Patient actions and reactions after receiving negative results from expanded carrier screening.

With the expansion of carrier screening to general preconception and prenatal patient populations, most patients will receive negative results, which we define as indicating <25% risk of having a child with a genetic condition. Because there is limited experience with expanded carrier screening, it is important to understand how receiving negative results affects patients, especially as providers, payers, and policymakers consider whether to offer it. In this mixed-methods study, we asked preconception patients enrolled in the NextGen study about their expectations and experiences receiving negative expanded carrier screening results. Participants completed surveys at study enrollment (n = 110 women, 51 male partners), after receiving carrier results (n = 100 women, 38 male partners), after receiving secondary findings (n = 98 women, 36 male partners), and 6 months after receiving results (n = 95 women, 28 male partners). We also interviewed a subset of participants 12 to 24 months after receiving results (n = 24 women, 12 male partners). We found minimal negative emotional impact and privacy concerns, increased confidence in reproductive plans, and few changes to health behaviors, although some patients made health decisions based on misunderstandings of their results. These findings suggest that expanded carrier screening causes minimal psychosocial harms, but systems are needed to reduce the risk of misinterpreting results.

Modulation of cystic fibrosis lung disease by variants in interleukin-8.

Cystic fibrosis pulmonary disease is characterized by excessive and prolonged inflammation. CF Pulmonary disease severity exhibits considerable variation that, to some extent, appears to be due to the presence of modifier genes. Several components of the inflammatory response are known to have altered regulation in the CF lung. Genetic variants in 52 inflammatory genes were tested for associations with lung disease indices in a CF patient population (n=737) homozygous for the DeltaF508 cystic fibrosis transmembrane conductance regulator mutation. Variants in three inflammatory genes showed significant genotypic associations with CF lung disease severity, including IL8 and previously reported TGFbeta1 (P< or =0.05). When analyzed by gender, it was apparent that IL8 variant associations were predominantly due to males. The IL8 variants were tested in an additional CF population (n=385) and the association in males verified (P< or =0.01). The IL8 variants were in strong linkage disequilibrium with each other (R2> or =0.82), while variants in neighboring genes CXCL6, RASSF6 and PF4V1 did not associate (P> or =0.26) and were in weaker LD with each other and with the IL8 variants (0.01< or =R2< or =0.49). Studies revealed differential expression between the IL8 promoter variant alleles (P<0.001). These results suggest that IL8 variants modify CF lung disease severity and have functional consequences.

Demographic and phenotypic features of 70 families segregating Barrett's oesophagus and oesophageal adenocarcinoma.

BACKGROUND: Based on reported familial patterns, inheritance of a predisposition of developing Barrett's oesesophagus (BO) and oesophageal adenocarcinoma (OAC) likely follows an autosomal dominant model of most inherited cancer syndromes. oesophagus (BO) and oesophageal adenocarcinoma (OAC) likely follows an autosomal dominant model of most inherited cancer syndromes. AIMS: We analysed the phenotypic features of 70 familial BO/OAC families accrued for the purpose of initiating a linkage study to search for genes that contribute to susceptibility for BO/OAC. METHODS: Families with young or familial BO/OAC were recruited from participating institutions and self-referral from advertisement. RESULTS: A total of 70 families (173 affected and 784 unaffected individuals) were recruited into this study. Mean ages of diagnosis of BO and OAC among males were 50.6 and 57.4 years, respectively; among females, 52.1 and 63.5 years, respectively. The standardised incidence ratio (SIR) of cancers other than OAC or oesophagogastric junctional adenocarcinoma (OGJAC), among probands was 0.71. Seventy one percent of the pedigrees have "typical" structures with less than three affected individuals. Power calculations under realistic model assumptions suggest that if genetic heterogeneity is absent or limited, then DNA collection from members of these pedigrees could enable the identification of a novel candidate susceptibility gene for BO/OAC in a genome scan. CONCLUSIONS: This is the largest series of families with BO/OAC yet reported, features of which are consistent with inherited germline predisposition. Further, the SIR of cancers other than OAC/OGJAC was 0.71 among 70 probands, indicating these individuals were not more likely to develop non-OAC cancers.

HER2 evaluation and its impact on breast cancer treatment decisions.

