Gastrointestinal stromal tumor in Carney's triad with laparoscopic total gastrectomy: a case report.

INTRODUCTION: Carney's triad is a rare syndrome characterized by the co-occurrence of gastric gastrointestinal stromal tumor (GIST), pulmonary chondroma, and extra-adrenal paraganglioma. We present a case of a young woman with GISTs associated with this triad. CASE PRESENTATION: A 28-year-old woman was identified with multiple gastric tumors and a right lung nodule during a routine health check-up. CT scans and upper gastrointestinal endoscopy revealed a 50 mm mass on the lesser curvature of the stomach, along with two additional gastric lesions and a 20 mm nodule in the right lung. The patient had a history of right middle lobectomy at the age of 19 for pulmonary chondroma. During surgery, enlarged lymph nodes were observed, indicating metastasis, which necessitated a total gastrectomy with radical (D2) lymph node dissection. Pathological examination confirmed seven GISTs, with immunohistochemical staining positive for KIT (+), DOG1 (+), and negative for SDHB (-). The postoperative course was uneventful, and the patient was discharged on the seventh postoperative day. Despite opting out of adjuvant imatinib therapy, she remains disease-free 2 years postoperatively. CONCLUSIONS: This case underscores the necessity of total gastrectomy with lymph node dissection due to the high incidence of metastasis in GISTs associated with Carney's triad. Further research is required to determine the optimal extent of lymph node dissection in such cases.

Embryonic stem cell factor FOXD3 (Genesis) defects in gastrointestinal stromal tumors.

Gastrointestinal stromal tumors (GISTs) are mesenchymal neoplasms, believed to originate from the interstitial cells of Cajal (ICC), often caused by overexpression of tyrosine kinase receptors (TKR) KIT or PDGFRA. Here, we present evidence that the embryonic stem cell factor FOXD3, first identified as 'Genesis' and involved in both gastrointestinal and neural crest cell development, is implicated in GIST pathogenesis; its involvement is investigated both in vitro and in zebrafish and a mouse model of FOXD3 deficiency. Samples from a total of 58 patients with wild-type GISTs were used for molecular analyses, including Sanger sequencing, comparative genomic hybridization, and methylation analysis. Immunohistochemistry and western blot evaluation were used to assess FOXD3 expression. Additionally, we conducted in vitro functional studies in tissue samples and in transfected cells to confirm the pathogenicity of the identified genetic variants. Germline partially inactivating FOXD3 sequence variants (p.R54H and p.Ala88_Gly91del) were found in patients with isolated GISTs. Chromosome 1p loss was the most frequent chromosomal abnormality identified in tumors. In vitro experiments demonstrate the impairment of FOXD3 in the presence of those variants. Animal studies showed disruption of the GI neural network and changes in the number and distribution in the ICC. FOXD3 suppresses KIT expression in human cells; its inactivation led to an increase in ICC in zebrafish, as well as mice, providing evidence for a functional link between FOXD3 defects and KIT overexpression leading to GIST formation.

Rapidly growing proliferative pulmonary chondroma: A case report.

INTRODUCTION: Pulmonary chondroma, a component of Carney's triad, is commonly unilateral and multiple, and progresses slowly. Herein, we report a case of a chondrogenic tumour that grew and proliferated during follow-up. PRESENTATION OF CASE: A female patient in her 20s presenting with a cough was found to have a 1.4-cm nodule in the left lung on computed tomography (CT). After 18 months' follow-up, CT revealed that the original nodule had increased to 2.2 cm, and a new 1.3-cm nodule had appeared. She was then referred to our hospital and underwent a robot-assisted lower lobectomy of the left lung. The tumour was diagnosed as a chondrogenic tumour. She had no problems after the surgery or during follow-up; other signs of the Carney's triad were ruled out. Twenty-six months postoperatively, there was no evidence of recurrence. DISCUSSION: One report suggests that the growth of pulmonary chondroma is slow, but the present case showed an increase in both the size and number of tumours within 2 years without any symptoms. The chondroma did not recur after the surgery, though her pulmonary tumours had grown and proliferated rapidly. Furthermore, it has been reported that an average of 8.4 years is needed for another sign of Carney's triad to appear; therefore, careful follow-up should be continued. CONCLUSION: This report suggests that pulmonary chondroma can grow and proliferate rapidly and asymptomatically, and can be controlled by complete resection.

