Dyskeratosis congenita (DC) is an inherited bone marrow failure syndrome in which the known susceptibility genes (DKC1, TERC, and TERT) belong to the telomere maintenance pathway; patients with DC have very short telomeres. We used multicolor flow fluorescence in situ hybridization analysis of median telomere length in total blood leukocytes, granulocytes, lymphocytes, and several lymphocyte subsets to confirm the diagnosis of DC, distinguish patients with DC from unaffected family members, identify clinically silent DC carriers, and discriminate between patients with DC and those with other bone marrow failure disorders. We defined "very short" telomeres as below the first percentile measured among 400 healthy control subjects over the entire age range. Diagnostic sensitivity and specificity of very short telomeres for DC were more than 90% for total lymphocytes, CD45RA؉/CD20؊ naive T cells, and CD20؉ B cells. Granulocyte and total leukocyte assays were not specific; CD45RA؊ memory T cells and CD57؉ NK/NKT were not sensitive. We observed very short telomeres in a clinically normal family member who subsequently developed DC. We propose adding leukocyte subset flow fluorescence in situ hybridization telomere length measurement to the evaluation of patients and families suspected to have DC, because the correct diagnosis will substantially affect patient management. (Blood.

Background Li-Fraumeni syndrome (LFS) is an autosomal dominant cancer predisposition syndrome characterized by very high lifetime cancer risk and early age at diagnosis of a wide cancer spectrum. Precise estimates for first and subsequent cancers risk are lacking. Methods The NCI’s LFS Study includes families meeting diagnostic criteria for LFS or Li-Fraumeni-like syndrome, and individuals with a germline TP53 mutation, choroid plexus carcinoma, adrenocortical carcinoma, or ≥3 cancers. We estimated cumulative risk and annual hazards for first and second cancer among TP53 mutation carriers (TP53+) using MATLAB. Results We evaluated 286 TP53+ individuals from 107 families. Cumulative cancer incidence was 50% by age 31 among TP53+ females and 46 among males, and nearly 100% by age 70 for both. Cancer risk was highest after age 20 for females, mostly due to breast cancer, while among males risk was higher in childhood and later adulthood. Among females, the cumulative incidence by age 70 for breast cancer, soft tissue sarcoma (STS), brain cancer, and osteosarcoma were 54%, 15%, 6%, and 5%, respectively. Among males, the incidence was 22%, 19%, and 11% for STS, brain cancer, and osteosarcoma. 49% of those with one cancer developed at least another cancer after a median of 10 years. Average age-specific risk of developing a second cancer was comparable to that of developing a first cancer. Conclusions Cumulative cancer risk in TP53+ individuals was high and varied by gender, age, and cancer type. Additional work, including prospective risk estimates, is needed to better inform personalized risk management.

Summary Fanconi anaemia (FA), dyskeratosis congenita (DC), Diamond-Blackfan anaemia (DBA), and Shwachman-Diamond syndrome (SDS) comprise major inherited bone marrow failure syndromes (IBMFS). Adverse events include severe bone marrow failure (BMF), myelodysplastic syndrome (MDS), acute myeloid leukaemia (AML), and solid tumours (ST). The natural history of FA is well characterised; hazard rates in the other syndromes have not yet been quantified. An open cohort was established at the National Cancer Institute (NCI) in 2002. Patients enrolled prior to December, 2007 were followed up to December, 2008. Diagnoses were confirmed with standard tests. Age-associated risks of adverse events were calculated. Most patients in each syndrome survived to young adulthood. Patients with FA had earlier onset of cancers, need for stem cell transplant, and death; followed by DC; DBA and SDS were mildest. While FA and DC patients had markedly increased risks of cancer, AML and MDS, there were no cases of leukaemia in DBA or SDS patients. The NCI cohort provides the first direct quantitative comparison of timing and magnitude of cancer risk in the IBMFS. The findings demonstrate that both FA and DC are major cancer susceptibility syndromes. The IBMFS, historically considered paediatric disorders, have important management implications for physicians treating adult patients.

