Cowden Syndrome Patients Research Articles

Genetic analysis of a Chinese pedigree affected with Cowden syndrome due to variant of PTEN gene

To explore the clinical features and genetic etiology of a Chinese pedigree affected with Cowden syndrome (CS). A CS pedigree diagnosed in November 2022 at the Ningde Municipal Hospital Affiliated to Ningde Normal University was selected as the study subject. Clinical data were collected, and genetic testing was carried out for available members. Pathogenicity analysis was carried out for the candidate variant. The proband, a 7-year-old male, was found to have autism and intellectual disability. Whole exome sequencing revealed that he has harbored a c.462_463del (p.F154Lfs25) variant of the PTEN gene. The proband's 35-year-old mother, who was diagnosed with pulmonary hamartomas at our hospital, has manifested with lipomas, nodular goiter, and adenomas. Sanger sequencing confirmed that she was also heterozygous for the c.462_463del (p.F154Lfs25) variant of the PTEN gene. No other family members has carried the same variant. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the variant was classified as pathogenic (PVS1+PM2_Supporting+PM6). The newly discovered c.462_463del (p.F154Lfs*25) variant of the PTEN gene probably underlay the CS in this pedigree. CS patients have higher risk for developing malignant tumors. Clinicians should be aware of this condition and emphasize follow-up of the patients.

Spinal Dural Arteriovenous Fistulas in a Patient with Cowden Syndrome and a Phosphatase and Tensin Homolog Mutation.

Cowden syndrome (CS) is an autosomal dominant syndrome characterized by the development of hamartomas and an increased cancer risk. Most CS patients harbor mutations in the phosphatase and tensin homolog (PTEN) gene. We herein report a 70-year-old patient with CS who presented with lower extremity weakness caused by multiple thoracic dural arteriovenous fistulas. Genetic testing revealed a truncated PTEN mutation (c.485_487delACAinsCC and p.D162Afs*5). Vascular malformations are common in CS, particularly in the extremities. However, spinal dural arteriovenous fistulas (AVFs) are extremely rare. Furthermore, in our case, the number of AVFs increased, and both lower limbs became flaccid four months after embolization. Therefore, we suggest that physicians carefully observe the changes in symptoms for prolonged periods after embolization.

Cowden Syndrome Case Report: Use of an Ultrasonic Surgical Aspirator for Cosmetic Removal of Lip Hamartomas

Cowden syndrome (CS) is an autosomal dominant condition that is relatively rare.CS patients can have tumorsderived from all three germlines. They can present with mucocutaneous hamartomas or other benign tumors, and have an increased risk of malignancies of the thyroid, breast, kidney, GI tract, and skin. In our clinic, a 40-year-old CS patient presented for thyroidectomy after fine needle aspiration was suspicious for papillary thyroid carcinoma (PTC). Another major concern was the cosmetic appearance of her lips, which were diffusely covered with small hamartomas. We were able to remove these in a novel manner using a cavitron ultrasonic surgical aspirator (CUSA; Integra Lifesciences, Princeton, NJ, USA). Using the CUSA tangential to the lip surface allowed for removal of the hamartomas in a way that created a smooth and cosmetically appealing outcome for the patient. The use of an ultrasonic surgical aspirator is a novel way to cosmetically treat hamartomas of the lip for CS patients.

AMBRA1 p.Gln30Arg Mutation, Identified in a Cowden Syndrome Family, Exhibits Hyperproliferative Potential in hTERT-RPE1 Cells.

