SNP'ing at nasopharyngeal cancer susceptibility: for whom the bell TOLLs.
Explore the source record for details and available documents.
Genetic Predisposition to Disease↗
Biomedical subjects
Micheala A Aldred
Publications and source records attributed to Micheala A Aldred.
Mutations of the TGF-beta type II receptor BMPR2 in pulmonary arterial hypertension.
Pulmonary arterial hypertension (PAH) is clinically characterized by a sustained elevation in mean pulmonary artery pressure leading to significant morbidity and mortality. The disorder is typically sporadic, and in such cases the term idiopathic PAH (IPAH) is used. However, cases that occur within families (familial PAH (FPAH)) display similar clinical and histopathological features, suggesting a common etiology. Heterozygous mutations of a type II member of the TGF-beta cell signaling superfamily known as BMPR2 on chromosome 2q33 have been identified in many kindreds with FPAH, yet display both reduced penetrance and sex bias. This report presents the compilation of data for 144 distinct mutations that alter the coding sequence of the BMPR2 gene identified in 210 independent PAH subjects. This large data set characterizes the extent of sequence variation and reveals that the majority (71%) of mutations in FPAH and IPAH comprise nonsense, frameshift, and splice-site defects, and gene rearrangements. These predict premature termination of the transcript with likely loss through the process of nonsense-mediated decay (NMD). A total of 44 missense mutations were identified that substitute amino acid residues at highly conserved sites within recognized functional domains of the mature receptor. We assess this category of mutations in the context of their heterogeneous effects on cell signaling when assayed by in vitro cell-based systems. Disease-causing mutation hot-spots within BMPR2 are summarized. Taken together, these observations are likely to aid in the development of targeted mutation detection strategies relevant for patient management. Finally, we examine the age- and sex-dependent reduced penetrance of BMPR2 mutations by reviewing bmpr2 animal models and the requirement for additional genetic and/or environmental modifiers of disease. In conclusion, these data provide compelling genetic evidence that haploinsufficiency is the predominant molecular mechanism underlying disease predisposition, and support the concept of a critical threshold of signaling activity below which disease may be precipitated.
Bone Morphogenetic Protein Receptors, Type II↗
BMPR2 gene rearrangements account for a significant proportion of mutations in familial and idiopathic pulmonary arterial hypertension.
Mutations of the BMPR2 gene predispose to pulmonary arterial hypertension (PAH), a serious, progressive disease of the pulmonary vascular system. However, despite the fact that most PAH families are consistent with linkage to the BMPR2 locus, sequencing only identifies mutations in some 55% of familial cases and between 10% and 40% of cases without a family history (idiopathic or IPAH). We therefore conducted a systematic analysis for larger gene rearrangements in panels of both familial and idiopathic PAH cases that were negative on sequencing of coding regions. Analysis of exon dosage across the entire gene using Multiplex Ligation-dependent Probe Amplification identified nine novel rearrangements and enabled full characterization at the exon level of previously reported deletions. Overall, BMPR2 rearrangements were identified in 7 of 58 families and 6 of 126 IPAH cases, suggesting that gross rearrangements underlie around 12% of all FPAH cases and 5% of IPAH. Importantly, two deletions encompassed all functional protein domains and are predicted to result in null mutations, providing the strongest support yet that the predominant molecular mechanism for disease predisposition is haploinsufficiency. Dosage analysis should now be considered an integral of part of the molecular work-up of PAH patients.
Bone Morphogenetic Protein Receptors, Type II↗
Genetics of pseudohypoparathyroidism types Ia and Ic.
Pseudohypoparathyroidism (PHP) types Ia and Ic result from heterozygous inactivating mutations of Gs alpha, the alpha-subunit of the heterotrimeric stimulatory G-protein, Gs. Both are characterized by a combination of Albright's hereditary osteodystrophy and, when the mutation is maternally inherited, end-organ resistance to multiple hormones. Due to complex tissue-specific imprinting of Gs alpha, paternally-derived mutations do not usually lead to hormone resistance. More than 100 mutations have been characterized in patients with PHP-Ia and one mutation in type Ic. These are scattered throughout the gene, with one significant mutational hotspot in exon 7. Identification of mutations in a clinical service setting is important for accurate genetic counselling and clinical management of affected families. However, only 70-80% of mutations are identified by direct sequencing of coding exons and splice junctions. Screening for whole exon deletions and intronic or regulatory mutations in mutation-negative families is therefore now an important priority to establish the full mutational spectrum in these conditions.
Fibrous Dysplasia, Polyostotic↗
Genetic classification of benign and malignant thyroid follicular neoplasia based on a three-gene combination.