Condroma pulmonar y paraganglioma carotídeo como manifestaciones de la tríada de Carney: reporte de un caso / Pulmonary chondroma and carotid paraganglioma as expressions of Carney's triad: report of a case

Resumen Objetivos: Presentar caso clínico y revisión de la literatura sobre asociación de tumores poco frecuentes compatibles con diagnóstico de tríada de Carney. Paciente y Métodos: Revisión de ficha clínica de paciente de sexo femenino de 39 años de edad con antecedentes de asma, quien acude a servicio de urgencias por síntomas respiratorios. En estudio con imágenes se evidencia masa pulmonar en lóbulo superior derecho probablemente hamartoma y masa en la bifurcación carotídea izquierda compatible con posible paraganglioma. Se completó el estudio con endoscopia digestiva alta sin evidencia de tumor gástrico y PET-CT (tomografía de emisión de positrones-tomografía computarizada) que descartó otras lesiones. Resultados: La paciente fue sometida a resección quirúrgica de ambos tumores (pulmonar y carotídeo). En estudio histopatológico diferido, se plantean los diagnósticos de paraganglioma carotideo y hamartoma pulmonar, el cual, luego de una segunda revisión histopatológica, es corregido a condroma pulmonar. Discusión: La tríada de Carney se compone por la asociación de al menos 2 de 3 tumores: tumor estromal gastrointestinal (GIST), paraganglioma extra-adrenal y condroma pulmonar. Su expresión es variable, coexistiendo en forma completa en solo el 22% de los casos. Conclusión: Los pacientes con sospecha de tríada de Carney deben recibir evaluación multidisciplinaria, estudio completo en búsqueda de tumores asociados y seguimiento a largo plazo por posibles recurrencias o metástasis.

Objective: To present a clinical case and review of the literature on the infrequent association of pulmonary and extra thoracic tumors compatible with Carney's triad. Patient and Methods: Review of clinical records of a 39 years-old female patient with history of asthma who presented in the emergency department with respiratory symptoms. An imaging study showed a pulmonary mass in the right upper lobe with the aspect of hamartoma and a mass in the left carotid artery bifurcation compatible with a possible paraganglioma. Upper gastrointestinal endoscopy showed no evidence of gastric tumor and a PET-CT (Positron Emission Tomography - Computed Tomography) excluded other lesions. Results: Patient underwent surgical resection of both tumors (pulmonary and carotid). Diagnosis of carotid paraganglioma and pulmonary hamartoma were stated by histopathology. However, lung tumor after a second pathological analysis was confirmed to be a pulmonary chondroma. Discussion: Carney's triad is defined by the association of at least 2 of 3 tumors: Gastrointestinal Stromal Tumor (GIST), extraadrenal paraganglioma and pulmonary chondroma. Its expression is variable, coexisting completely in only 22% of cases. Conclusion: Patients with suspected Carney's triad should receive a multidisciplinary assessment, a complete study searching associated tumors and long-term follow-up for recurrences or metastases.

Carney Triad, Carney-Stratakis Syndrome, 3PAS and Other Tumors Due to SDH Deficiency.