Updated from their original publication in 2004, these cancer genetic counseling recommendations describe the medical, psychosocial, and ethical ramifications of counseling at-risk individuals through genetic cancer risk assessment with or without genetic testing. They were developed by members of the Practice Issues Subcommittee of the National Society of Genetic Counselors Familial Cancer Risk Counseling Special Interest Group. The information contained in this document is derived from extensive review of the current literature on cancer genetic risk assessment and counseling as well as the personal expertise of genetic counselors specializing in cancer genetics. The recommendations are intended to provide information about the process of genetic counseling and risk assessment for hereditary cancer disorders rather than specific information about individual syndromes. Essential components include the intake, cancer risk assessment, genetic testing for an inherited cancer syndrome, informed consent, disclosure of genetic test results, and psychosocial assessment. These recommendations should not be construed as dictating an exclusive course of management, nor does use of such recommendations guarantee a particular outcome. These recommendations do not displace a health care provider's professional judgment based on the clinical circumstances of a client.

These cancer genetic counseling recommendations describe the medical, psychosocial, and ethical ramifications of identifying at-risk individuals through cancer risk assessment with or without genetic testing. They were developed by members of the Practice Issues Subcommittee of the National Society of Genetic Counselors Cancer Genetic Counseling Special Interest Group. The information contained in this document is derived from extensive review of the current literature on cancer genetic risk assessment and counseling as well as the personal expertise of genetic counselors specializing in cancer genetics. The recommendations are intended to provide information about the process of genetic counseling and risk assessment for hereditary cancer disorders rather than specific information about individual syndromes. Key components include the intake (medical and family histories), psychosocial assessment (assessment of risk perception), cancer risk assessment (determination and communication of risk), molecular testing for hereditary cancer syndromes (regulations, informed consent, and counseling process), and follow-up considerations. These recommendations should not be construed as dictating an exclusive course of management, nor does use of such recommendations guarantee a particular outcome. These recommendations do not displace a health care provider's professional judgment based on the clinical circumstances of a client.

Objectives-Given the importance of the dissemination of accurate family history to assess disease risk, we characterized the gatherers, disseminators, and blockers of health information within families at high genetic risk of cancer.Methods-A total of 5466 personal network members of 183 female participants of the Breast Imaging Study from 124 families with known mutations in the BRCA1/2 genes (associated with high risk of breast, ovarian, and other types of cancer) were identified by using the Colored EcoGenetic Relationship Map (CEGRM). Hierarchical nonlinear models were fitted to characterize information gatherers, disseminators, and blockers.Results-Gatherers of information were more often female (P<.001), parents (P<.001), and emotional support providers (P<.001). Disseminators were more likely female first-and seconddegree relatives (both P<.001), family members in the older or same generation as the participant (P<.001), those with a cancer history (P<.001), and providers of emotional (P<.001) or tangible support (P<.001). Blockers tended to be spouses or partners (P<.001) and male, first-degree relatives (P<.001).Correspondence should be sent to Laura M. Koehly, PhD, Building 31, Room B1B37D, 31 Center Drive-MSC 2073, Bethesda, MD 20892 (koehlyl@mail.nih. gov) Contributors All authors were part of team discussions leading to developing the research questions and the design and execution of this study. L. M. Koehly developed the specific hypotheses, analysis plan, and codebook for data construction; completed the analysis; and led the writing of the article. J. A. Peters and R. Kenen originated and published the CEGRM concept as a research assessment tool. J. A. Peters subsequently translated the concept into a clinical research protocol and conducted the participant interviews. L. M. Hoskins conducted participant interviews and coded responses. A. L. Ersig and N. R. Kuhn aided in developing the codebook for data construction and coded interview responses. J. T. Loud contributed to the design of the parent study, recruited study participants, and performed medical assessment within the study protocol. M. H. Greene contributed to the design and funding of the parent study. All authors contributed to the writing of the article.The views expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the Department of Health and Human Services or the US government. NIH Public Access Author ManuscriptAm J Public Health. Author manuscript; available in PMC 2010 January 7. Conclusions-Our results provide insight into which family members may, within a familybased intervention, effectively gather family risk information, disseminate information, and encourage discussions regarding shared family risk.Acquiring accurate information regarding familial disease risk is a key component of a proactive approach to health care. This information is needed both to permit an accurate risk assessment and to develop appropriate, cost-effective prevention and risk-r...

These data suggest clinical utility of baseline WBMRI in TP53 germline mutation carriers and may form an integral part of baseline clinical risk management in this high-risk population.

Purpose: Patients seeking genetic testing for inherited breast cancer risk are typically educated by genetic counselors; however, the growing demand for cancer genetic testing will likely exceed the availability of counselors trained in this area. We compared the effectiveness of counseling alone versus counseling preceded by use of a computer-based decision aid among women referred to genetic counseling for a family or personal history of breast