Does a somatic deletion in RET clarify the sporadic nature of medullary thyroid carcinoma?
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Carcinoma, Medullary↗
Biomedical subjects
O Gimm
Publications and source records attributed to O Gimm.
HRPT2 mutations are associated with malignancy in sporadic parathyroid tumours.
BACKGROUND: Hyperparathyroidism is a common endocrinopathy characterised by the formation of parathyroid tumours. In this study, we determine the role of the recently identified gene, HRPT2, in parathyroid tumorigenesis. METHODS: Mutation analysis of HRPT2 was undertaken in 60 parathyroid tumours: five HPT-JT, three FIHP, three MEN 1, one MEN 2A, 25 sporadic adenomas, 17 hyperplastic glands, two lithium associated tumours, and four sporadic carcinomas. Loss of heterozygosity at 1q24-32 was performed on a subset of these tumours. RESULTS: HRPT2 somatic mutations were detected in four of four sporadic parathyroid carcinoma samples, and germline mutations were found in five of five HPT-JT parathyroid tumours (two families) and two parathyroid tumours from one FIHP family. One HPT-JT tumour with germline mutation also harboured a somatic mutation. In total, seven novel and one previously reported mutation were identified. "Two-hits" (double mutations or one mutation and loss of heterozygosity at 1q24-32) affecting HRPT2 were found in two sporadic carcinomas, two HPT-JT-related and two FIHP related tumours. CONCLUSIONS: The results in this study support the role of HRPT2 as a tumour suppressor gene in sporadic parathyroid carcinoma, and provide further evidence for HRPT2 as the causative gene in HPT-JT, and a subset of FIHP. In light of the strong association between mutations of HRPT2 and sporadic parathyroid carcinoma demonstrated in this study, it is hypothesised that HRPT2 mutation is an early event that may lead to parathyroid malignancy and suggest intragenic mutation of HRPT2 as a marker of malignant potential in both familial and sporadic parathyroid tumours.
Adult↗
An update on thyroid surgery.
Surgery has been the treatment of choice for many disorders of the thyroid gland, both benign and malignant, for many decades. However, surgery has not been invariable but has continued to change in accordance with research results. In benign cases, surgery has generally evolved to be as organ preserving as possible. In several instances, however, a more radical extent of resection seems justified in order to ensure that the risk of recurrence is as low as possible. For instance, total thyroidectomy may be beneficial in patients with endemic multinodular goitre or young patients with Graves' disease and accompanying cold nodules or high levels of autoantibodies. Several tools, e.g. magnifying glasses, bipolar coagulation forceps and neuromonitoring, are available to identify and preserve the recurrent laryngeal nerve and the parathyroid glands, hence keeping the morbidity at a low level. Most recently, minimally invasive surgery has been successfully used in treating both benign and malignant disorders of the thyroid gland. In the case of malignant disorders, minimally invasive surgery may become an attractive alternative to open surgery if a limited surgical extent is justified, e.g. in patients with micro-PTC (papillary thyroid carcinoma, diameter less than 1 cm). Whether a limited surgical approach is also justified in other cases, e.g. in any patient with intrathyroidal PTC or patients with micro-FTC (follicular thyroid carcinoma), remains to be shown and is the subject of ongoing investigations. One of the most intriguing recent discoveries is the identification of genotype-phenotype correlations in patients with hereditary medullary thyroid carcinoma. In these patients, the timing and extent of surgery may depend not only on the patient's age and serum levels of the tumour marker calcitonin but also on the specific germline RET proto-oncogene mutation. Surgery will certainly continue to play an important role in the treatment of thyroid diseases and may be increasingly based on individual findings instead of general recommendations.
Adenocarcinoma, Follicular↗
Calcitonin kinetics in the early postoperative period of medullary thyroid carcinoma.