Thyroid carcinoma is a common endocrine cancer with a favorable prognosis if subjected to timely treatment. However, the clinical identification of follicular thyroid carcinoma (FTC) among patients with benign thyroid nodules is still a challenge. Preoperative fine needle aspiration-based cytology cannot always differentiate follicular carcinomas from benign follicular neoplasias. Because current methods fail to improve preoperative diagnosis of thyroid nodules, new molecular-based diagnoses should be explored. We conducted a microarray-based study to reveal the genetic profiles unique to FTC and follicular adenomas (FAs), to identify the most parsimonious number of genes that could accurately differentiate between benign and malignant follicular thyroid neoplasia. We confirmed our data by quantitative RT-PCR and immunohistochemistry in two independent validation sets with a total of 114 samples. We were able to identify three genes, cyclin D2 (CCND2), protein convertase 2 (PCSK2), and prostate differentiation factor (PLAB), that allow the accurate molecular classification of FTC and FA. Two independent validation sets revealed that the combination of these three genes could differentiate FTC from FA with a sensitivity of 100%, specificity of 94.7%, and accuracy of 96.7%. In addition, our model allowed the identification of follicular variants of papillary thyroid carcinoma with an accuracy of 85.7%. Three-gene profiling of thyroid nodules can accurately predict the diagnosis of FTC and FA with high sensitivity and specificity, thus identifying promising targets for further investigation to ultimately improve preoperative diagnosis.
Adenocarcinoma, Follicular↗
Investigation of second genetic hits at the BMPR2 locus as a modulator of disease progression in familial pulmonary arterial hypertension.
BACKGROUND: Primary pulmonary arterial hypertension (PAH) is a potentially devastating condition resulting from occlusion of the pulmonary arterioles by the formation of vascular lesions. Heterozygous mutations in the gene encoding the bone morphogenetic protein receptor type II (BMPR2) have been identified in both familial (FPAH) and idiopathic PAH. Mutant alleles are typically of low penetrance, indicating that other factors are required for the onset of PAH. Previous reports have suggested that the characteristic plexiform lesions in affected lungs are akin to neoplasia, showing monoclonal expansion and microsatellite instability. We hypothesized that in patients with germline mutations, BMPR2 might behave as a classic tumor suppressor gene, with somatic loss of the wild-type allele contributing to disease progression. METHODS AND RESULTS: To test this hypothesis, plexiform and concentric vascular lesions were serially microdissected from lung explant tissue derived from 7 FPAH cases. DNA was analyzed for loss of heterozygosity at BMPR2 and for microsatellite instability (MSI) at 5 loci. MSI was detected in 1 of 37 lesions at a single locus, BAT-26, whereas heterozygosity at BMPR2 was retained at all informative loci. We also describe a FPAH patient carrying biallelic constitutional missense mutations of BMPR2 who manifested disease at a stage and manner similar to heterozygous patients. CONCLUSIONS: Taken together, these data demonstrate that MSI is uncommon in FPAH and suggest that somatic loss of the remaining wild-type BMPR2 allele in heterozygous mutation carriers likely does not play a significant role in modulating the onset or progression of FPAH.
Adult↗
Transforming growth factor-beta receptor mutations and pulmonary arterial hypertension in childhood.
BACKGROUND: Pulmonary arterial hypertension (PAH) is a potentially fatal vasculopathy that can develop at any age. Adult-onset disease has previously been associated with mutations in BMPR2 and ALK-1. Presentation in early life may be associated with congenital heart disease but frequently is idiopathic. METHODS AND RESULTS: We performed mutation analysis in genes encoding receptor members of the transforming growth factor-beta cell-signaling pathway in 18 children (age at presentation <6 years) with PAH. Sixteen children were initially diagnosed with idiopathic PAH and 2 with PAH in association with congenital heart defects. Germ-line mutations were observed in 4 patients (22%) (age at disease onset, 1 month to 6 years), all of whom presented with idiopathic PAH. The BMPR2 mutations (n=2, 11%) included a partial gene deletion and a nonsense mutation, both arising de novo in the proband. Importantly, a missense mutation of ALK-1 and a branch-site mutation of endoglin were also detected. Presenting clinical features or progression of pulmonary hypertension did not distinguish between patients with mutations in the different genes or between those without mutations. CONCLUSIONS: The cause of PAH presenting in childhood is heterogeneous in nature, with genetic defects of transforming growth factor-beta receptors playing a critical role.
Activin Receptors, Type I↗
Silencing of the maternally imprinted tumor suppressor ARHI contributes to follicular thyroid carcinogenesis.
