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1.  Disclosing Individual CDKN2A Research Results to Melanoma Survivors: Interest, Impact, and Demands on Researchers 
Background
Whether to return individual research results from cancer genetics studies is widely debated, but little is known about how participants respond to results disclosure or about its time and cost burdens on investigators.
Methods
We recontacted participants at one site of a multicenter genetic epidemiologic study regarding their CDKN2A gene test results and implications for melanoma risk. Interested participants were disclosed their results by telephone and followed for 3 months.
Results
Among 39 patients approached, 27 were successfully contacted, and 19 (70% uptake) sought results, including three with mutations. Prior to disclosure, participants endorsed numerous benefits of receiving results (mean = 7.7 of 9 posed), including gaining information relevant to their children’s disease risk. Mean psychological well-being scores did not change from baseline, and no decreases to melanoma prevention behaviors were noted. Fifty-nine percent of participants reported that disclosure made participation in future research more likely. Preparation for disclosure required 40 minutes and $611 per recontact attempt. An additional 78 minutes and $68 was needed to disclose results.
Conclusion
Cancer epidemiology research participants who received their individual genetic research results showed no evidence of psychological harm or false reassurance from disclosure and expressed strong trust in the accuracy of results. Burdens to our investigators were high, but protocols may differ in their demands and disclosure may increase participants’ willingness to enroll in future studies.
Impact
Providing individual study results to cancer genetics research participants poses potential challenges for investigators, but many participants desire and respond positively to this information.
doi:10.1158/1055-9965.EPI-10-1045
PMCID: PMC3833711  PMID: 21307304
2.  Risk of Non-Melanoma Cancers in First-Degree Relatives of CDKN2A Mutation Carriers 
The purpose of this study was to quantify the risk of cancers other than melanoma among family members of CDKN2A mutation carriers using data from the Genes, Environment and Melanoma study. Relative risks (RRs) of all non-melanoma cancers among first-degree relatives (FDRs) of melanoma patients with CDKN2A mutations (n = 65) and FDRs of melanoma patients without mutations (n = 3537) were calculated as the ratio of estimated event rates (number of cancers/total person-years) in FDRs of carriers vs noncarriers with exact Clopper–Pearson-type tests and 95% confidence intervals (CIs). All statistical tests were two-sided. There were 56 (13.1%) non-melanoma cancers reported among 429 FDRs of mutation carriers and 2199 (9.4%) non-melanoma cancers in 23 452 FDRs of noncarriers. The FDRs of carriers had an increased risk of any cancer other than melanoma (56 cancers among 429 FDRs of carrier probands vs 2199 cancers among 23 452 FDRs of noncarrier probands; RR = 1.5, 95% CI = 1.2 to 2.0, P = .005), gastrointestinal cancer (20 cancers among 429 FDRs of carrier probands vs 506 cancers among 23 452 FDRs of noncarrier probands; RR = 2.4, 95% CI = 1.4 to 3.7, P = .001), and pancreatic cancer (five cancers among 429 FDRs of carrier probands vs 41 cancers among 23 452 FDRs of noncarrier probands; RR = 7.4, 95% CI = 2.3 to 18.7, P = .002). Wilms tumor was reported in two FDRs of carrier probands and three FDRs of noncarrier probands (RR = 40.4, 95% CI = 3.4 to 352.7, P = .005). The lifetime risk of any cancer other than melanoma among CDKN2A mutation carriers was estimated as 59.0% by age 85 years (95% CI = 39.0% to 75.4%) by the kin-cohort method, under the standard assumptions of Mendelian genetics on the genotype distribution of FDRs conditional on proband genotype.
doi:10.1093/jnci/djs221
PMCID: PMC3379723  PMID: 22534780
3.  Gene Expression Patterns in Mismatch Repair-Deficient Colorectal Cancers Highlight the Potential Therapeutic Role of Inhibitors of the PI3K-AKT-mTOR pathway 
Purpose
High-frequency microsatellite instable (MSI-H) tumors account for roughly 15% of colorectal cancers (CRC). Therapeutic decisions for CRC are empirically based and currently do not emphasize molecular subclassification despite of the increasing collection of gene expression information. Our objective was to identify low molecular weight compounds with preferential activity against MSI CRCs using combined gene expression data sets.
