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.
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.
Guidelines for clinical management in Li-Fraumeni syndrome, a multiple-organ cancer predisposition condition, are limited. Whole-body magnetic resonance imaging (WBMRI) may play a role in ...surveillance of this high-risk population.
To assess the clinical utility of WBMRI in germline TP53 mutation carriers at baseline.
Clinical and research surveillance cohorts were identified through the Li-Fraumeni Exploration Research Consortium.
Cohorts that incorporated WBMRI for individuals with germline TP53 mutations from January 1, 2004, through October 1, 2016, were included.
Data were extracted by investigators from each cohort independently and synthesized by 2 investigators. Random-effects meta-analysis methods were used to estimate proportions.
The proportions of participants at baseline in whom a lesion was detected that required follow-up and in whom a new primary malignant neoplasm was detected.
A total of 578 participants (376 female 65.1% and 202 male 34.9%; mean SD age, 33.2 17.1 years) from 13 cohorts in 6 countries were included in the analysis. Two hundred twenty-five lesions requiring clinical follow-up were detected by WBMRI in 173 participants. Sixty-one lesions were diagnosed in 54 individuals as benign or malignant neoplasms. Overall, 42 cancers were identified in 39 individuals, with 35 new localized cancers treated with curative intent. The overall estimated detection rate for new, localized primary cancers was 7% (95% CI, 5%-9%).
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.
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.
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 Eco-Genetic Relationship Map (CEGRM). Hierarchical nonlinear models were fitted to characterize information gatherers, disseminators, and blockers.
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 second-degree 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).
Our results provide insight into which family members may, within a family-based intervention, effectively gather family risk information, disseminate information, and encourage discussions regarding shared family risk.
Eligibility guidelines for genetic testing may be revisited, given technological advances, plummeting costs, and proposals for population mutation screening. A key property of eligibility criteria is ...the tradeoff between the number of mutation carriers identified versus population members tested. We assess the fractions of mutation carriers identified, versus women undergoing mutation testing, for
founder mutation screening in U.S. Ashkenazi-Jewish women.
carrier probabilities, based on personal/family history, were calculated using the risk-prediction tool BRCAPRO for 4,589 volunteers (102 mutation carriers) in the population-based Washington Ashkenazi Study. For each carrier-probability threshold between 0% and 10%, we compared the percentage of founder mutations detected versus the percentage of women requiring mutation testing. PCR mutation testing was conducted at the NIH for the 3 Ashkenazi-Jewish founder mutations (5382insC and 185delAG in
, and 6174delT in
).
Identifying 90% of
founder mutations required testing the 60% of Ashkenazi-Jewish women with carrier probabilities exceeding 0.56%, potentially avoiding mutation testing for approximately 0.7 to 1.1 million U.S. Ashkenazi-Jewish women. Alternatively, testing the 44% whose carrier probability exceeded 0.78% identified 80% of mutation carriers, increasing to 89% of mutation carriers when accounting for cascade testing triggered after mutation-positive daughters were identified by screening. We present data on all carrier-probability thresholds, e.g., a 5% threshold identified 46% of mutation carriers while testing 10% of women.
Different carrier-probability thresholds offered diverse tradeoffs between numbers of identified mutation carriers versus women tested. Low carrier-probability thresholds identified 90% of
founder mutation carriers, without testing approximately 1 million U.S. Ashkenazi-Jewish women with lowest carrier probabilities.
In general, this risk-based framework could provide useful new options to consider during eligibility-criteria development for population mutation screening.
Establishment of an optimal cancer surveillance program is important to reduce cancer-related morbidity and mortality in individuals with Li-Fraumeni syndrome, a rare, highly penetrant cancer ...predisposition syndrome.
To determine the feasibility and efficacy of a comprehensive cancer screening regimen in Li-Fraumeni syndrome, using multiple radiologic techniques, including rapid whole-body magnetic resonance imaging (MRI) and laboratory measurements.