Succinate dehydrogenase (SDH) is a key respiratory enzyme that links Krebs cycle and electron transport chain and is comprised of four subunits SDHA, SDHB, SDHC and SDHD. All SDH-deficient tumors are caused by or secondary to loss of SDH activity. As many as half of the familial cases of paragangliomas (PGLs) and pheochromocytomas (PHEOs) are due to mutations of the SDHx subunits. Gastrointestinal stromal tumors (GISTs) associated with SDH deficiency are negative for KIT/PDGFRA mutations and present with distinctive clinical features such as early onset (usually childhood or adolescence) and almost exclusively gastric location. SDH-deficient GISTs may be part of distinct clinical syndromes, Carney-Stratakis syndrome (CSS) or dyad and Carney triad (CT). CSS is also known as the dyad of GIST and PGL; it affects both genders equally and is inherited in an autosomal dominant manner with incomplete penetrance. CT is a very rare disease; PGL, GIST and pulmonary chondromas constitute CT which shows female predilection and may be a mosaic disorder. Even though there is some overlap between CT and CSS, as both are due to SDH deficiency, CSS is caused by inactivating germline mutations in genes encoding for the SDH subunits, while CT is mostly caused by a specific pattern of methylation of the SDHC gene and may be due to germline mosaicism of the responsible genetic defect.

Carney triad: A case report, characteristics and literature review of this rare entity.

INTRODUCTION AND IMPORTANCE: Carney triad is a rare entity of unknown etiology, characterized by the association of tumors with low incidence such as: gastric leiomyosarcoma, pulmonary chondroma and extra-adrenal paraganglioma. We show a case of Carney triad diagnosed in our center that has some different characteristics to the typical presentation of this patology, and a review of the literature. CASE PRESENTATION: We present the case of a 47-year-old men who was admitted to our hospital for upper gastrointestinal bleeding and anemia. The patient was diagnosed of gastric GIST (gastrointestinal stromal tumor), pulmonary nodule and retroperitoneal nodule close to iliac bifurcation. A review of his medical history revealed that he had undergone surgery at 18-year-old for gastric leiomiosarcoma, subtotal gastrectomy performed with gastroenteric anastomosis type Billroth II. The patient underwent total gastrectomy with a end-lateral esophago-jejune mechanical anastomosis and retroperitoneal tumor was also excised. Pathological result confirmed gastric GIST, and extra-adrenal paraganglioma. CLINICAL DISCUSSION: We review the available literature to determinate the characteristics and the most appropriate management for this syndrome. The trend is surgical treatment of gastric GIST and paraganglioma, preferred conservative treatment in pulmonary chondroma. It is under discussion whether gastric tumors Carney syndrome is considered GIST, because the Carney triad lesions in stomach are different clinically, pathologically, and etiologically from GIST of stomach. CONCLUSION: Carney's triad is a low prevalence entity, with a limited number of publications, so the presentation of the syndrome may be different from the presentation described in the literature.

SDHA Germline Variants in Adult Patients With SDHA-Mutant Gastrointestinal Stromal Tumor.

BACKGROUND: SDH-deficient gastrointestinal stromal tumors (GIST) account for 20-40% of all KIT/PDGFRA-negative GIST and are due to mutations in one of the four SDH-complex subunits, with SDHA mutations as the most frequent. Here we sought to evaluate the presence and prevalence of SDHA variants in the germline lineage in a population of SDHA-deficient GIST. METHODS: Germline SDHA status was assessed by Sanger sequencing on a series of 14 patients with gastric SDHA-deficient GIST. RESULTS: All patients carried a germline SDHA pathogenic variant, ranging from truncating, missense, or splicing variants. The second hit was the loss of the wild-type allele or an additional somatic mutation. One-third of the patients were over 50 years old. GIST was the only disease presentation in all cases except one, with no personal or familial cancer history. Seven metastatic cases received a multimodal treatment integrating surgery, loco-regional and medical therapy. The mean follow-up time was of 10 years, confirming the indolent clinical course of the disease. CONCLUSION: SDHA germline variants are highly frequent in SDHA-deficient GIST, and the disease may occur also in older adulthood. Genetic testing and surveillance of SDHA-mutation carriers and relatives should be performed.