INTRODUCTION: Calcitonin is a sensitive marker for medullary thyroid carcinoma. Normalisation of calcitonin levels following resection of medullary thyroid carcinoma has been described after a few hours; however, it may be observed more than 4 weeks after surgery. The aim of this study was to correlate the postoperative calcitonin kinetics with preoperative calcitonin levels and tumour stage. Furthermore, we wanted to test the prognostic impact of the calcitonin kinetics. Therefore, only patients with postoperative normalisation of calcitonin levels (biochemical cure) were included in this study. METHODS: Fourteen biochemically cured patients were analysed, including measurement of postoperative basal and pentagastrin-stimulated calcitonin concentration. With respect to the time of postoperative basal calcitonin normalisation, patients were classified into two groups: (A) patients with normalisation of basal calcitonin levels within 24 h and (B) patients with normalisation of basal calcitonin levels later than 24 h postoperatively. RESULTS: Eight patients were found to have normalisation of basal calcitonin levels within 24 h (group A). In the remaining six patients (group B), the period to normalisation of basal calcitonin levels varied from 6 days to 14 days and longer. There were no differences between the two groups with regard to tumour size, number and pattern of lymph node metastases and tumour stage. However, preoperative basal calcitonin levels were significantly different (258 ng/ml vs 955 ng/ml, P<0.01). In the group with slow-decreasing calcitonin levels, no strong correlation between the preoperative level and the postoperative time to normalisation of basal calcitonin levels could be established, which may be due to the small number of patients. After a median follow-up of 21 months, no patient developed tumour recurrence. However, an increased basal calcitonin level was observed in one patient from group B. All other patients had normal basal and peak calcitonin levels. CONCLUSION: Using a highly sensitive calcitonin assay, we demonstrated that normalisation of basal calcitonin levels may be delayed in patients suffering from medullary thyroid carcinoma. The lack of correlation of preoperative levels and the time to normalisation of the basal calcitonin levels, as well as the positive pentagastrin test in some of the patients, argues that this phenomenon is not simply due to prolonged biochemical calcitonin elimination. Nevertheless, a prognostic influence could not be shown in this study due to the short follow up-period. Further investigations and a longer follow-up are necessary to determine the nature and the prognostic impact of delayed normalisation of calcitonin levels.
Adult↗
Over-representation of a germline variant in the gene encoding RET co-receptor GFRalpha-1 but not GFRalpha-2 or GFRalpha-3 in cases with sporadic medullary thyroid carcinoma.
In contrast to the hereditary form of medullary thyroid carcinoma (MTC), little is known about the etiology of sporadic MTC. Somatic gain-of-function mutations in the RET proto-oncogene, encoding a receptor tyrosine kinase, are found in an average of 40% of sporadic MTC. We analysed 31 sporadic MTC for somatic and germline variants in GFRA1, GFRA2 and GFRA3 which encode the co-receptors of RET. Although there were no somatic mutations in any of the three genes, a sequence variant (-193C>G) in the 5'-UTR of GFRA1 was found in 15% of cases. Three patients were heterozygous (het); another three patients homozygous (hom) for the G variant. The G allele was not observed in 31 race-matched normal controls. Hence, the relative frequency of this variant in sporadic MTC cases and controls differed significantly (P<0.05). Since this variant lies in the 5' UTR, likely at the transcriptional start site, we analysed for differential expression of GFRalpha-1 at the transcript and protein levels. At the mRNA level, GFRA1 was over-expressed in tumors harboring the rare variant (P=0.06). The presence of the G polymorphic allele seemed to be associated with increased expression by immunostaining for GFRalpha-1. Interestingly, cytoplasmic staining was stronger in intensity for het patients and nuclear staining predominant in hom cases. In conclusion, mutation analysis of GFRA1, GFRA2 and GFRA3 revealed over-representation of a rare variant in GFRA1 (-193C>G) in the germline of sporadic MTC cases. Our data suggest that the mechanism is related to over-expression of GFRalpha-1 and differential subcellular compartmentalization but the precise mechanism as to how it acts as a low penetrance susceptibility allele for the development of sporadic MTC remains to be elucidated.
Carcinoma, Medullary↗
Mutation analysis of NTRK2 and NTRK3, encoding 2 tyrosine kinase receptors, in sporadic human medullary thyroid carcinoma reveals novel sequence variants.