Baseline evaluation of a prospective cancer screening study was conducted from June 1, 2012, to July 30, 2016, at the National Cancer Institute, National Institutes of Health (an academic research facility). Participants included 116 individuals with Li-Fraumeni syndrome with a germline TP53 pathogenic variant who were aged 3 years or older at the time of baseline screening and had not received active cancer therapy at least 6 months prior to screening.
Detection of prevalent cancer with multimodal screening techniques and the need for additional evaluation.
Of the 116 study participants, 77 (66.4%) were female; median age was 37.6 years (range, 3-68 years). Baseline cancer screening led to the diagnosis of cancer in 8 (6.9%) individuals (2 lung adenocarcinomas, 1 osteosarcoma, 1 sarcoma, 1 astrocytoma, 1 low-grade glioma, and 2 preinvasive breast cancers ductal carcinoma in situ); all but 1 required only resection for definitive treatment. A total of 40 (34.5%) participants required additional studies to further investigate abnormalities identified on screening, with 32 having incidental, benign, or normal findings, resulting in a false-positive rate of 29.6%. Non-MRI techniques, including baseline blood tests, abdominal ultrasonography in children, mammography, and colonoscopy, did not lead to a diagnosis of prevalent cancer in our cohort.
This study describes the establishment and feasibility of an intensive cancer surveillance protocol for individuals with Li-Fraumeni syndrome. Prevalent cancers were detected at an early stage with baseline whole-body, brain, and breast MRI. Prospective screening of the participants is under way.
First some background material, then several papers on genetic counselor training, genetic counseling in specialty practices of cardiovascular and cancer genetics, papers presenting legal and ethical ...issues, incorporation of new counseling models, and finally, consideration of similarities and differences of genetic counseling and psychotherapy. Recent research has also emphasized the addition of social psychological theories and shared decision-making models. Since its inception we have aimed to deconstruct the Bcounseling^ in genetic counseling through a new definition Resta 2006, defining training competencies (Ferrier et al. 2013; Fine et al. 1996), publication of peer-reviewed papers that offer insights into the counseling process and more recently defining and validating a proposed genetic counseling model, the Reciprocal Engagement Model (REM) (Hartmann et al. 2015; Mc-Carthy-Veach et al. 2007; Redlinger-Grosse et al. 2016). ...we especially wanted to address the tension between trying to encourage rich psychological encounters between genetic counselors and our clients and the need to clearly define and distinguish the professional roles of genetic counselors and psychotherapists. ...in conjunction with this new paper, we have invited a commentary about the intersection of genetic counseling and psychotherapy (Redlinger-Grosse 2016). ...we close this issue with a paper that explores the interpersonal experience of several genetic counselors and their patients who maintained an ongoing personal connection after the completion of genetic counseling (Williams et al. 2016).
Familial aggregations of testicular germ cell tumor (FTGCT) have been well described, suggesting the existence of a hereditary TGCT subset. Approximately 1.4% of newly diagnosed TGCT patients report ...a positive family history of TGCT. Sons and siblings of TGCT patients have four- to sixfold and eight- to tenfold increases in TGCT risk respectively. Segregation analyses suggest an autosomal recessive mode of inheritance. Linkage analyses have identified several genomic regions of modest interest, although no high-penetrance cancer susceptibility gene has been mapped yet. These data suggest that the combined effects of multiple common alleles, each conferring modest risk, might underlie familial testicular cancer. Families display a mild phenotype: the most common number of affected families is 2. Age at diagnosis is 2-3 years younger for familial versus sporadic cases. The ratio of familial seminoma to nonseminoma is 1.0. FTGCT is more likely to be bilateral than sporadic TGCT. This syndrome is cancer site specific. Testicular microlithiasis is a newly recognized FTGCT component. Candidate gene-association studies have implicated the Y chromosome gr/gr deletion and PDE11A gene mutations as genetic modifiers of FTGCT risk. Two genomewide association studies of predominantly sporadic but also familial cases of TGCT have implicated the KIT-ligand, SPRY4, and BAK1 genes as TGCT risk modifiers. All five loci are involved in normal testicular development and/or male infertility. These genetic data provide a novel insight into the genetic basis of FTGCT, and an invaluable guide to future TGCT research.
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