Laparoscopic gastrectomy with lymph node dissection for the treatment of remnant stomach gastrointestinal stromal tumors in incomplete-type Carney's triad: a case report.

BACKGROUND: We report a rare case of gastrointestinal stromal tumors (GISTs) in Carney's triad, successfully treated using laparoscopic gastrectomy with lymph node dissection after chemotherapy. CASE PRESENTATION: A 21-year-old woman presented to our hospital for treatment of recurrent GISTs. The patient had been admitted for treatment 11 years prior, with black stools being the chief presenting complaint at that time. On examination at that time, multiple submucosal tumors in the pyloric antrum and multiple pulmonary tumors had been observed. She underwent open partial gastrectomy, and the diagnosis of GISTs was confirmed. She was administered tyrosine kinase inhibitors to treat lung metastases from 2 months after surgery. Due to the increasing size of the lung tumors, a right upper lobectomy was performed 9 years after the index gastric surgery. Histopathological examination of the lung specimen, in combination with re-examination of the gastric specimens, was indicative of incomplete-type Carney's triad. Eleven years after the index gastric surgery, multiple GISTs were observed in her entire stomach. Tumor biopsy revealed a succinate dehydrogenase deficiency, confirming the diagnosis of recurrent GISTs. For treatment, the patient underwent laparoscopic completion gastrectomy, with D1 plus lymph node dissection. CONCLUSION: This is a first case report of completion gastrectomy performed laparoscopically for the treatment of GISTs associated with incomplete-type Carney's triad. The recurrent GISTs developed over a protracted period of 11 years from the index gastric surgery to tumor recurrence.

[Wild-type gastroinestinal stromal tumors]. / Les tumeurs stromales gastro-intestinales sauvages.

Gastrointestinal stromal tumors (GIST) are the most common non-epithelial tumors of the gastrointestinal tract. Wild-type GISTs (WT-GIST) consist of a rare heterogeneous group characterized by the lack of activating mutations in the tyrosine kinase receptor (Kit) and/or platelet derived growth factor receptor A (PDGFRA). However, WT-GIST is characterized by other genomic alterations, including dehydrogenase succinate (SDH) deficiency or mutations in the Ras pathway. Recent studies have reported many mutations in others genes that may be incriminated in the development of WT-GISTs. Moreover, WT-GIST is frequently associated with hereditary cancer syndromes such as the Carney Triad and Type 1 Neurofibromatosis (NF1). WT-GIST affects usually young and pediatric patients. Most WT-GIST subtypes are insensitive to imatinib; therefore, their therapeutic management is somewhat different from usual GISTs. This review resumes the molecular and therapeutic features of this rare entity.

Multiple gastrointestinal stromal tumors: analysis of clinicopathologic characteristics and prognosis of 20 patients.

PURPOSE: Multiple gastrointestinal stromal tumors (GISTs) are rare. The aim of this study was to investigate the clinicopathologic characteristics and prognosis of multiple GISTs. PATIENTS AND METHODS: Between May 2003 and June 2018, patients who underwent surgery for multiple GISTs were retrospectively analyzed. Exons 9, 11, 13, and 17 of the KIT gene, and exons 12, and 18 of the PDGFRA gene were examined in 34 tumors from 20 patients. RESULTS: A total of 20 patients with multiple GISTs were enrolled. There were 11 females and nine males with a median age of 59 years (range: 37-80 years). Of these cases, 16 were sporadic cases and four were associated with GIST syndromes (two cases of Carney triad and two cases of neurofibromatosis type 1 [NF1]). The most common presentation was gastrointestinal bleeding. Carney triad GISTs did not exhibit KIT/PDGFRA mutations. One of the NF1 patients was a KIT/PDGFRA wild-type, and the other patient had a PDGFRA mutation. Of the sporadic cases, one shared the same KIT gene mutation within each GIST and one had two lesions that were both wild-type for KIT and PDGFRA. Different KIT mutations among individual tumors were detected in seven patients. During the median follow-up period of 66 months (range: 3-183 months), four patients developed liver or abdominal metastases, three of whom expired due to the disease. The rates of recurrence-free survival and overall surviva at 5 years were 65.8% and 76.7%, respectively. CONCLUSION: Multiple GISTs may occur as sporadic tumors or as an additional component of specific syndromes (eg, Carney triad and NF1) that display different clinicopathologic characteristics based on their particular underlying mechanisms. The overall prognosis of patients with multiple GISTs is comparable to that of patients with only a single GIST.