Somatic mutations in the proto-oncogene RET are found in 25% to 80% of sporadic medullary thyroid carcinomas (MTCs). The significance of somatic RET mutation in MTC initiation and progression, however, remains unknown. Like RET, TRK is a neurotrophic receptor tyrosine kinase. Immunostaining has shown that only a subset of normal C cells expresses Trk family receptors, but in C-cell hyperplasia, they consistently express NTRK2, with variable expression of NTRK1 and NTRK3. In later stages of MTC, NTRK2 expression was reduced while NTRK3 expression was increased. In the context of these data, we sought to determine whether sequence variants in NTRK2 and NTRK3 are responsible for these differences in protein expression. We determined the genomic structure of NTRK2 and found that it consists of at least 17 exons varying in size from 36 to 306 bp. Mutation analysis of sporadic MTC did not reveal any sequence variants in NTRK2 but did reveal 3 variants in NTRK3, c.573C >T (N191N, exon 5), c.678T > C (N226N, exon 6) and c.1488C > G (A496A, exon 12) occurring among 19 chromosomes (31%), 1 chromosome (2%) and 24 chromosomes (39%), respectively. Corresponding germline also harbored these variants. There was a trend toward excess association of the NTRK3 variant c.1488C > G (A496A) in cases (24/62 chromosomes, 39%) compared to controls (18/62, 29%), but this difference did not reach significance (p > 0.05). The remaining 2 NTRK3 variants occurred with similar frequencies between MTC cases and population-matched controls (19 vs. 17 and 1 vs. 0, p > 0.05). We conclude that sequence variants in NTRK2 and NTRK3 are not likely to be responsible for large differences in expression at the protein level, but we cannot exclude very low penetrance effects.
Carcinoma, Medullary↗
Thyroid cancer.
Four types of thyroid cancer comprise more than 98% of all thyroid malignancies. Papillary thyroid carcinoma (PTC) may have a very benign course while undifferentiated thyroid carcinoma (UTC) belongs to the most aggressive human malignancies. A variety of genes have been identified to be involved in the pathogenesis of thyroid carcinoma. Somatic Ras mutations seem to be an early event and are frequently found in follicular thyroid carcinomas. Somatic rearrangements of RET and TRK are almost exclusively found in PTC and may be found in early stages. Germline RET missense mutations lead to hereditary medullary thyroid carcinoma (MTC). In contrast, the significance of somatic RET mutations in sporadic MTC is unknown. p53 seems to play a crucial role in the dedifferentiation process of thyroid carcinoma. The precise role of PTEN remains to be elucidated. The only clearly identified exogenous factor that may lead to thyroid carcinoma (mainly PTC) is radiation. Of interest, radiation is capable to induce RET rearrangements. In general, early diagnosis is mandatory to enable the chance of cure. Surgery is the treatment of choice. Depending on the tumour type, surgery in combination with either radioiodine, external radiation or chemotherapy often enables the control of local tumour burden. In MTC and UTC, once thyroid cancer is spread to distant organs, efficacious therapeutic agents are almost non-existing. However, our growing knowledge of genes involved in thyroidal oncogenesis may contribute to the development of more effective treatment modalities. Some preliminary data on gene therapy are quite promising.
Adenocarcinoma, Follicular↗
Transient ectopic expression of PTEN in thyroid cancer cell lines induces cell cycle arrest and cell type-dependent cell death.
The tumour suppressor gene PTEN/MMAC1/TEP1 has been implicated in a variety of human cancers and several inherited hamartoma tumour syndromes, including Cowden syndrome, which has a high risk of breast and thyroid cancer. We have previously reported that overexpression of PTEN in MCF-7 breast cancer cells induces cell cycle arrest and apoptosis. In this study, we analysed PTEN status at both the structural and expression levels and explored PTEN's growth-suppressive effects on thyroid. We found that 1 of 10 thyroid cancer lines [follicular thyroid carcinoma FTC-133] had hemizygous deletion and a splice variant IVS4--19G-->A in the remaining allele. Four lines, including FTC-133, express PTEN mRNA at low levels. In general, PTEN protein levels correlated with mRNA levels, except for NPA87, which has low levels of transcript and relatively high levels of PTEN protein. Transient expression of PTEN in seven thyroid cancer cell lines resulted in G(1) arrest in two well differentiated papillary thyroid cancer lines (PTCs) and both G(1) arrest and cell death in the remaining five lines, including three FTCs, one poorly differentiated PTC and one undifferentiated thyroid cancer. The level of phosphorylated Akt was inversely correlated with the endogenous level of PTEN protein and overexpression of PTEN-blocked Akt phosphorylation in all cells analysed. Our results suggest that downregulation of PTEN expression at the mRNA level plays a role in PTEN inactivation in thyroid cancer and PTEN exerts its tumour-suppressive effect on thyroid cancer through the inhibition of cell cycle progression alone or both cell cycle progression and cell death.
Adenocarcinoma, Follicular↗
["Physiological" and "neoplastic" C-cell hyperplasia of the thyroid. Morphologically and biologically distinct entities?].