Cowden syndrome (CS) is a rare autosomal dominant disorder associated with multiple hamartomatous and neoplastic lesions in various organs. Most CS patients have been found to have germline mutations in the PTEN tumor suppressor. In the present study, we investigated the causative gene of CS in a family of PTEN (phosphatase and tensin homolog deleted on chromosome 10) -negative CS patients. Whole exome sequencing analysis revealed AMBRA1 (Autophagy and Beclin 1 Regulator 1) as a novel candidate gene harboring two germline variants: p.Gln30Arg (Q30R) and p.Arg1195Ser (R1195S). AMBRA1 is a key regulator of the autophagy signaling network and a tumor suppressor. To functionally validate the role of AMBRA1 in the clinical manifestations of CS, we generated AMBRA1 depletion and Q30R mutation in hTERT-RPE1 (humanTelomerase Reverse Transcriptase-immortalized Retinal Pigmented Epithelial cells) using the CRISPR-Cas9 gene editing system. We observed that both AMBRA1-depleted and mutant cells showed accumulation in the S phase, leading to hyperproliferation, which is a characteristic of hamartomatous lesions. Specifically, the AMBRA1 Q30R mutation disturbed the G1/S transition of cells, leading to continuous mitotic entry of mutant cells, irrespective of the extracellular condition. From our analysis of primary ciliogenesis in these cells, we speculated that the mitotic entry of AMBRA1 Q30R mutants could be due to non-functional primary cilia that lead to impaired processing of extracellular sensory signals. Additionally, we observed a situs inversus phenotype in ambra1-depleted zebrafish, a developmental abnormality resulting from dysregulated primary ciliogenesis. Taken together, we established that the AMBRA1 Q30R mutation that we observed in CS patients might play an important role in inducing the hyperproliferative potential of cells through regulating primary ciliogenesis.

Cancer risk and genotype-phenotype correlation in Japanese patients with Cowden syndrome.

Cowden syndrome (CS) is an autosomal-dominant hereditary disorder caused by a germline PTEN variant and characterized by multiple hamartomas and a high risk of cancers. However, no detailed data on CS in Asian patients nor genotype-phenotype correlation have been reported. We performed the first Japanese nationwide questionnaire survey on CS and obtained questionnaire response data on 49 CS patients. Patients included 26 females (median age 48 years). The incidence of breast, thyroid, endometrium, and colorectal cancer was 32.7%, 12.2%, 19.2% (among females), and 6.1%, respectively. The incidence of any cancers was relatively high among all patients (46.9%, 23/49), and particularly female patients (73.1%, 19/26), compared with previous reports from Western countries. Gastrointestinal (GI) polyps were more frequently found throughout the GI tract compared with previous studies. PTEN variants were detected in 95.6% (22/23) of patients; 12 in the N-terminal region (11 in phosphatase domain) and 10 in the C-terminal (C2 domain) region. The incidence of cancer in the C2 domain group was significantly higher than in the N-terminal region (phosphatase) group. All female patients with C2 domain variant had breast cancer. Our data suggest that Japanese patients with CS, particularly female patients and patients with C2 domain variant may have a high risk of cancers.

Medulloblastoma and Cowden syndrome: Further evidence of an association.

Cowden syndrome (CS) is an autosomal dominant hamartoma and tumor predisposition syndrome caused by heterozygous pathogenic germline variants in PTEN in most affected individuals. Major features include macrocrania, multiple facial tricholemmomas, acral and oral keratoses and papillomas, as well as mammary, non-medullary thyroid, renal, and endometrial carcinomas. Lhermitte-Duclos disease (LDD), or dysplastic gangliocytoma of the cerebellum, is the typical brain tumor associated with CS; the lifetime risk for LDD in CS patients has been estimated to be as high as 30%. In contrast, medulloblastoma is much rarer in CS, with only 4 reported cases in the literature. We report a 5th such patient. All 5 patients were diagnosed between 1 and 2 years of age and not all showed the pathognomonic clinical stigmata of CS at the time of their medulloblastoma diagnosis. Where detailed information was available, the medulloblastoma was of the SHH-subtype, in keeping with the observation that in sporadic medulloblastomas, PTEN-alterations are usually encountered in the SHH-subtype. Medulloblastomas can be associated with several tumor-predisposition syndromes and of the 4 medulloblastoma subtypes, SHH-medulloblastomas in children have the highest prevalence of predisposing germline variants (approx. 40%). CS should be added to the list of SHH-medulloblastoma-associated syndromes. Germline analysis of PTEN should be performed in infants with SHH-medulloblastomas, regardless of their clinical phenotype, especially if they do not carry pathogenic germline variants in PTEN or PTEN, the most commonly altered predisposing genes in this age-group. In addition, these cases show that CS has a biphasic brain tumor distribution, both in regards to the age of onset and the tumor type: a small number of CS patients develop a medulloblastoma in infancy while many more develop LDD in adulthood.