BACKGROUND: Eighteen to twenty percent of breast cancer tumors show abnormal amplification of the Human Epidermal growth factor Receptor 2 (HER2) gene and increased expression of the associated protein. HER2 amplification is associated with rapid tumor proliferation and shorter disease-free and overall survival. Because women with HER2 amplification are more likely to benefit from treatment with the drug trastuzumab, testing for HER2 is recommended to guide therapy. However, little is known about use of HER2 testing in real-world settings. This study examined uptake, use, appropriateness of HER2 testing, and the relationship between HER2 test results and treatment decisions. METHODS: We assessed electronic data from 3,634 patients with invasive breast cancer diagnosed from 1998 to 2007 in a large integrated health system. We collected data on patient and tumor characteristics, HER2 testing status, test results, and trastuzumab treatment. RESULTS: From 1998 to 2000, the percent of patients who underwent HER2 evaluation increased from 12 to 94%; <3% of women with ductal carcinoma in situ, for whom HER2 testing is not recommended, were tested. Trastuzumab use increased 5-fold after 2004, when guidelines expanded to include recommending adjuvant treatment for early-stage breast cancer in addition to metastatic treatment. Ninety-five percent of women receiving trastuzumab had a positive HER2 result. After 2004, 55% of women with invasive breast cancer and overexpression of HER2 received trastuzumab treatment; this ranged from 44% of women with localized breast cancer to 80% of women with distant metastatic disease. CONCLUSIONS: These findings illustrate appropriate and effective implementation of a HER2 testing strategy in a managed care setting.

Health-related direct-to-consumer genetic tests: a public health assessment and analysis of practices related to Internet-based tests for risk of thrombosis.

BACKGROUND: Recent years have seen increased concern about direct-to-consumer (DTC) genetic testing (i.e., the sale and use of genetic tests without involving a health care provider). Numerous professional organizations have developed policies in this area. However, little systematic evidence exists to inform public policy about these tests. METHODS: We conducted a systematic search to identify genetic tests that are sold DTC without involving a health care provider. We evaluated the practices of companies offering DTC genetic tests for risk of thrombosis using criteria from multiple sources and a minimal set of key practices. RESULTS: We identified 84 instances of currently available health-related DTC genetic tests sold on 27 Web sites; the most common were for pharmacogenomics (12), risk of thrombosis (10), and nutrigenomics (10). For the DTC genetic tests for risk of thrombosis, we found low adherence to recommendations. Online information was frequently incomplete and had low agreement with professional recommendations. CONCLUSION: Our findings document the rapid growth in the availability of health-related DTC genetic tests and highlight the need to improve the delivery of DTC genetic tests. A major implication of this study is the need for the scientific and medical community to develop consistent recommendations to increase their impact.

Familial aggregation of Barrett's oesophagus, oesophageal adenocarcinoma, and oesophagogastric junctional adenocarcinoma in Caucasian adults.

BACKGROUND: Although familial clusters of Barrett's oesophagus and oesophageal adenocarcinoma have been reported, a familial predisposition to these diseases has not been systematically investigated. AIMS: To determine whether Barrett's oesophagus and oesophageal (or oesophagogastric junctional) adenocarcinoma aggregate in families. PATIENTS AND METHODS: A structured questionnaire eliciting details on reflux symptoms, exposure history, and family history was given to Caucasian case (n=58) subjects with Barrett's oesophagus, oesophageal adenocarcinoma, or oesophagogastric junctional adenocarcinoma, and to Caucasian control (n=106) subjects with symptomatic gastro-oesophageal reflux disease without Barrett's oesophagus. Reported diagnoses of family members were confirmed by review of medical records. RESULTS: The presence of a positive family history (that is, first or second degree relative with Barrett's oesophagus, oesophageal adenocarcinoma, or oesophagogastric junctional adenocarcinoma) was significantly higher among case subjects compared with controls (24% v 5%; p<0.005). Case subjects were more likely to be older (p<0.001) and male (74% v 43% male; p<0.0005) compared with control subjects. In a multivariate logistic regression analysis, family history was independently associated with the presence of Barrett's oesophagus, oesophageal adenocarcinoma, or oesophagogastric junctional adenocarcinoma (odds ratio 12.23, 95% confidence interval 3.34-44.76) after adjusting for age, sex, and the presence of obesity 10 or more years prior to study enrollment. CONCLUSIONS: Individuals with Barrett's oesophagus, oesophageal adenocarcinoma, or oesophagogastric junctional adenocarcinoma are more likely to have a positive family history of Barrett's oesophagus, oesophageal adenocarcinoma, or oesophagogastric junctional adenocarcinoma than individuals without Barrett's oesophagus, oesophageal adenocarcinoma, or oesophagogastric junctional adenocarcinoma. A positive family history should be considered when making decisions about screening endoscopy in patients with symptoms of gastro-oesophageal reflux.