Experimental Design
Three expression/query signatures (discovery data set) characterizing MSI-H CRC were matched with information derived from changes induced in cell lines by 164 compounds, using the systems biology tool “Connectivity Map”. A series of sequential filtering and ranking algorithms were used to select the candidate compounds. Compounds were validated using two additional expression/query signatures (validation data set). Cytotoxic, cell cycle and apoptosis effects of validated compounds were evaluated in a panel of cell lines.
Results
Fourteen of the 164 compounds were validated as targeting MSI-H cells lines using the bioinformatics approach; Rapamycin, LY-294002, 17-AAG and Trichostatin-A were the most robust candidate compounds. In vitro results showed that MSI-H cell lines due to hypermethylation of MLH1 are preferentially targeted by Rapamycin (18.3 vs 4.4 μM, P=0.0824) and LY-294002 (15.02 vs 10.37 μM, P=0.0385) when compared to MSS cells. Preferential activity was also observed in MSH2 and MSH6-mutant cells.
Conclusion
Our study demonstrates that the PI3K-AKT-mTOR pathway is of special relevance in mismatch repair-deficient CRC. In addition, we show that amalgamation of gene expression information across studies provides a robust approach for selection of potential therapies corresponding to specific groups of patients.
doi:10.1158/1078-0432.CCR-08-2432
PMCID: PMC3425357  PMID: 19351759
Microsatellite instability; colorectal cancer; gene expression patterns; rapamycin; mTOR pathway; PI3K inhibitors
4.  Returning Individual Research Results: Development of a Cancer Genetics Education and Risk Communication Protocol 
The obligations of researchers to disclose clinically and/or personally significant individual research results are highly debated, but few empirical studies have addressed this topic. We describe the development of a protocol for returning research results to participants at one site of a multicenter study of the genetic epidemiology of melanoma. Protocol development involved numerous challenges: (1) deciding whether genotype results merited disclosure; (2) achieving an appropriate format for communicating results; (3) developing education materials; (4) deciding whether to retest samples for additional laboratory validation; (5) identifying and notifying selected participants; and (6) assessing the impact of disclosure. Our experience suggests potential obstacles depending on researcher resources and the design of the parent study, but offers a process by which researchers can responsibly return individual study results and evaluate the impact of disclosure.
doi:10.1525/jer.2010.5.3.17
PMCID: PMC3159194  PMID: 20831418
genetic testing; cancer; CDKN2A; risk communication; return of research results; protocol development
5.  Recreational physical activity modifies the association between a common GH1 polymorphism and colorectal cancer risk 
Growth hormone may be associated with the development of colorectal cancer directly and/or indirectly via increased serum level of IGF-I. Regular physical activity can decrease insulin-resistance and modulates IGF-I production. A common polymorphism in the GH1 gene, rs2665802, was previously shown to be associated with lower IGF-I levels and decreased colorectal cancer (CRC) risk. We investigated the association of this polymorphism and physical activity with colorectal cancer risk in a case-control study.
Methods
The analysis includes 3041 (1402 cases and 1639 controls) participants in the Molecular Epidemiology of Colorectal Cancer study, a population-based case-control study in Northern Israel. Analysis was carried out separately in two sets. The first set included 1248 subjects (625 cases, 623 controls), and the second validation set consisted of 1793 subjects (777 cases, 1016 controls).
Results
No association was found between the studied polymorphism and CRC risk. However, evaluation of gene-environment interactions revealed an interaction between leisure time physical activity and the GH1 polymorphism, which was consistent in both sets(p-interaction=0.005). The genotype AA was associated with decreased risk of CRC among individuals who did not engage in any such activity; OR=0.76(0.52–0.98), whereas the same genotype was marginally associated with increased risk among individuals who reported physical activity; OR=1.38(0.98–1.94).
Conclusions
We found that the A allele of the rs2665802 polymorphism is associated with reduced risk of CRC only among physically inactive individuals, indicating an interaction between physical activity and the GH/IGF-I system. A replication of the observed findings and further investigation of the underlying mechanism is warranted.
doi:10.1158/1055-9965.EPI-08-0062
PMCID: PMC2665206  PMID: 19064544

Results 1-5 (5)