Dataset Information

Distinct expression profiles for PTEN transcript and its splice variants in Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome.

ABSTRACT: Cowden syndrome (CS) and Bannayan-Riley-Ruvalcaba syndrome (BRRS) are autosomal dominant hamartoma syndromes. Germline PTEN mutations have been associated with 85% of CS cases and 65% of BRRS cases and also with other disorders, which are collectively referred to as the "PTEN hamartoma tumor syndrome." The human PTEN gene has been previously found to express two naturally occurring splice variants (SVs). Recently, we identified eight novel naturally occurring PTEN SVs that result in different downstream signaling effects: SV3a, SV3b, SV3c (inclusion of various lengths of intron 3 3' of exon 3), SV5a, SV5b, SV5c, SV5d (inclusion of various lengths of intron 5 3' of exon 5), and SV Delta Ex6 (deletion of exon 6). We therefore sought to characterize the relative expression of 5', middle, and 3' full-length PTEN mRNA (FL-PTEN) and also of these eight PTEN SVs in 85 (65 female and 20 male) patients with CS/BRRS (with or without PTEN mutations) compared with 27 controls, using a SYBR green quantitative polymerase chain reaction method. Significantly reduced FL-PTEN levels were found in the probands, compared with those of controls (P < .01). Apart from FL-PTEN, SV3a is the most consistently relatively underexpressed in patients compared with controls. The patients showed relative underexpression of SV3a and SV3b and overexpression of SV5b (P = .005, P = .02, and P = .04, respectively). Indeed, there appears to be an SV expressional genotype-phenotype correlation in which the SV expressional profiles are distinct among CS, CS-like, and BRRS. The reduced FL-PTEN transcript expression, associated with differential expression of PTEN SVs, regardless of PTEN mutation status, supports the concept that modulation of PTEN inactivation may also occur at the transcription level influencing the specific phenotypes seen in these syndromes.

SUBMITTER: Sarquis MS

PROVIDER: S-EPMC1474112 | biostudies-literature | 2006 Jul

REPOSITORIES: biostudies-literature

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Distinct expression profiles for PTEN transcript and its splice variants in Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome.

Sarquis Marta S MS Agrawal Shipra S Shen Lei L Pilarski Robert R Zhou Xiao-Ping XP Eng Charis C

American journal of human genetics 20060522 1

Cowden syndrome (CS) and Bannayan-Riley-Ruvalcaba syndrome (BRRS) are autosomal dominant hamartoma syndromes. Germline PTEN mutations have been associated with 85% of CS cases and 65% of BRRS cases and also with other disorders, which are collectively referred to as the "PTEN hamartoma tumor syndrome." The human PTEN gene has been previously found to express two naturally occurring splice variants (SVs). Recently, we identified eight novel naturally occurring PTEN SVs that result in different do ...[more]

PMID: 16773562

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Project description:Patients with heritable cancer syndromes characterized by germline PTEN mutations (termed PTEN hamartoma tumor syndrome, PHTS) benefit from PTEN-enabled cancer risk assessment and clinical management. PTEN-wildtype patients (~50%) remain at increased risk of developing certain cancers. Existence of germline mutations in other known cancer susceptibility genes has not been explored in these patients, with implications for different medical management. We conducted a 4-year multicenter prospective study of incident patients with features of Cowden/Cowden-like (CS/CS-like) and Bannayan-Riley-Ruvalcaba syndromes (BRRS) without PTEN mutations. Exome sequencing and targeted analysis were performed including 59 clinically actionable genes from the American College of Medical Genetics and Genomics (ACMG) and 24 additional genes associated with inherited cancer syndromes. Pathogenic or likely pathogenic cancer susceptibility gene alterations were found in 7 of the 87 (8%) CS/CS-like and BRRS patients and included MUTYH, RET, TSC2, BRCA1, BRCA2, ERCC2 and HRAS. We found classic phenotypes associated with the identified genes in 5 of the 7 (71.4%) patients. Variant positive patients were enriched for the presence of second malignant neoplasms compared to patients without identified variants (OR = 6.101, 95% CI 1.143-35.98, p = 0.035). Germline variant spectrum and frequencies were compared to The Cancer Genome Atlas (TCGA), including 6 apparently sporadic cancers associated with PHTS. With comparable overall prevalence of germline variants, the spectrum of mutated genes was different in our patients compared to TCGA. Intriguingly, we also found notable enrichment of variants of uncertain significance (VUS) in our patients (OR = 2.3, 95% CI 1.5-3.5, p = 0.0002). Our data suggest that only a small subset of PTEN-wildtype CS/CS-like and BRRS patients could be accounted for by germline variants in some of the known cancer-related genes. Thus, the existence of alterations in other and more likely non-classic cancer-associated genes is plausible, reflecting the complexity of these heterogeneous hereditary cancer syndromes.