The two most common subtypes of thyroid cancer, follicular thyroid carcinoma (FTC) and papillary thyroid carcinoma, have been extensively studied, but our fundamental understanding of the molecular events in thyroid epithelial oncogenesis is still limited. Unreported data from our previous published global gene expression analysis revealed that the tumor suppressor gene aplysia ras homolog I (ARHI) is frequently underexpressed in FTCs. In this study, we elucidated the frequency and mechanism of ARHI silencing in benign and malignant thyroid neoplasia. We demonstrated that underexpression of ARHI occurs principally in FTCs (P = 0.0018), including its oncocytic variant (11 of 13), even at minimally invasive stage but not classic papillary thyroid carcinoma (two of seven) or follicular adenoma (FA) (three of 14). FTCs show strong allelic imbalance with reduction in copy number/loss of heterozygosity (LOH) in 69%, compared with less than 10% for FAs. In combination with our LOH data, bisulfite sequencing in a subset of samples revealed that FA displays a symmetric methylation pattern, likely representing one unmethylated allele and one presumptively imprinted allele, whereas FTC shows a virtually complete methylation pattern, representing LOH of the nonimprinted allele with only the hypermethylated allele remaining. Furthermore, we showed that pharmacologic inhibition of histone deacetylation but not demethylation could reactivate ARHI expression in the FTC133 FTC cell line. Therefore, our data suggest that silencing of the putative maternally imprinted tumor suppressor gene ARHI, primarily by large genomic deletion in conjunction with hypermethylation of the genomically imprinted allele, serves as a key early event in follicular thyroid carcinogenesis.
Adenocarcinoma, Follicular↗
Papillary and follicular thyroid carcinomas show distinctly different microarray expression profiles and can be distinguished by a minimum of five genes.
PURPOSE: We have previously conducted independent microarray expression analyses of the two most common types of nonmedullary thyroid carcinoma, namely papillary thyroid carcinoma (PTC) and follicular thyroid carcinoma (FTC). In this study, we sought to combine our data sets to shed light on the similarities and differences between these tumor types. MATERIALS AND METHODS: Microarray data from six PTCs, nine FTCs, and 13 normal thyroid samples were normalized to remove interlaboratory variability and then analyzed by unsupervised clustering, t test, and by comparison of absolute and change calls. Expression changes in four genes not previously implicated in thyroid carcinogenesis were verified by reverse transcriptase polymerase chain reaction on these same samples, together with eight additional FTC tumors. RESULTS: PTCs showed two distinct groups of genes that were either over- or underexpressed compared with normal thyroid, whereas the predominant changes in FTCs were of decreased expression. Five genes could collectively distinguish the two tumor types. PTCs showed overexpression of CITED1, claudin-10 (CLDN10), and insulin-like growth factor binding protein 6 (IGFBP6) but showed no change in expression of caveolin-1 (CAV1) or -2 (CAV2); conversely, FTCs did not express CLDN10 and had decreased expression of IGFBP6 and/or CAV1 and CAV2. CONCLUSION: PTC and FTC show distinctive microarray expression profiles, suggesting that either they have different molecular origins or they diverge distinctly from a common origin. Furthermore, if verified in a larger series of tumors, these genes could, in combination with known tumor-specific chromosome translocations, form the basis of a valuable diagnostic tool.
Adenocarcinoma, Follicular↗
Low prevalence of MYOC mutations in UK primary open-angle glaucoma patients limits the utility of genetic testing.
Primary open angle glaucoma (POAG) affects 1% of people over age 40. Early detection and treatment can prevent blindness, but the disease is often asymptomatic until a late stage. Positive family history is an important risk factor and previous studies indicate that approximately 5% of POAG results from mutations in the myocilin ( MYOC) gene, raising the possibility of identifying individuals genetically predisposed to glaucoma. We collected DNA samples from 426 unselected UK POAG patients and analyzed them for MYOC mutations. The Q368X mutation was found in six patients (1.4%). No other mutations were identified, suggesting that amongst patients unselected for family history, the prevalence of MYOC mutations in the UK is lower than in other populations. Genetic and glaucoma screening was offered to first-degree relatives of these six probands (group 1) and of age/sex-matched mutation-negative controls (group 2). Of 11 group-1 relatives, three carried Q368X, one of whom already had glaucoma. Notably, of the 13 relatives in both groups who were mutation negative, one was already being treated for ocular hypertension. We therefore caution against changing glaucoma surveillance regimens in such individuals and suggest that routine untargeted genetic testing for MYOC mutations in patients with POAG would be of limited value until additional significant genetic risk factors are identified.
Adult↗
Molecular classification of parathyroid neoplasia by gene expression profiling.