C-cell hyperplasia (CCH) occurs regularly in the setting of type 2 multiple endocrine neoplasia (MEN2), either separately or in association with medullary thyroid carcinoma (MTC). It can also accompany sporadic MTC and appear without any tumour association. To test the practicability of the terms "physiologic" and "neoplastic", 18 cases with incidental sporadic, non-MTC associated CCH were investigated and the morphological patterns were described. We found CCH of various degrees, including so-called neoplastic CCH. In 16 of the 18 cases, a MEN2 setting could be ruled out by mutation analysis of the RET proto-oncogene. Morphologically, one can not distinguish with certainty between sporadic and hereditary or reactive and tumour-associated CCH. While MEN2-associated CCH can be regarded as true preneoplasia, sporadic CCH possesses variable biologic potential. The preneoplastic potential of sporadic CCH is still obscure. A pure morphological distinction between "physiologic" and "neoplastic" CCH regardless of the RET status should not be used.
Adult↗
Diagnosis and therapy of sporadic and familial medullary thyroid carcinoma.
Medullary thyroid carcinoma (MTC) is a rare thyroid malignancy. About 75% are sporadic (sMTC) while the remaining 25% are hereditary (hMTC). The treatment of choice for both sMTC and hMTC is surgery. An adequate initial operation provides the best chance of cure. Hence, the diagnosis of MTC should be made preoperatively. In sMTC, ultrasound, ultrasound-guided fine-needle aspiration cytology and measurement of calcitonin levels (basal and after injection of calcitonin-stimulating reagents, e.g., pentagastrin) are sensitive diagnostic tools. In hMTC, identification of a germline mutation in the proto-oncogene RET is sufficient for making the diagnosis. Total thyroidectomy is recommended in all patients, sporadic and hereditary. In addition, lymphadenectomy of the cervicocentral and both cervicolateral compartments should be performed. The only indication to perform a less extensive operation may be given in young patients with hMTC. Sufficient treatment of MTC beyond local disease is still non-existent. Future research should concentrate on this issue.
Adolescent↗
Cloning and characterization of the human GFRA2 locus and investigation of the gene in Hirschsprung disease.
The glial-cell-line-derived neurotrophic factor (GDNF) family receptors alpha (GFRalpha) are cell surface bound glycoproteins that mediate interactions of the GDNF ligand family with the RET receptor. These interactions are crucial to the development of the kidney and some peripheral nerve lineages. In humans, mutations of RET or RET ligands are associated with the congenital abnormality Hirschsprung disease (HSCR) in which nerves and ganglia of the hind gut are absent. As the GFRalpha family are required for normal activation of the RET receptor, they are also candidates for a role in HSCR. The GFRA2 gene, which is required for the development of the myenteric nerve plexus, is an excellent candidate gene for HSCR. In this study, we cloned the human GFRA2 locus, characterized the gene structure, and compared it with other GFRA family members. We further investigated the GFRA2 gene for mutations in a panel of HSCR patients. GFRA2 has nine coding exons that are similar in size and organization to those of other GFRA family genes. We identified six sequence variants of GFRA2, four of which did not affect the amino acid sequence of the GFRalpha-2 protein. Two further changes that resulted in amino acid substitutions were found in exon 9 and were predicted to lie in the amino acid sequence encoding the glycosylphosphatidylinositol-linkage signal of GFRalpha-2. There was no difference in frequency of any of the sequence variants between control and HSCR populations. Our data indicate that members of the GFRA gene family are closely related in intron/exon structure and in sequence. We have not detected any correlation between sequence variants of GFRA2 and the HSCR phenotype.
Base Sequence↗
Multiple endocrine neoplasia type 2: clinical aspects.
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Adrenal Gland Neoplasms↗
Genotype-phenotype correlations in hereditary medullary thyroid carcinoma: oncological features and biochemical properties.
In hereditary medullary thyroid carcinoma (MTC), few genotype-phenotype correlations have been established. RET genotypes (exons 10, 11, 13, and 14) of 63 patients with hereditary MTC (from November 1994 to October 1999) were correlated with age at diagnosis, sex, the TNM system, and basal calcitonin levels. Mutations in exons 10, 11, 13, and 14 were demonstrated in 22% (14 of 63), 54% (34 of 63), 21% (13 of 63), and 3% (2 of 63). The median ages at diagnosis differed significantly (38, 27, 52, and 62 yr; P = 0.003). When grouped by cysteine codons (exons 10 and 11 vs. exons 13 and 14), this difference became even more evident (30 vs. 56 yr; P = 0.001). Apart from age at diagnosis, no other significant associations were noted. Based hereon, three MTC risk groups were devised according to genotype: a high risk group (codons 634 and 618) with the youngest ages of 3 and 7 yr at diagnosis; an intermediate risk group (codons 790, 620, and 611) with ages of 12, 34, and 42 yr; and a low risk group (codons 768 and 804) with ages of 47 and 60 yr, respectively. Age at diagnosis was unrelated to specific nucleotide and amino acid exchange within each codon. The current data demonstrate that there is a significant genotype-phenotype correlation, allowing for a more individualized approach to the timing and extent of prophylactic surgery.
