 30 women's experiences communicating genetic risk to their relatives. RESULTS: Six themes were identified: response to genetic test results, reason for communication, feelings about communication, reflection after communication, results of communication, and needs. CONCLUSION: Women with cancer found to have BRCA1/2 gene mutations tended to share their genetic test results within the family. The main motives for sharing test results were the desire to encourage relatives to get tested and moral and ethical convictions. Women needed explicit information regarding cancer risk and risk-reducing strategies to act upon. IMPLICATIONS FOR PRACTICE: The women's feelings and reflections about the communication process were varied and suggest that personalized genetic risk communication interventions may better support women with BRCA1/2 gene mutations during and after communication with relatives. Long-term follow-up of those women is essential because of the need for informed decision on risk-reducing strategies.

Establishing the Genomic Knowledge Matrix for Nursing Science.

PURPOSE: To establish the knowledge needed to integrate the multiple branches of omics into nursing research to accelerate achieving the research recommendations of the Genomic Nursing Science Blueprint. METHODS: The creation of the Genomic Knowledge Matrix occurred in three phases. In phase 1, the Omics Nursing Science and Education Network (ONSEN) Education Workgroup completed an evidence, bioinformatics, and technology review to inform the components of the Matrix. The ONSEN Advisory Panel then reviewed and integrated revisions. Phase 3 solicited targeted public comment focused on education and research experts, and applicable revisions were made. FINDINGS: The Genomic Knowledge Matrix establishes the following content areas: cellular and molecular biology, system physiology, microbiology, and translational bioinformatics as the minimum required preparation for nurse scientists to understand omics and to integrate this knowledge into research. The Matrix also establishes levels of understanding needed to function based on the role of the nurse scientist. CONCLUSIONS: The Genomic Knowledge Matrix addresses knowledge important for nurse scientists to integrate genomics into their research. Building on prior recommendations and existing genomic competencies, the Matrix was designed to present key knowledge elements critical to understand omics that underpin health and disease. Knowledge depth varies based on the research role. CLINICAL RELEVANCE: The Genomic Knowledge Matrix provides the vital guidance for training nurse scientists in the integration of genomics. The flexibility of the Matrix also provides guidance to inform fundamental genomic content needed in core science content in undergraduate and graduate level nursing curricula.

Candidate gene/loci studies in cleft lip/palate and dental anomalies finds novel susceptibility genes for clefts.

PURPOSE: We revisited 42 families with two or more cleft-affected siblings who participated in previous studies. Complete dental information was collected to test the hypothesis that dental anomalies are part of the cleft phenotype spectrum, and can provide new opportunities for identification of cleft susceptibility genes. METHODS: Genotypes from 1489 single nucleotide polymorphism markers located in 150 candidate genes/loci were reanalyzed. Two sets of association analyses were carried out. First, we ran the analysis solely on the cleft status. Second, we assigned affection to any cleft or dental anomaly (tooth agenesis, supernumerary teeth, and microdontia) and repeated the analysis. RESULTS: Significant over-transmission was seen for a single nucleotide polymorphism in ankyrin repeat and sterile alpha motif domain containing 6 (rs4742741, 9q22.33; P = 0.0004) when a dental anomaly phenotype was included in the analysis. Significant over-transmission was also seen for a single nucleotide polymorphism in ERBB2 (rs1810132, 17q21.1; P = 0.0006). In the clefts only data, the most significant result was also for ERBB2 (P = 0.0006). Other markers with suggestive P values included interferon regulatory factor 6 and 6q21-q23 loci. In contrast to the above results, suggestive over-transmission of markers in GART, DPF3, and neurexin 3 were seen only when the dental anomaly phenotype was included in the analysis. CONCLUSIONS: These findings support the hypothesis that some loci may contribute to both clefts and congenital dental anomalies. Thus, including dental anomalies information in the genetics analysis of cleft lip and palate will provide new opportunities to map susceptibility loci for clefts.

A genome wide linkage scan for cleft lip and palate and dental anomalies.

We revisited 46 families with two or more siblings affected with an orofacial cleft that participated in previous genome wide studies and collected complete dental information. Genotypes from 392 microsatellite markers at 10 cM intervals were reanalyzed. We carried out four sets of genome wide analyses. First, we ran the analysis solely on the cleft status. Second, we assigned to any dental anomaly (tooth agenesis, supernumerary teeth, and microdontia) an affection status, and repeated the analysis. Third, we ran only the 19 families where the proband had a cleft with no dental anomalies. Finally, we ran only the 27 families that had a proband with cleft and additional dental anomalies outside the cleft area. Chromosomes (1, 2, 6, 8, 16, and 19) presented regions with LOD scores >2.0. Chromosome 19 has the most compelling results in our study. The LOD scores increased from 3.11 (in the scan of all 46 families with clefts as the only assigned affection status) to 3.91 when the 19 families whose probands present with no additional dental anomalies were studied, suggesting the interval 19p13.12-19q12 may contain a gene that contributes to clefts but not to dental anomalies. On the other hand, we found a LOD score of 3.00 in the 2q22.3 region when dental anomalies data were added to the analysis to define affection status. Our preliminary results support the hypothesis that some loci may contribute to both clefts and congenital dental anomalies. Also, adding dental anomalies information will provide new opportunities to map susceptibility loci for clefts.

PVRL1 variants contribute to non-syndromic cleft lip and palate in multiple populations.

Poliovirus Receptor Like-1 (PVRL1) is a member of the immunoglobulin super family that acts in the initiation and maintenance of epithelial adherens junctions and is mutated in the cleft lip and palate/ectodermal dysplasia 1 syndrome (CLPED1, OMIM #225000). In addition, a common non-sense mutation in PVRL1 was discovered more often among non-syndromic sporadic clefting cases in Northern Venezuela in a previous case-control study. The present work sought to ascertain the role of PVRL1 in the sporadic forms of orofacial clefting in multiple populations. Multiple rare and common variants from all three splice isoforms were initially ascertained by sequencing 92 Iowan and 86 Filipino cases and CEPH controls. Using a family-based analysis to examine these variants, the common glycine allele of the G361V coding variant was significantly overtransmitted among all orofacial clefting phenotypes (P = 0.005). This represented G361V genotyping from over 800 Iowan, Danish, and Filipino families. Among four rare amino acid changes found within the V1 and C1 domains, S112T and T131A were found adjacent to critical amino acid positions within the V1 variable domain, regions previously shown to mediate cell-to-cell and cell-to-virus adhesion. The T131A variant was not found in over 1,300 non-affected control samples although the alanine is found in other species. The serine of the S112T variant position is conserved across all known PVRL1 sequences. Together these data suggest that both rare and common mutations within PVRL1 make a minor contribution to disrupting the initiation and regulation of cell-to-cell adhesion and downstream morphogenesis of the embryonic face.