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ABSTRACT: Family history-based risk assessment (FHRA) is a genetic tool for identifying those at risk of disease. Genome-wide association studies have shown that single nucleotide polymorphisms (SNP) are statistically associated with low- to moderate-level risks of diseases. There has been limited study of complementarity for these two assessment methods. We sought to compare cancer risk categorizations from FHRA and from Navigenics Personal Genome Screening (PGS). We compared FHRA with PGS for breast (22 females), prostate (22 males), and colon cancer (44 males and females) assessed by kappa (κ) statistic. We also assessed each participant's hereditary risk based on clinical criteria and/or gene-test results. Both FHRA and PGS placed 59%, 68% and 44% of participants into the same risk categories for breast, prostate, and colon cancer, respectively. Overall, however, there was little concordance in FHRA versus PGS for all three cancer risks (κ<0.2). FHRA assigned 22 with hereditary risk compared with PGS, which identified one as high risk (P<0.0001). We assessed nine with hereditary colorectal cancer risk, five with germline mutations, but none were classified as PGS high risk (P=0.0001). FHRA and PGS may be complementary tools for cancer risk assessment. However, evaluation of family history remains the standard to evaluate an individual's cancer risk until further research.
European journal of human genetics: EJHG 01/2012; 20(5):547-51. · 3.56 Impact Factor
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Hartmut P H Neumann,
Zoran Erlic,
Carsten C Boedeker,
Lisa A Rybicki,
Mercedes Robledo,
Mario Hermsen,
Francesca Schiavi,
Maurizio Falcioni,
Pingling Kwok,
Catherine Bauters, [......],
Matti Välimäki,
Witold Szyfter,
Ulrich Finckh,
Klaus Zerres,
Alberto Cascon,
Giuseppe Opocher,
Gerd J Ridder,
Andrzej Januszewicz,
Carlos Suarez,
Charis Eng
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ABSTRACT: Multiple genes and their variants that lend susceptibility to many diseases will play a major role in clinical routine. Genetics-based cost reduction strategies in diagnostic processes are important in the setting of multiple susceptibility genes for a single disease. Head and neck paraganglioma (HNP) is caused by germline mutations of at least three succinate dehydrogenase subunit genes (SDHx). Mutation analysis for all 3 costs approximately US$2,700 per patient. Genetic classification is essential for downstream management of the patient and preemptive management of family members. Utilizing HNP as a model, we wanted to determine predictors to prioritize the most heritable clinical presentations and which gene to begin testing in HNP presentations, to reduce costs of genetic screening. Patients were tested for SDHB, SDHC, and SDHD intragenic mutations and large deletions. Clinical parameters were analyzed as potential predictors for finding germline mutations. Cost reduction was calculated between prioritized gene testing compared with that for all genes. Of 598 patients, 30.6% had SDHx germline mutations: 34.4% in SDHB, 14.2% SDHC, and 51.4% SDHD. Predictors for an SDHx mutation are family history [odds ratio (OR), 37.9], previous pheochromocytoma (OR, 10.9), multiple HNP (OR, 10.6), age <or=40 years (OR, 4.0), and male gender (OR, 3.5). By screening only preselected cases and a stepwise approach, 60% cost reduction can be achieved, with 91.8% sensitivity and 94.5% negative predictive value. Our data give evidence that clinical parameters can predict for mutation and help prioritize gene testing to reduce costs in HNP. Such strategy is cost-saving in the practice of genetics-based personalized health care.
Cancer Research 04/2009; 69(8):3650-6. · 7.86 Impact Factor
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BMJ (Clinical research ed.). 01/2009; 339:b4253.
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ABSTRACT: Individuals with PTEN mutations have Cowden syndrome (CS), associated with breast, thyroid, and endometrial neoplasias. Many more patients with features of CS, not meeting diagnostic criteria (termed CS-like), are evaluated by clinicians for CS-related cancer risk. Germline mutations in succinate dehydrogenase subunits SDHB-D cause pheochromocytoma-paraganglioma syndrome. One to five percent of SDHB/SDHD mutation carriers have renal cell or papillary thyroid carcinomas, which are also CS-related features. SDHB-D may be candidate susceptibility genes for some PTEN mutation-negative individuals with CS-like cancers. To address this hypothesis, germline SDHB-D mutation analysis in 375 PTEN mutation-negative CS/CS-like individuals was performed, followed by functional analysis of identified SDH mutations/variants. Of 375 PTEN mutation-negative CS/CS-like individuals, 74 (20%) had increased manganese superoxide dismutase (MnSOD) expression, a manifestation of mitochondrial dysfunction. Among these, 10 (13.5%) had germline mutations/variants in SDHB (n = 3) or SDHD (7), not found in 700 controls (p < 0.001). Compared to PTEN mutation-positive CS/CS-like individuals, those with SDH mutations/variants were enriched for carcinomas of the female breast (6/9 SDH versus 30/107 PTEN, p < 0.001), thyroid (5/10 versus 15/106, p < 0.001), and kidney (2/10 versus 4/230, p = 0.026). In the absence of PTEN alteration, CS/CS-like-related SDH mutations/variants show increased phosphorylation of AKT and/or MAPK, downstream manifestations of PTEN dysfunction. Germline SDH mutations/variants occur in a subset of PTEN mutation-negative CS/CS-like individuals and are associated with increased frequencies of breast, thyroid, and renal cancers beyond those conferred by germline PTEN mutations. SDH testing should be considered for germline PTEN mutation-negative CS/CS-like individuals, especially in the setting of breast, thyroid, and/or renal cancers.
The American Journal of Human Genetics 08/2008; 83(2):261-8. · 10.60 Impact Factor
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ABSTRACT: Smith-Magenis syndrome (SMS) is a complex disorder that includes mental retardation, craniofacial and skeletal anomalies, and behavioral abnormalities. We report the molecular and genotype-phenotype analyses of 31 patients with SMS who carry 17p11.2 deletions or mutations in the RAI1 gene.
Patients with SMS were evaluated by fluorescence in situ hybridization and/or sequencing of RAI1 to identify 17p11.2 deletions or intragenic mutations, respectively, and were compared for 30 characteristic features of this disorder by the Fisher exact test.
In our cohort, 8 of 31 individuals carried a common 3.5 Mb deletion, whereas 10 of 31 individuals carried smaller deletions, two individuals carried larger deletions, and one individual carried an atypical 17p11.2 deletion. Ten patients with nondeletion harbored a heterozygous mutation in RAI1. Phenotypic comparison between patients with deletions and patients with RAI1 mutations show that 21 of 30 SMS features are the result of haploinsufficiency of RAI1, whereas cardiac anomalies, speech and motor delay, hypotonia, short stature, and hearing loss are associated with 17p11.2 deletions rather than RAI1 mutations (P<.05). Further, patients with smaller deletions show features similar to those with RAI1 mutations.
Although RAI1 is the primary gene responsible for most features of SMS, other genes within 17p11.2 contribute to the variable features and overall severity of the syndrome.
Genetics in Medicine 07/2006; 8(7):417-27. · 4.76 Impact Factor
