Germline PTEN Mutations Research Articles

Abstract P4-04-04: Targeted resequencing of germline PTEN-negative patients with Cowden disease reveals alternate mechanism of molecular alteration

Abstract Introduction Cowden disease belongs to the PTEN hamartoma tumor syndrome (PHTS) group, defined by germline PTEN heterozygous inactivation. Describing the PTEN germline mutation in Cowden disease patients is of particular importance for their breast cancer and thyroid carcinoma predisposition evaluation. Material & methods Targeted resequencing was done on germline DNA of 22 index cases patients with a Cowden disease clinically well established since they do not demonstrate any PTEN mutation analyzed using our current screening method (EMMA, Enhanced Mismatch Mutation Analysis, similar to high resolution melting). The 565 exons of 34 genes of interest together with the entire genomic locus of PTEN were captured using the SureSelect oligonucleotide library capture (Agilent technologies). The bioinformatics resources Suredesign, Ensembl human genome v70 and a UCSC repeat masker least stringent were used to create the capture design. This gave us 28405 unique 120-mers oligonucleotide probes which were duplicated 1 to 16 times depending on the GC content or the size of the targeted regions (maximum boosting performance criteria). For each gene of interest, an exon of the surrounding gene was also captured in order to define the extent of gross gene rearrangement. Samples were prepared according the manufacturer's recommendations. Results Each of the 22 Cowden disease patients demonstrates a mean rate of 70 intronic mutations in the entire genomic locus of PTEN. All of those for which the minor allelic frequency is unknown, were subjected to splicing site bioinformatic prediction. For one patient, the prediction reveals the apparition of a splicing site in a deep intronic mutation of the large intron 1 of PTEN. Furthermore, next generation sequencing (NGS) seems to be more sensitive than our current screening method since for two patients, a germline mosaic exonic heterozygous inactivating mutation of PTEN was detected and confirmed by Sanger sequencing on different biological samples. The level of mosaicism was evaluated by NGS at 3 to 12% depending on the sample and confirmed by pyrosequencing. In addition, some mutations were identified in exons of genes encoding proteins of the PI3Kinase pathway, which could be involved in disease belonging to the PHTS group. With an increasing sensitivity, NGS is a powerful tool to detect low frequency variant. This could used to explain at a molecular level Cowden disease with no initially detectable PTEN mutation. Clinical and biological rationale, bioinformatics workflow and comprehensive results will be presented. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-04-04.

Cowden Syndrome and the PTEN Hamartoma Tumor Syndrome: Systematic Review and Revised Diagnostic Criteria

PTEN hamartoma tumor syndrome (PHTS) refers to a spectrum of disorders caused by mutations in the phosphatase and tensin homolog (PTEN) gene. Diagnostic criteria for Cowden syndrome, the principal PTEN-related disorder, were first established in 1996 before the identification of the PTEN gene and the ability to molecularly confirm a clinical diagnosis. These consortium criteria were based on clinical experience and case reports in the existing literature, with their inherent selection biases. Although it was initially reported that approximately 80% of patients with Cowden syndrome had an identifiable germline PTEN mutation, more recent work has shown these diagnostic criteria to be far less specific. In addition, increasing evidence has documented the association of a broader spectrum of clinical features with PTEN mutations. Our goal was to develop revised, evidence-based diagnostic criteria and to include features of the broader spectrum of PTEN-related clinical syndromes. We performed a systematic search and review of the medical literature related to clinical features reported in individuals with a PTEN mutation and/or a related clinical diagnosis. We found no sufficient evidence to support inclusion of benign breast disease, uterine fibroids, or genitourinary malformations as diagnostic criteria. There was evidence to include autism spectrum disorders, colon cancer, esophageal glycogenic acanthosis, penile macules, renal cell carcinoma, testicular lipomatosis, and vascular anomalies. We propose revised, evidence-based criteria covering the spectrum of PTEN-related clinical disorders. Additional research on clinical features associated with PTEN mutations is warranted.

Cowden syndrome complicated by a gastrointestinal stromal tumor

To our knowledge, this is the first report of Cowden syndrome complicated by a gastrointestinal stromal tumor (GIST) of the small bowel. A 42-year-old female patient was found to have an abdominal mass that was diagnosed as the cause of anemia and was surgically extracted. The surgical specimen was found to be a GIST. During the same period, the patient underwent an endoscopic examination of the entire gastrointestinal tract. She was also diagnosed as having Cowden syndrome based on gastrointestinal polyps and skin, thyroid and breast lesions. Cowden syndrome is associated with germline mutations in the tumorsuppressor gene PTEN. PTEN expression may be essential to tumor growth and is a predictive biomarker of the prognosis of both diseases. The present report of such a case is expected to further the analysis of Cowden syndrome.