Identification of a Cowden syndrome patient with a novel PTEN mutation and establishment of patient-derived induced pluripotent stem cells

Cowden syndrome (CS) is an autosomal dominant inherited disorder characterized by multiple hamartomas in various organs such as the mucosa, skin, and gastrointestinal tract. Patients with CS are at high risk for breast and thyroid cancers. Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a tumor suppressor gene that negatively regulates the AKT pathway, and PTEN mutations are known to be the major causes of this syndrome. However, the pathogenesis of this syndrome has not been clarified. Here, we present a case of a Japanese woman with multiple oral polyps, breast cancer, and thyroid cancer who was clinically diagnosed with CS. We obtained DNA and RNA samples from the patient’s peripheral blood mononuclear cells (PBMCs) and buccal mucosa tumor. Next-generation sequencing revealed novel germline mutations (c.1020delT and c.1026G > A) in exon 8 of PTEN. Sanger sequencing identified no PTEN transcript from the mutant allele. Furthermore, CS-specific induced pluripotent stem cells (CS-iPSCs) were established from PBMCs of the patient under feeder- and serum-free culture. Compared with healthy PBMCs and iPSCs, both of the CS-derived PBMCs and CS-iPSCs exhibited significantly reduced expression of the PTEN transcript. The transcriptional variant, PTENδ, was increased in CS-iPSCs, suggesting that it may be the cause of the disease.

S0174 Intramucosal Lipoma in Gastrointestinal Biopsy Is More Predictive and Remains an Important Clue for Cowden Syndrome Than Ganglioneuroma

INTRODUCTION: Cowden syndrome (CS), also known as PTEN hamartoma syndrome is an autosomal dominant disorder with multiple hamartomas involving organs derived from all three grem cell layers. The overall prevelance of Cowden syndrome is 1 per million. It has an increased predisposition to colorectal cancer. Gastrointestinal (GI) polyps of various histologic types including hyperplastic polyps, ganglioneuromas and hamartomatous polyps have been reported in 35–85% CS patients, with ganglioneuromas considered the most specific GI finding. Intramucosal lipomas have been recently reported associated with CS. However, the significance of intramucosal lipomas, compared to ganglioneuromas, in predicting CS have not yet been fully characterized. METHODS: We conducted a retrospective study enrolling 55 patients with either intramucosal lipomas or ganglioneuromas in GI polyps biopsied during 2010–2019 (over 70,000 cases). A total number of 190 polyps from those patients were reviewed. RESULTS: We identified 15 patients having germline PTEN mutation or clinical CS. Among those, nine patients (9/15) had 13 intramucosal lipomas and six (6/15) had 13 ganglioneuromas. Of 40 patients without CS, 12 patients (12/40) had 14 intramucosal lipomas and 22 patients (22/40) had 30 ganglioneuromas. Forty-eight percent 48% (13/27) intramucosal lipomas were associated with CS versus 30% (13/43) of ganglioneuromas. Three CS patients had both intramucosal lipoma and ganglioneuroma, which was not seen in patients without CS. In addition, four CS patients (4/15, 27%) had two intramucosal lipomas while only one patient without CS (1/40, 2.5%) had more than one lipoma. CONCLUSION: Intramucosal lipomas are uncommon and easily overlooked by clinicians and pathologists, despite their diagnostic significance for Cowden syndrome (PTEN hamartoma tumor syndrome), an inherited multiorgan cancer syndrome. Clinical features remain the cornerstone of diagnosis as only 25–35% of patients harbor identifiable PTEN mutations. Our data provide evidence that intramucosal lipomas are important harbingers of Cowden syndrome. It is more common in CS than ganglioneuroma and has a higher value in predicting CS in our study. Presence of both intramucosal lipomas and ganglioneuromas or multiple intramucosal lipomas is highly specific for CS. Gastrointestinal pathologists, gastroenterologists, and geneticists should increase their awareness of this subtle but diagnosable lesion strongly associated with Cowden syndrome in order to screen for CS.Figure 1.: (A, C) Intramucosal lipoma in CS. (B, D) Ganglioneuroma in CS.Table 1Table 2