Loss of succinate dehydrogenase B immunohistochemical expression distinguishes pulmonary chondromas from hamartomas.

AIMS: Pulmonary chondromas, which are rare cartilaginous neoplasms that often arise in the setting of Carney triad, are morphologically similar to pulmonary hamartomas, which are much more common. There is evidence that succinate dehydrogenase (SDH) deficiency drives neoplasia in patients with Carney triad, and SDHB immunohistochemistry can be used as a surrogate marker to detect SDH deficiency. The aim of this study was to investigate the utility of SDHB immunohistochemistry in distinguishing pulmonary chondromas from hamartomas. METHODS AND RESULTS: Immunohistochemistry for SDHB (clone 21A11AE7) was performed on histological sections from six cases of pulmonary chondroma and 33 cases of pulmonary hamartoma. SDHB expression was retained in all 33 pulmonary hamartomas, and lost in the majority of evaluable chondromas (five of six). Of the five patients with chondromas showing SDHB loss, four had definitive Carney triad. Most patients with pulmonary hamartomas were older males with small solitary masses, whereas chondromas often presented as multiple masses in young females. CONCLUSION: Loss of SDHB immunohistochemical expression can be useful for differentiating pulmonary chondromas from hamartomas, and potentially identifying patients with Carney triad.

Gastrointestinal Stromal Tumors: The GIST of Precision Medicine.

The discovery of activated KIT mutations in gastrointestinal (GI) stromal tumors (GISTs) in 1998 triggered a sea change in our understanding of these tumors and has ushered in a new paradigm for the use of molecular genetic diagnostics to guide targeted therapies. KIT and PDGFRA mutations account for 85-90% of GISTs; subsequent genetic studies have led to the identification of mutation/epimutation of additional genes, including the succinate dehydrogenase (SDH) subunit A, B, C, and D genes. This review focuses on integrating findings from clinicopathologic, genetic, and epigenetic studies, which classify GISTs into two distinct clusters: an SDH-competent group and an SDH-deficient group. This development is important since it revolutionizes our current management of affected patients and their relatives, fundamentally, based on the GIST genotype.

Succinate dehydrogenase (SDH) deficiency, Carney triad and the epigenome.

In this report, we review the relationship between succinate dehydrogenase (SDH) deficiency and the epigenome, especially with regards to two clinical conditions. Carney triad (CT) is a very rare disease with synchronous or metachronous occurrence of at least three different tumor entities; gastric gastrointestinal stromal tumor (GIST), paraganglioma (PGL), and pulmonary chondroma. This condition affects mostly females and it is never inherited. Another disease that shares two of the tumor components of CT, namely GIST and PGL is the Carney-Stratakis syndrome (CSS) or dyad. CSS affects both genders during childhood and adolescence. We review herein the main clinical features and molecular mechanisms behind those two syndromes that share quite a bit of similarities, but one is non-hereditary (CT) whereas the other shows an autosomal-dominant, with incomplete penetrance, inheritance pattern (CSS). Both CT and CSS are caused by the deficiency of the succinate dehydrogenase (SDH) enzyme. The key difference between the two syndromes is the molecular mechanism that causes the SDH deficiency. Most cases of CT show down-regulation of SDH through site-specific hyper-methylation of the SDHC gene, whereas CSS cases carry inactivating germline mutations within one of the genes coding for the SDH subunits A, B, C, or D (SDHA, SDHB, SDHC, and SDHD). There is only partial overlap between the two conditions (there are a few patients with CT that have SDH subunit mutations) but both lead to increased methylation of the entire genome in the tumors associated with them. Other tumors (outside CT and CSS) that have SDH deficiency are associated with increased methylation of the entire genome, but only in CT there is site-specific methylation of the SDHC gene. These findings have implications for diagnostics and the treatment of patients with these, often metastatic tumors.