The current classification of sporadic parathyroid neoplasia, specifically the distinction of adenoma from multiple gland neoplasia (double adenoma and nonfamilial primary hyperplasia) is problematic and results in a relatively high rate of clinical error. Oligonucleotide microarrays (Affymetrix U133A) were used to evaluate parathyroid samples from 61 patients; 35 adenomas, 10 nonfamilial multiple gland neoplasia, 3 familial primary hyperplasia, 8 renal-induced hyperplasia, and 5 from patients without parathyroid disease (normals). A multiclass comparison using supervised clustering identified distinct gene signatures for each class of parathyroid samples. We developed a predictor model that correctly identified 34 of 35 cases of adenoma, 9 of 10 cases of nonfamilial multiple gland neoplasia, and identified a minimum set of 11 genes for the distinction of adenoma versus multiple gland neoplasia. All methods of unsupervised clustering showed two related but different types of parathyroid adenomas that we have arbitrarily designated as type 1 and type 2 adenomas. Multiple gland parathyroid neoplasia, which represents either synchronous or asynchronous autonomous growth in two, three, or all four parathyroid glands, is a distinct molecular entity and does not represent the molecular pathogenesis of adenoma occurring in multiple glands.
Adenoma↗
Caveolin-1 and caveolin-2,together with three bone morphogenetic protein-related genes, may encode novel tumor suppressors down-regulated in sporadic follicular thyroid carcinogenesis.
Thyroid cancer is common, occurring in 1% of the general population. The relative frequencies of two of the most common subtypes of thyroid carcinoma, follicular (FTC) and papillary (PTC), vary depending on the regional prevalence of iodine deficiency. Although PTC has been more extensively studied, the etiology of sporadic FTC is poorly understood. To further elucidate this, we conducted microarray expression comparison of FTC tumors and normal thyroid tissue. Three commonly down-regulated genes, caveolin-1, caveolin-2, and GDF10/BMP3b, were chosen for further study on the basis of their localization to two chromosomal regions, 7q31.1 and 10q11.1, that commonly show loss of heterozygosity in FTC. Two additional genes, glypican-3 and a novel chordin-like gene, were also analyzed in view of their involvement in bone morphogenetic protein signaling and possible interaction with GDF10. Each of these five genes was down-regulated in >or=15 of 19 FTC tumors (79%) by semiquantitative reverse transcription-PCR. Caveolin-1 showed preferential down-regulation of its beta-isoform at both the mRNA and protein level, suggesting a distinct function for this isoform. Caveolin-1 is of particular functional interest because it has been shown to interact with PTEN, the tumor suppressor gene mutated in Cowden syndrome, an inherited multiple hamartoma syndrome that includes predisposition to FTC. Immunohistochemical analysis of 141 thyroid tumors of various histological types showed significantly fewer caveolin-1-positive tumors in FTCs, including insular type tumors, and Hurthle cell carcinomas in comparison with normal thyroid. PTC and anaplastic thyroid carcinomas did not show significant down-regulation, and thus, caveolin-1 may become a useful molecular marker to differentiate the various histologies of thyroid malignancies.
Adenocarcinoma, Follicular↗
Peroxisome proliferator-activated receptor gamma is frequently downregulated in a diversity of sporadic nonmedullary thyroid carcinomas.
Peroxisome proliferator-activated receptor gamma (PPARgamma) has previously been implicated in the pathogenesis of follicular thyroid carcinoma (FTC), where a translocation with PAX8 has been reported in some 50% of tumors in three small series. The resultant fusion protein inhibits normal PPARgamma function by a dominant-negative mechanism. In a series of 19 FTCs, we identified this translocation in only two tumors (10.5%). However, microarray analysis and semiquantitative RT-PCR demonstrated greatly reduced PPARgamma expression in 13 of 17 (76%) nontranslocation tumors. Immunohistochemical analysis of 142 thyroid tumors showed a statistically significant reduction in PPARgamma immunoreactive protein, not only in FTCs but also in papillary thyroid carcinomas and Hurthle cell carcinomas. This suggests that while the overall frequency of the PAX8-PPARgamma translocation in FTCs may be lower than previously thought, functional downregulation of PPARgamma is a key event in multiple types of thyroid neoplasia and is a possible target for therapeutic intervention.
Carcinoma↗
Constitutional deletion of chromosome 20q in two patients affected with albright hereditary osteodystrophy.
Albright hereditary osteodystrophy (AHO) results from heterozygous inactivation of G(s)alpha, encoded by the GNAS1 locus on the distal long arm of chromosome 20. This autosomal dominant condition is characterized by short stature, obesity, shortening of the metacarpals and metatarsals, and variable mental retardation and may also include end-organ resistance to multiple hormones. Small insertions and deletions or point mutations of GNAS1 are found in approximately 80% of patients with AHO. The remainder may be accounted for by larger genomic rearrangements, but none have been reported to date. We now describe two patients with constitutional 20q deletions and features of AHO. Such deletions are rare in the published literature and have not previously been associated with AHO. Molecular genetic analysis confirmed complete deletion of GNAS1 in both patients. Parental origin could be determined in both cases and provides further support for the parent-of-origin effect on the biochemical status of patients with AHO.
Adolescent↗