Abstract PR03: YAP/TAZ requirement in mesenchyme-originated intestinal hamartomatous polyposis

Abstract Hamartomatous polyposis syndromes (HPS) are rare genetic syndromes, including Peutz-Jeghers syndrome (PJS) and PTEN hamartoma tumor syndrome (Cowden and Bannayan-Riley-Ruvalcaba syndromes), which are caused by germline mutations of STK11 (LKB1) and PTEN genes, respectively. HPS is characterized by the development of hamartomatous polyps in the GI tract; however, the cellular origins and molecular mechanism underlying hamartomatous polyposis remain poorly understood. Here we demonstrate that specific disruption or deletion of Stk11 or Pten in mouse GI mesenchyme, but not in the epithelium, generates hamartomatous polyps histologically resembling GI polyps observed in PJS and Cowden syndrome patients. Genetically, we show that mTOR activity is essential for Pten but not Stk11 deletion-driven hamartomatous polyposis. Furthermore, we show that AMPK1/2 deletion is not able to initiate PJS polyp formation. However, we find significant upregulation of mesenchymal YAP/TAZ activity in PJS polyps and demonstrate that YAP/TAZ in gut mesenchyme are required for Stk11 deletion-induced PJS hamartomatous polyposis. Our studies suggest a mesenchymal origin of GI polyps in HPS and reveal the distinct roles of YAP/TAZ and mTOR in gut mesenchyme during hamartomatous polyposis, which likely have important therapeutic implication for treating these HPSs. This abstract is also being presented as Poster A06. Citation Format: Jennifer L. Cotton, Kyvan Dang, Qi Li, Randy L. Johnson, Y. Tony Ip, Xu Wu, Junhao Mao. YAP/TAZ requirement in mesenchyme-originated intestinal hamartomatous polyposis [abstract]. In: Proceedings of the AACR Special Conference on the Hippo Pathway: Signaling, Cancer, and Beyond; 2019 May 8-11; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(8_Suppl):Abstract nr PR03.

Occurrence and Natural History of Thyroid Cancer in Patients with Cowden Syndrome

Introduction: Cowden syndrome patients are at an increased risk of developing differentiated thyroid carcinoma (DTC). There are limited studies of thyroid cancer biology within this population. We aimed to describe the frequency and progression of DTC in this population. Method: We reviewed all patients with clinically or genetically confirmed Cowden syndrome treated at our institution between 1979 and 2017. Presentation, operative details, pathology, and adjuvant treatment for all thyroid diseases were analyzed. Results: Forty-seven patients were identified. Thirty-seven received a clinical diagnosis while 10 tested positive on genetic testing for the PTEN gene. Average follow-up time was 10 years. Twenty-three patients underwent a total thyroidectomy. Nine patients were diagnosed with thyroid cancer, with a mean age of 28.5 years, 4 cases of the follicular variant of papillary thyroid cancer (PTC), 4 of PTC, and 1 of cystic PTC. One patient required an interval lateral neck dissection but no patients developed distant metastasis. Fourteen patients underwent thyroidectomy, 12 due to follicular adenoma, Hürthle cell adenoma, or multinodular goiter, 1 due to Graves’ disease, and 1 who elected to undergo a prophylactic thyroidectomy. No mortality was associated with thyroid cancer in these patients. Conclusion: Patients with Cowden syndrome are at a significantly increased risk of developing DTC and have a younger age of onset. In this study, 20% of the patients with Cowden syndrome were diagnosed with DTC, but distant metastasis and overall mortality were absent. Clinical features were similar to those of sporadic DTC, proving that, apart from screening, Cowden syndrome-related DTC can be treated in similar fashion.

An update on the CNS manifestations of brain tumor polyposis syndromes.