An unusual case of incomplete Carney triad: an 18-year-old girl suffering from multiple benign tumors.

Carney triad is a rare syndrome that involves gastrointestinal stromal tumor (GIST), pulmonary chondroma and extra-adrenal paraganglioma. Patients presenting GIST and pulmonary chondroma account for 72.7% of all incomplete Carney triad cases. Clinically, it is mainly diagnosed by radiological images and pathological results. Some studies have elucidated the pathogenesis of Carney triad. Surgical resection is the preferred treatment for Carney triad. Generally speaking, the prognosis of patients with Carney triad has been satisfied. According to current reports, the rate of 40-year survival is up to 73%. The case reports an 18-year-old girl suffering from pulmonary chondroma and posterior mediastinal paraganglioma, simultaneously with pulmonary hamartoma, breast fibroma and lower limb chondroma.

"Wild type" GIST: Clinicopathological features and clinical practice.

Gastrointestinal stromal tumor (GIST) is a mesenchymal tumor of the gastrointestinal tract. Mutation of KIT and PDGFRA genes is implicated in the tumorigenesis. Approximately 10% of GISTs do not harbor mutation of these genes, and they are designated as "wild type" GIST. They are classified into succinate dehydrogenase (SDH)-deficient and non-SDH-deficient groups. SDH-deficient group includes Carney triad and Carney Stratakis syndrome. The patients are young women. Tumors occur in the antrum of the stomach, and tumor cells are epithelioid. Lymph node metastasis is frequent. The non-SDH-deficient group includes neurofibromatosis (NF) type 1 and GISTs with mutations of BRAF, KRAS, and PIK3CA and with the ETV6-NTRK3 fusion gene. GIST in NF occurs in the small intestine, and tumor cells are spindle shaped. GIST with BRAF mutation arises in the small intestine. Attention to the age, gender, family history and other neoplasms may raise the prediction of syndromic disease. Location of the tumor, morphology, and pleomorphism of the tumor cells are further informative. Lymphovascular invasion should be carefully evaluated. The determination of KIT expression is essential for the diagnosis. When wild type GIST is suspected, intensive genetic analysis is required. Further, a careful and long-time observation is recommended.

Syndromic gastrointestinal stromal tumors.

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of gastrointestinal tract. They feature heterogeneous triggering mechanisms, implying relevant clinical differences. The vast majority of GISTs are sporadic tumors. Rarely, however, GIST-prone syndromes occur, mostly depending on heritable GIST predisposing molecular defects involving the entire organism. These conditions need to be properly identified in order to plan appropriate diagnostic, prognostic and therapeutic procedures. Clinically, GIST-prone syndromes must be thought of whenever GISTs are multiple and/or associated with accompanying signs peculiar to the background tumorigenic trigger, either in single individuals or in kindreds. Moreover, syndromic GISTs, individually considered, tend to show distinctive features depending on the underlying condition. When applicable, genotyping is usually confirmatory. In GIST-prone conditions, the prognostic features of each GIST, defined according to the criteria routinely applied to sporadic GISTs, combine with the characters proper to the background syndromes, defining peculiar clinical settings which challenge physicians to undertake complex decisions. The latter concern preventive therapy and single tumor therapy, implying possible surgical and molecularly targeted options. In the absence of specific comprehensive guidelines, this review will highlight the traits characteristic of GIST-predisposing syndromes, with particular emphasis on diagnostic, prognostic and therapeutic implications, which can help the clinical management of these rare diseases.