Project description:Germline heterozygous PTEN mutations cause subsets of Cowden syndrome (CS) and Bannayan-Riley-Ruvalcaba syndrome (BRRS); these subsets are characterized by high risks of breast, thyroid, and other cancers and, in one subset, autism spectrum disorder (ASD). Up to 10% of individuals with PTENMUT CS, CS-like syndrome, or BRRS have germline SDHx (succinate dehydrogenase, mitochondrial complex II) variants, which modify cancer risk. PTEN contributes to metabolic reprogramming; this is a well-established role in a cancer context. Relatedly, SDH sits at the crossroad of the electron transport chain and tricarboxylic acid (TCA) cycle, two central bioenergetic pathways. Intriguingly, PTENMUT and SDHMUT individuals have reduced SDH catalytic activity, resulting in succinate accumulation; this indicates a common genotype-independent biochemical alteration. Here, we conducted a TCA targeted metabolomics study on 511 individuals with CS, CS-like syndrome, or BRRS with various genotypes (PTEN or SDHx, mutant or wild type [WT]) and phenotypes (cancer or ASD) and a series of 187 population controls. We found consistent TCA cycle metabolite alterations in cases with various genotypes and phenotypes compared to controls, and we found unique correlations of individual metabolites with particular genotype-phenotype combinations. Notably, increased isocitrate (p = 1.2 × 10-3), but reduced citrate (p = 5.0 × 10-4), were found to be associated with breast cancer in individuals with PTENMUT/SDHxWT. Conversely, increased lactate was associated with neurodevelopmental disorders regardless of genotype (p = 9.7 × 10-3); this finding was replicated in an independent validation series (n = 171) enriched for idiopathic ASD (PTENWT, p = 5.6 × 10-4). Importantly, we identified fumarate (p = 1.9 × 10-2) as a pertinent metabolite, distinguishing individuals who develop ASD from those who develop cancer. Our observations suggest that TCA cycle metabolite alterations are germane to the pathobiology of PTEN-related CS and BRRS, as well as genotype-independent ASD, with implications for potential biomarker and/or therapeutic value.

Project description:Germline intragenic mutations in PTEN are associated with 80% of patients with Cowden syndrome (CS) and 60% of patients with Bannayan-Riley-Ruvalcaba syndrome (BRRS). The underlying genetic causes remain to be determined in a considerable proportion of classic CS and BRRS without a polymerase chain reaction (PCR)-detectable PTEN mutation. We hypothesized that gross gene deletions and mutations in the PTEN promoter might alternatively account for a subset of apparently mutation-negative patients with CS and BRRS. Using real time and multiplex PCR techniques, we identified three germline hemizygous PTEN deletions in 122 apparently mutation-negative patients with classic CS (N=95) or BRRS (N=27). Fine mapping suggested that one deletion encompassed the whole gene and the other two included exon 1 and encompassed exons 1-5 of PTEN, respectively. Two patients with the deletion were diagnosed with BRRS, and one patient with the deletion was diagnosed with BRRS/CS overlap (features of both). Thus 3 (11%) of 27 patients with BRRS or BRRS/CS-overlap had PTEN deletions. Analysis of the PTEN promoter revealed nine cases (7.4%) harboring heterozygous germline mutations. All nine had classic CS, representing almost 10% of all subjects with CS. Eight had breast cancers and/or benign breast tumors but, otherwise, oligo-organ involvement. PTEN protein analysis, from one deletion-positive and five PTEN-promoter-mutation-positive samples, revealed a 50% reduction in protein and multiple bands of immunoreactive protein, respectively. In contrast, control samples showed only the expected band. Further, an elevated level of phosphorylated Akt was detected in the five promoter-mutation-positive samples, compared with controls, indicating an absence of or marked reduction in functional PTEN. These data suggest that patients with BRRS and CS without PCR-detected intragenic PTEN mutations be offered clinical deletion analysis and promoter-mutation analysis, respectively.

Dataset Information

Distinct expression profiles for PTEN transcript and its splice variants in Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome.

Publications

Distinct expression profiles for PTEN transcript and its splice variants in Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome.

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