Cancer predisposition syndromes are associated with an increased risk of developing primary malignancies. Here we discuss those which are associated with an increased risk of tumors of the central nervous system (CNS) and gastrointestinal (GI) tract. These can be grouped into those in which the CNS tumors predominate versus those in which the GI cancers predominate. The former include constitutional mismatch repair deficiency (CMMRD) syndrome, Li-Fraumeni syndrome (LFS), and Cowden syndrome (CS) while the latter include familial adenomatosis polyposis 1 (FAP1), Lynch syndrome and polymerase proofreading-associated polyposis syndrome (PPAP). Tumor specificity does exist as medulloblastoma occur in FAP, LFS and CMMRD while glioma are most commonly seen in all replication repair-deficient genes and LFS. Choroid plexus carcinoma is strictly observed in LFS while Cowden syndrome patients develop Lhermitte Duclos disease or meningioma. In each syndrome, specific types of low-grade and high-grade gastrointestinal cancers can occur, but these will be discussed elsewhere. Underlying cancer predisposition syndromes are important to consider when faced with brain tumors, particularly in the pediatric and young adult age groups, as identification of an underlying germ line mutation may change the upfront management of the patient and has implications for future cancer surveillance for both the patient and potentially affected family members. Considerations of family history, presence of skin lesions and consanguinity provide valuable information in identifying patients at potential increased risk.

Spectrum of gastrointestinal tract pathology in a multicenter cohort of 43 Cowden syndrome patients

Most patients with Cowden syndrome have lesions in the gastrointestinal tract, characterized by multiple polyps of various histologic types in the large bowel, polyps in the upper gastrointestinal tract, and esophageal glycogenic acanthosis. However, pathologists are often unaware of the distinctive polyposis phenotype of Cowden syndrome. In this multicenter study, we report the spectrum of gastrointestinal manifestations in a series of 43 Cowden syndrome patients who had at least one endoscopy. The median age at the first endoscopy was 46 years and 58% were women. In 24 of 29 (83%) tested patients, a pathogenic germline mutation in PTEN was identified. The histology from 199 endoscopy procedures (67 upper gastrointestinal endoscopy and 132 colonoscopies) was reviewed. Hamartomatous polyps of the large bowel were the most common lesions, present in 85% of patients. Hamartomatous polyps showed varied histology, including lymphoid aggregates in 55% of patients, a lipomatous component in 52%, a ganglioneuromatous component in 52%, and a fibrous-rich component in 14%. Polyps with at least two different stromal components were found in 55% of patients. Inflammatory polyps were present in 21% of patients. Conventional adenomas and serrated polyps were identified in 48% and 62% of patients, respectively. In the upper gastrointestinal tract, the most common lesions were esophageal glycogenic acanthosis (37%), gastric hamartomatous polyps (47%), and duodenal hamartomatous polyps (20%). All patients with glycogenic acanthosis who had a colonoscopy had hamartomatous polyps of the large bowel. In five patients, the diagnosis of Cowden syndrome was established after the pathology report raised suspicion for the diagnosis. Pathologists who are aware of the characteristic admixture of lesions in Cowden syndrome can play an essential role in recommending referral to genetic counseling and gene testing. Early diagnosis of Cowden syndrome is important, as these patients and their relatives are at increased risk for developing multiple cancers.

Elevated Radiation Therapy Toxicity in the Setting of Germline PTEN Mutation

Abstract Cells that lack PTEN function are radiation sensitive in cell culture-based experimental systems; therefore, patients with Cowden Syndrome (CS) may carry an increased risk for normal tissue injury after radiotherapy. Here we present the first such case of a patient with genetically-confirmed CS who, indeed, experienced greater than expected toxicity following two separate courses of radiotherapy. While a causal relationship between CS and radiation sensitivity remains unclear, this observation suggests the need for further study in larger cohorts of CS patients.

A novel missense PTEN mutation identified in a patient with macrocephaly and developmental delay

Phosphatase and tensin homolog (PTEN) plays an important role in tumor suppression. A germline mutation in the PTEN gene induces not only PTEN hamartoma tumor syndrome, including Cowden syndrome, but also macrocephaly/autism syndrome. Here, we describe a boy with macrocephaly/autism syndrome harboring a novel missense heterozygous PTEN mutation, c.959T>C (p.Leu320Ser). Interestingly, a previously reported nonsense mutation resulting in p.Leu320X was found in Cowden syndrome patients. Our case may be suggestive of a genotype-phenotype correlation.