Adolescent↗
Somatic mutation and germline variants of MINPP1, a phosphatase gene located in proximity to PTEN on 10q23.3, in follicular thyroid carcinomas.
Various genes have been identified to play a role in the pathogenesis of follicular thyroid tumors. Cowden syndrome is the only known familial syndrome with an increased risk of both follicular thyroid adenoma (FA) and carcinoma (FTC). Germline mutations in the tumor suppressor gene PTEN, which encodes a dual-specificity phosphatase, have been found in up to 80% of patients with Cowden syndrome suggesting a role of PTEN in the pathogenesis of follicular thyroid tumors. Although somatic intragenic mutations in PTEN, which maps to 10q23.3, are rarely found in follicular tumors, loss of heterozygosity (LOH) of markers within 10q22-24 occurs in about 25%. Recently, another phosphatase gene, MINPP1, has been localized to 10q23.3. MINPP1 has the ability to remove 3-phosphate from inositol phosphate substrates, a function that overlaps that of PTEN. Because of this overlapping function with PTEN and the physical location of MINPP1 to a region with frequent LOH in follicular thyroid tumors, we considered it to be an excellent candidate gene that could contribute to the pathogenesis of follicular thyroid tumors. We analyzed DNA from tumor and corresponding normal tissue from 23 patients with FA and 15 patients with FTC for LOH and mutations at the MINPP1 locus. LOH was identified in four malignant and three benign tumors. One of these FTCs with LOH was found to harbor a somatic c.122C > T or S41L mutation. We also found two germline sequence variants, c.809A > G (Q270R) and IVS3 + 34T > A. The c.809A > G variant was found in only one patient with FA but not in patients with FTC or normal controls. More interestingly, IVS3 + 34T > A was found in about 15% of FA cases and normal controls but not in patients with FTC. These results suggest a role for MINPP1 in the pathogenesis of at least a subset of malignant follicular thyroid tumors, and MINPP1 might act as a low penetrance predisposition allele for FTC.
Adenoma↗
Somatic and occult germ-line mutations in SDHD, a mitochondrial complex II gene, in nonfamilial pheochromocytoma.
Most pheochromocytomas are sporadic but about 10% are though to be hereditary. Although the etiology of most inherited pheochromocytoma is well known, little is known about the etiology of the more common sporadic tumor. Recently, germ-line mutations of SDHD, a mitochondria complex II gene, were found in patients with hereditary paraganglioma. We sought to determine whether SDHD plays a role in the development of sporadic pheochromocytomas and performed a mutation and deletion analysis of SDHD. Among 18 samples, we identified 4 heterozygous sequence variants (3 germ-line, 1 somatic). One germ-line SDHD mutation IVS1+2T>G (absent among 78 control alleles) is predicted to cause aberrant splicing. On reinvestigation, this patient was found to have a tumor of the carotid body, which was likely a paraganglioma. Another patient with malignant, extra-adrenal pheochromocytoma was found to have germ-line c.34G> A (G12S). However, this sequence variant was also found in 1 of 78 control alleles. The third, germ-line nonsense mutation R38X was found in a patient with extra-adrenal pheochromocytoma. The only somatic heterozygous mutation, c.242C>T (P81L), has been found in the germ line of two families with hereditary paraganglioma and is conserved among four eukaryotic multicellular organisms. Hence, this mutation is most likely of functional significance too. Overall, loss of heterozygosity in at least one of the two markers flanking SDHD was found in 13 tumors (72%). All of the tumors that already harbored intragenic SDHD mutations, whether germ-line or somatic, also had loss of heterozygosity. Our results indicate that SDHD plays a role in the pathogenesis of pheochromocytoma. Given the minimum estimated germline SDHD mutation frequency of 11% (maximum estimate up to 17%) in this set of apparently sporadic pheochromocytoma cases and if these data can be replicated in other populations, our observations might suggest that all such patients be considered for SDHD mutation analysis.
Adolescent↗
Expression of the PTEN tumour suppressor protein during human development.
