Genotype-Phenotype Correlation in NF1: Evidence for a More Severe Phenotype Associated with Missense Mutations Affecting NF1 Codons 844–848

Neurofibromatosis type 1 (NF1), a common genetic disorder with a birth incidence of 1:2,000–3,000, is characterized by a highly variable clinical presentation. To date, only two clinically relevant intragenic genotype-phenotype correlations have been reported for NF1 missense mutations affecting p.Arg1809 and a single amino acid deletion p.Met922del. Both variants predispose to a distinct mild NF1 phenotype with neither externally visible cutaneous/plexiform neurofibromas nor other tumors. Here, we report 162 individuals (129 unrelated probands and 33 affected relatives) heterozygous for a constitutional missense mutation affecting one of five neighboring NF1 codons—Leu844, Cys845, Ala846, Leu847, and Gly848—located in the cysteine-serine-rich domain (CSRD). Collectively, these recurrent missense mutations affect ∼0.8% of unrelated NF1 mutation-positive probands in the University of Alabama at Birmingham (UAB) cohort. Major superficial plexiform neurofibromas and symptomatic spinal neurofibromas were more prevalent in these individuals compared with classic NF1-affected cohorts (both p < 0.0001). Nearly half of the individuals had symptomatic or asymptomatic optic pathway gliomas and/or skeletal abnormalities. Additionally, variants in this region seem to confer a high predisposition to develop malignancies compared with the general NF1-affected population (p = 0.0061). Our results demonstrate that these NF1 missense mutations, although located outside the GAP-related domain, may be an important risk factor for a severe presentation. A genotype-phenotype correlation at the NF1 region 844–848 exists and will be valuable in the management and genetic counseling of a significant number of individuals

Strategies for discussing long-term prognosis when deciding on cancer screening for adults over age 75

BackgroundConsideration of older adults’ 10-year prognosis is necessary for high-quality cancer screening decisions. However, few primary care providers (PCPs) discuss long-term (10-year) prognosis with older adults.MethodsTo learn PCPs’ and older adults’ perspectives on and to develop strategies for discussing long-term prognosis in the context of cancer screening decisions, we conducted qualitative individual interviews with adults 76–89 and focus groups or individual interviews with PCPs. We recruited participants from 4 community and 2 academic Boston-area practices and completed a thematic analysis of participant responses to open-ended questions on discussing long-term prognosis.ResultsForty-five PCPs (21 community-based) participated in 7 focus groups or 7 individual interviews. Thirty patients participated; 19 (63%) were female, 13 (43%) were non-Hispanic Black, and 13 (43%) were non-Hispanic white. Patients and PCPs had varying views on the utility of discussing long-term prognosis. “For some patients and for some families having this information is really helpful,” (PCP participant). Some participants felt that prognostic information could be helpful for future planning, whereas others thought the information could be anxiety-provoking or of “no value” because death is unpredictable; still others were unsure about the value of these discussions. Patients often described thinking about their own prognosis. Yet, PCPs described feeling uncomfortable with these conversations. Patients recommended that discussion of long-term prognosis be anchored to clinical decisions, that information be provided on how this information may be useful, and that patient interest in prognosis be assessed before prognostic information is offered. PCPs recommended that scripts be brief. These recommendations were used to develop example scripts to guide these conversations.ConclusionsWe developed scripts and strategies for PCPs to introduce the topic of long-term prognosis with older adults and to provide numerical prognostic information to those interested. Future studies will need to test the effect of these strategies in practice.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/173015/1/jgs17723-sup-0001-supinfo.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/173015/2/jgs17723.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/173015/3/jgs17723_am.pd

Scripts and Strategies for Discussing Stopping Cancer Screening with Adults &gt; 75 Years: a Qualitative Study

BackgroundDespite guidelines recommending not to continue cancer screening for adults &gt; 75&nbsp;years old, especially those with short life expectancy, primary care providers (PCPs) feel ill-prepared to discuss stopping screening with older adults.ObjectiveTo develop scripts and strategies for PCPs to use to discuss stopping cancer screening with adults &gt; 75.DesignQualitative study using semi-structured interview guides to conduct individual interviews with adults &gt; 75&nbsp;years old and focus groups and/or individual interviews with PCPs.ParticipantsForty-five PCPs and 30 patients &gt; 75&nbsp;years old participated from six community or academic Boston-area primary care practices.ApproachParticipants were asked their thoughts on discussions around stopping cancer screening and to provide feedback on scripts that were iteratively revised for PCPs to use when discussing stopping mammography and colorectal cancer (CRC) screening.ResultsTwenty-one (47%) of the 45 PCPs were community based. Nineteen (63%) of the 30 patients were female, and 13 (43%) were non-Hispanic white. PCPs reported using different approaches to discuss stopping cancer screening depending on the clinical scenario. PCPs noted it was easier to discuss stopping screening when the harms of screening clearly outweighed the benefits for a patient. In these cases, PCPs felt more comfortable being more directive. When the balance between the benefits and harms of screening was less clear, PCPs endorsed shared decision-making but found this approach more challenging because it was difficult to explain why to stop screening. While patients were generally enthusiastic about screening, they also reported not wanting to undergo tests of little value and said they would stop screening if their PCP recommended it. By the end of participant interviews, no further edits were recommended to the scripts.ConclusionsTo increase PCP comfort and capability to discuss stopping cancer screening with older adults, we developed scripts and strategies that PCPs may use for discussing stopping cancer screening

Genetic diversity of the KIR/HLA system and susceptibility to hepatitis C virus-related diseases

Background The variability in the association of host innate immune response to Hepatitis C virus (HCV) infection requires ruling out the possible role of host KIR and HLA genotypes in HCV-related disorders: therefore, we therefore explored the relationships between KIR/HLA genotypes and chronic HCV infection (CHC) as they relate to the risk of HCV-related hepatocarcinoma (HCC) or lymphoproliferative disease progression. Methods and Findings We analyzed data from 396 HCV-positive patients with CHC (n = 125), HCC (118), and lymphoproliferative diseases (153), and 501 HCV-negative patients. All were HIV and HBV negative. KIR-SSO was used to determine the KIR typing. KIR2DL5 and KIR2DS4 variants were performed using PCR and GeneScan analysis. HLA/class-I genotyping was performed using PCR-sequence-based typing. The interaction between the KIR gene and ligand HLA molecules was investigated. Differences in frequencies were estimated using Fisher’s exact test, and Cochran-Armitage trend test. The non-random association of KIR alleles was estimated using the linkage disequilibrium test. We found an association of KIR2DS2/KIR2DL2 genes, with the HCV-related lymphoproliferative disorders. Furthermore, individuals with a HLA-Bw6 KIR3DL1+ combination of genes showed higher risk of developing lymphoma than cryoglobulinemia. KIR2DS3 gene was found to be the principal gene associated with chronic HCV infection, while a reduction of HLA-Bw4 + KIR3DS1+ was associated with an increased risk of developing HCC. Conclusions Our data highlight a role of the innate-systemin developing HCV-related disorders and specifically KIR2DS3 and KIR2D genes demonstrated an ability to direct HCV disease progression, and mainly towards lymphoproliferative disorders.Moreover the determination of KIR3D/HLA combination of genes direct the HCV progression towards a lymphoma rather than an hepatic disease. In this contest IFN-α therapy, a standard therapy for HCV-infection and lymphoproliferative diseases, known to be able to transiently enhance the cytotoxicity of NK-cells support the role of NK cells to counterstain HCV-related and lymphoproliferative diseases