Abstract 317: Role of KLLN in DNA damage-induced apoptosis is associated with the regulation of p53 phosphorylation and acetylation in breast cancer cells

Abstract KLLN was initially discovered as a target of p53 involved in S-phase checkpoint regulation. Germline hypermethylation in the promoter of KLLN is known to increase the predisposition for breast and clear cell renal cell carcinomas in PTEN-wildtype Cowden syndrome (CS) patients. KLLN is a known tumor suppressor protein and required for p53-mediated apoptosis. In this study, we explore the underlying mechanism by which KLLN regulates DNA damage response (DDR), specifically apoptosis. Our DDR studies were conducted on one breast normal and four breast cancer cell lines using doxorubicin as the DNA damaging agent. We initially showed that doxorubicin-induced DNA damage increases KLLN expression at 16h and 24h post-damage which could be abrogated by RNAi-mediated knockdown of KLLN expression. Response to DNA damage as determined by the presence of γH2AX foci formation and expression of γH2AX protein were both decreased after KLLN knockdown. Using TUNEL assay and cell viability studies, we demonstrated that a lack of KLLN expression decreases apoptosis and increases cell viability at 16h and 24h post-damage. Definitive markers of apoptosis such as cleavage of caspase 3 and PARP were also decreased. Since KLLN is a known transcription factor and regulates the expression of DDR genes such as TP53 and CHK1, we assessed the regulation of these genes in response to DNA damage and found that lack of KLLN expression did not affect the expression of either TP53 or CHK1. Cell cycle analysis results using flow cytometry also suggested that KLLN does not play a role in S-phase cell cycle regulation in response to DNA damage as was previously thought, since KLLN knockdown did not change accumulation of cells in S-phase after doxorubicin-induced DNA damage. DDR in cells is immediate and therefore we assessed the abrogation of DDR after KLLN knockdown at early timepoints (1h and 2h) post-damage. We found that lack of KLLN expression decreased Ser15 phosphorylation of p53 and Thr68 phosphorylation of CHK2 at 1h and 2h post-damage. KLLN regulation of p53-mediated apoptosis could also be associated with its interaction with deleted in breast cancer (DBC1). DBC1 is a known inhibitor of SIRT1, a deacetylase that is known for its inhibitory deacetylation of p53. Phosphorylated DBC1 binds to SIRT1 and inhibits its deacetylation of p53. We found that lack of KLLN expression decreased the phosphorylation of DBC1 on Thr454 in response to DNA damage. Therefore, KLLN displays a 2-pronged regulation of the activation of p53 and the downstream cascade of proteins involved in apoptosis. SIGNIFICANCE: Our study demonstrates a clear role for KLLN in DNA damage-induced apoptosis and elucidates the underlying mechanism through the regulation of p53 phosphorylation and deacetylation in response to DNA damage. Our observations add to the basis of KLLN as a tumor suppressor and as a susceptibility gene for inherited cancers. Citation Format: Madhav Sankunny, Charis Eng. Role of KLLN in DNA damage-induced apoptosis is associated with the regulation of p53 phosphorylation and acetylation in breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 317.

Characterization of cryptic splicing in germline PTEN intronic variants in Cowden syndrome.

Germline mutations in the tumor‐suppressor gene PTEN predispose to subsets of Cowden syndrome (CS), Bannayan–Riley–Ruvalcaba syndrome, and autism. Evidence‐based classification of PTEN variants as either deleterious or benign is urgently needed for accurate molecular diagnosis and gene‐informed genetic counseling. We studied 34 different germline PTEN intronic variants from 61 CS patients, characterized their PTEN mRNA processing, and analyzed PTEN expression and downstream readouts of P‐AKT and P‐ERK1/2. While we found that many mutations near splice junctions result in exon skipping, we also identified the presence of cryptic splicing that resulted in premature termination or a shift in isoform usage. PTEN protein expression is significantly lower in the group with splicing changes while P‐AKT, but not P‐ERK1/2, is significantly increased. Our observations of these PTEN intronic variants should contribute to the determination of pathogenicity of PTEN intronic variants and aid in genetic counseling.

Insertion of Alu elements at a PTEN hotspot in Cowden syndrome.