Carney triad, SDH-deficient tumors, and Sdhb+/- mice share abnormal mitochondria.

Carney triad (CTr) describes the association of paragangliomas (PGL), pulmonary chondromas, and gastrointestinal (GI) stromal tumors (GISTs) with a variety of other lesions, including pheochromocytomas and adrenocortical tumors. The gene(s) that cause CTr remain(s) unknown. PGL and GISTs may be caused by loss-of-function mutations in succinate dehydrogenase (SDH) (a condition known as Carney-Stratakis syndrome (CSS)). Mitochondrial structure and function are abnormal in tissues that carry SDH defects, but they have not been studied in CTr. For the present study, we examined mitochondrial structure in human tumors and GI tissue (GIT) of mice with SDH deficiency. Tissues from 16 CTr tumors (n=12), those with isolated GIST (n=1), and those with CSS caused by SDHC (n=1) and SDHD (n=2) mutations were studied by electron microscopy (EM). Samples of GIT from mice with a heterozygous deletion in Sdhb (Sdhb(+) (/-), n=4) were also studied by EM. CTr patients presented with mostly epithelioid GISTs that were characterized by plump cells containing a centrally located, round nucleus and prominent nucleoli; these changes were almost identical to those seen in the GISTs of patients with SDH. In tumor cells from patients, regardless of diagnosis or tumor type, cytoplasm contained an increased number of mitochondria with a 'hypoxic' phenotype: mitochondria were devoid of cristae, exhibited structural abnormalities, and were of variable size. Occasionally, mitochondria were small and round; rarely, they were thin and elongated with tubular cristae. Many mitochondria exhibited amorphous fluffy material with membranous whorls or cystic structures. A similar mitochondrial hypoxic phenotype was seen in Sdhb(+) (/-) mice. We concluded that tissues from SDH-deficient tumors, those from mouse GIT, and those from CTr tumors shared identical abnormalities in mitochondrial structure and other features. Thus, the still-elusive CTr defect(s) is(are) likely to affect mitochondrial function, just like germline SDH-deficiency does.

A bittersweet symphony.

This issue analyzes new work expanding the range of how genetic dysregulation of succinate dehydrogenase subunit (SDHx) genes can cause cancer syndromes with a prominent endocrine component, in this case Carney triad, which is characterized by gastrointestinal stromal tumors, paraganglioma, and pulmonary chondromas.

Aberrant DNA hypermethylation of SDHC: a novel mechanism of tumor development in Carney triad.

Carney triad (CT) is a rare condition with synchronous or metachronous occurrence of gastrointestinal stromal tumors (GISTs), paragangliomas (PGLs), and pulmonary chondromas in a patient. In contrast to Carney-Stratakis syndrome (CSS) and familial PGL syndromes, no germline or somatic mutations in the succinate dehydrogenase (SDH) complex subunits A, B, C, or D have been found in most tumors and/or patients with CT. Nonetheless, the tumors arising among patients with CT, CSS, or familial PGL share a similar morphology with loss of the SDHB subunit on the protein level. For the current study, we employed massive parallel bisulfite sequencing to evaluate DNA methylation patterns in CpG islands in proximity to the gene loci of all four SDH subunits. For the first time, we report on a recurrent aberrant dense DNA methylation at the gene locus of SDHC in tumors of patients with CT, which was not present in tumors of patients with CSS or PGL, or in sporadic GISTs with KIT mutations. This DNA methylation pattern was correlated to a reduced mRNA expression of SDHC, and concurrent loss of the SDHC subunit on the protein level. Collectively, these data suggest epigenetic inactivation of the SDHC gene locus with functional impairment of the SDH complex as a plausible alternate mechanism of tumorigenesis in CT.