The tumour suppressor gene PTEN, localized to 10q23.3, is the susceptibility gene for Cowden syndrome (CS) and Bannayan-Riley-Ruvalcaba (BRR) syndrome, two hamartoma syndromes with an increased risk of breast and thyroid tumours. Somatic mutations have been found in a variety of human tumours. Functional studies have revealed that PTEN plays a fundamental role in cellular growth, death, adhesion and migration. RNA in situ hybridization using the pten coding region in mouse embryos showed ubiquitous transcription, providing evidence that pten could play a versatile role throughout murine development. Nothing is known regarding the pattern of PTEN expression during human development. Here, we present the pattern of PTEN expression during human development using a specific monoclonal antibody and examine the relationship of the temporal and spatial expression pattern to the clinical manifestations of CS and BRR, the somatic genetic data in sporadic cancers, the murine knockout models and the RNA expression data in mouse embryos. We observed mainly high-level PTEN expression in tissues (e.g. skin, thyroid and central nervous system) known to be involved in CS and BRR. In addition, we identified tissues (e.g. peripheral nervous system, autonomomic nervous system and upper gastrointestinal tract) with high PTEN expression not commonly known to play a role in these syndromes nor in sporadic tumorigenesis in those organs. This knowledge may help in identifying roles for PTEN which, as of today, are unknown or even unsuspected.
Digestive System↗
Improved prediction of calcitonin normalization in medullary thyroid carcinoma patients by quantitative lymph node analysis.
BACKGROUND: The aim of this study was to identify better prognostic parameters for normalization of serum calcitonin in medullary thyroid carcinoma (MTC) patients. METHODS: In 73 patients who had undergone systematic lymph node dissection for MTC between September 1995 and November 1998, preoperative (n = 29) and postoperative (n = 65) basal and stimulated serum calcitonin were correlated with the pTNM classification and the number of positive regional lymph nodes and compartments. RESULTS: In contrast to pT and M, there was a significant correlation between postoperative calcitonin and the pN category. With rising numbers of positive lymph nodes (0, 1-9, 10-19, and > or = 20), postoperative basal and stimulated calcitonin increased exponentially, and gross distant metastases (M1) occurred more frequently (0%, 4%, 13%, and 50%; P = 0.013). Conversely, serum calcitonin was less often normalized (65%, 31%, 0%, and 0%; P = 0. 003). There was a close correlation between the number of positive lymph nodes and the number of affected compartments (P < 0.001; r = 0.93). Irrespective of location, involvement of 10 or more lymph nodes and more than 2 compartments precluded normalization of serum calcitonin. CONCLUSIONS: Quantitative lymph node analysis of MTC improves prediction of calcitonin normalization. When more than two compartments are involved, normalization of serum calcitonin cannot be attained. Surgery should then be less extensive and more directed at preventing local complications.
Adult↗
Germline and germline mosaic PTEN mutations associated with a Proteus-like syndrome of hemihypertrophy, lower limb asymmetry, arteriovenous malformations and lipomatosis.
Germline PTEN mutations cause Cowden syndrome (CS) and Bannayan-Riley-Ruvalcaba syndrome (BRR), two hamartoma-tumour syndromes, and somatic PTEN alterations have been shown to participate, to a greater or lesser extent, in a wide variety of sporadic neoplasia. PTEN is a tumour suppressor and dual-specificity phosphatase which affects apoptosis via its lipid phosphatase activity in the phosphoinositol-3-kinase and AKT pathway as well as inhibiting cell spreading via the focal adhesion kinase pathway. CS and BRR share some features, such as hamartomas and lipomatosis. To determine whether other syndromes characterized by overgrowth and lipomas are part of the PTEN syndrome spectrum, we ascertained six individuals with overgrowth and lipomas but who did not meet the diagnostic criteria for CS or BRR. Five had Proteus syndrome and one, a Proteus-like syndrome. When germline DNA and DNA from at least one involved tissue per case were examined for PTEN mutations, only the Proteus-like patient was found to harbour a germline R335X mutation. Interestingly, a lipomatous mass, an epidermoid naevus and arteriovenous malformation tissue, all of which were sampled from physically distinct sites, were all found to carry a second hit R130X mutation on the allele opposite the germline R335X. Both mutations have been described in CS and BRR. We postulate that the second hit, R130X, occurred early in embryonic development and may even represent germline mosaicism. Thus, PTEN may be involved in Proteus-like syndrome with its implications for cancer development in the future.
Arteriovenous Malformations↗