Cowden syndrome (CS) is an inherited autosomal dominant disorder associated with germline pathogenic variants of the PTEN tumor suppressor gene. Its phenotypical expression is highly variable and the existence of patients with a CS suggestive phenotype without pathogenic PTEN variant may be related to genetic heterogeneity. In order to explore this hypothesis through the detection of potentially deleterious variants enabling us to identify a new candidate gene, we performed whole-exome sequencing (WES) in a series of 22 CS patients without detectable PTEN pathogenic variant using conventional methods for mutation screening. We failed to identify a novel candidate gene, but interestingly in two patients WES revealed the presence of two distinct, previously undescribed Alu insertions with the same break points in exon 5. These insertions were not found in a series of 35 breast carcinomas that showed a loss of PTEN expression without a detectable alteration of this gene. This study reveals the presence of a PTEN Alu insertion hotspot involved in CS, and suggests that undetected PTEN pathogenic variants could contribute to CS.

Cowden syndrome-associated germline succinate dehydrogenase complex subunit D (SDHD) variants cause PTEN-mediated down-regulation of autophagy in thyroid cancer cells.

Thyroid cancer is a major component cancer of Cowden syndrome (CS), a disorder typically associated with germline mutations in PTEN. Germline variants in succinate dehydrogenase genes (SDHx) co-occurring with PTEN germline mutations confer a 2-fold increased prevalence (OR 2.7) of thyroid cancer compared to PTEN-associated CS but 50% decreased prevalence (OR 0.54) of thyroid cancer compared to SDHx-associated CS. We have previously shown that CS-associated SDHD variants G12S and H50R induce PTEN oxidation and nuclear accumulation in thyroid cancer. Our current study shows that SDHD-G12S and -H50R variants cause down-regulation of autophagy, demonstrating a role for SDHD in autophagy-associated pathogenesis of differentiated thyroid cancer. These findings could explain the increased prevalence of thyroid cancer in CS patients with SDHx germline mutations compared to those with PTEN mutations alone. Importantly, we demonstrate the dependence of this process on functional wild-type PTEN with reversal of decreased autophagy after PTEN knockdown. The latter could explain the clinically observed decrease in thyroid cancer prevalence in patients with co-existent PTEN mutations and SDHx variants. We also show that SDHD-G12S/H50R promotes mono-ubiquitination of PTEN, causing its translocation into the nucleus, upregulation of AKT and consequent phosphorylation of FOXO3a. Furthermore, SDHD-G12S/H50R-mediated increase in acetylation of FOXO3a further enhances AKT-associated phosphorylation of FOXO3a. This combination of phosphorylation and acetylation of FOXO3a results in its nuclear export for degradation and consequent down-regulation of FOXO3a-target autophagy-related gene (ATG) expression. Overall, our study reveals a novel mechanism of crosstalk amongst SDHD, PTEN and autophagy pathways and their potential roles in thyroid carcinogenesis.

Hidden association of Cowden syndrome, PTEN mutation and meningioma frequency

Cowden syndrome (CS) is clinically presented by multiple hamartomas, often with mucocutaneous lesions, goiter, breast cancer and gastrointestinal polyps. CS is a genetic disorder of autosomal dominant inheritance and is one distinct syndrome of the phosphatase and tensin homolog on chromosome 10 (PTEN) hamartoma tumor spectrum. Noteworthy, PTEN germline mutations are related to a wide range of brain tumors. We performed a systematic analysis and review of the medical literature for Cowden syndrome and meningioma and additionally present the case of a 29-year- old CS patient diagnosed with multiple meningiomas. We found strong evidence for high incidence of brain tumors in CS patients. In particular meningiomas and gangliocytomas/Lhermitte-Duclos disease were often associated with 8% and 9% respectively in CS patients. Since aberrations in chromosome 10q are associated with meningiomas, it is likely that the underlying mutations in CS drive to a certain extent neoplastic meningioma growth. We propose to include meningiomas and brain tumors in the major criteria spectrum of CS-related disorders. This could warrant early diagnosis of brain lesions and close therapy, as well as better monitoring of patients with CS.

Diabetes and the breast

Diabetes and the breast