PTEN Germline Mutations in Patients Initially Tested for Other Hereditary Cancer Syndromes: Would Use of Risk Assessment Tools Reduce Genetic Testing?

PTEN Hamartoma Tumor syndrome (PHTS) includes patients with Cowden syndrome or other syndromes with germline mutation of the PTEN tumor suppressor gene. The risk for breast, colorectal, and endometrial cancer and polyposis is increased, creating clinical overlap with hereditary breast and ovarian cancer (HBOC), Lynch syndrome (LS), and adenomatous polyposis syndromes (APS). We reviewed our series of patients with PHTS to determine how often testing criteria for these syndromes were met and how often other-gene testing was ordered before testing PTEN. Patients were prospectively recruited by relaxed International Cowden Consortium criteria or presence of known germline PTEN mutation. Mutations were identified by mutation scanning/multiplex ligation-dependent probe amplification analysis and confirmed by sequencing/quantitative polymerase chain reaction. Patients were excluded if they were adopted, were <18 years of age, or if they were diagnosed with Cowden syndrome before 1998. Standard risk-assessment models were applied to determine whether patients met HBOC testing criteria, LS-relevant Amsterdam II/Bethesda 2004 criteria, or had adenomatous polyps. Prior probability of PTEN mutation was estimated with the Cleveland Clinic PTEN risk calculator. Of 137 PTEN mutation-positive adult probands, 59 (43.1%) met testing criteria for HBOC or LS. Of these, 45 (32.8%) were first offered HBOC, LS, or APS testing. Of those who underwent APS testing, none of the six patients met criteria. Initial risk assessment by a genetics specialist was significantly associated with immediate PTEN testing in patients also meeting HBOC testing criteria. Using this PTEN risk assessment tool could have spared gene testing for 22 unlikely syndromes, at a total cost of $66,080. PHTS is an important differential diagnosis for patients referred for HBOC, LS, or APS. Risk assessment tools may help focus genetic analysis and aid in the interpretation of multiplex testing.

Cancer risk and genotype–phenotype correlations in PTEN hamartoma tumor syndrome

Patients with germline PTEN mutations are at high risk of developing benign and malignant tumours. We aimed to evaluate the cumulative risk of several types of cancer and of dysplastic cerebellar gangliocytoma (Lhermitte-Duclos disease, LDD). In addition, genotype-phenotype correlations in PTEN hamartoma tumour syndrome (PHTS) were assessed. Data on patients with PTEN mutations were collected from clinical genetic centres in Western Europe, Australia, and the USA. The cumulative risk of developing cancers of the breast, thyroid, endometrium, skin, kidneys, colorectum, and lungs, and also LDD was calculated by Kaplan-Meier methods. Associations between mutations and cancer were assessed by Chi square means. A total of 180 germline PTEN mutation carriers, 81 males (45%), from nine countries were included. The cumulative risk of developing any cancer and/or LDD at age 60 was 56% for males and 87% for females (p = 0.001). Females had significant higher risks of developing breast cancer, thyroid cancer, and LDD than males. The only genotype-phenotype correlation identified was a lower frequency of thyroid cancer in patients with missense mutations (p = 0.014). In conclusion, PHTS patients, particularly females, have a substantial risk of developing one or more tumours from a broad tumour spectrum. Major genotype-phenotype associations could not be identified.

Differential expression of PTEN gene correlates with phenotypic heterogeneity in three cases of patients showing clinical manifestations of PTEN hamartoma tumour syndrome

Cowden syndrome (CS), Bannayan-Riley-Ruvalcaba syndrome (BRRS) and proteus syndrome are disorders known as PTEN hamartoma tumour syndrome (PHTS), that can show remarkable clinical overlap and are all caused by germline PTEN mutations.We here present two families, one affected by CS and the other affected by BRRS, both carriers of specific pathogenetic missense mutation in exon 5 of PTEN gene, within the catalitic domain. Both PHTS families exhibited extremely variable phenotypes, showing inter- and intra- familial variability. One of the two characterised mutations, the c.320A- > T; p.107Asp- > Val, identified in the CS family, was not previously described in the literature. Furthermore, the BRRS family, carrier of the c.406 T- > C; p.136Cys- > Arg mutation, shows a substantial alteration of PTEN protein expression that well correlates with intra-familial phenotypic variability.Finally, we describe an apparently sporadic case of an 80-year-old man, with a very low level of PTEN mRNA and protein expression, both in healthy and tumour colon mucosa, associated with a very atypical phenotype. He developed a metastatic colorectal carcinoma, macrocephaly and pheochromocytoma.According to literature data, our observations confirm that PTEN mutations of catalytic domain can cause different syndromes. We suggest that PTEN expression could represent one of the mechanisms involved in the remarkable heterogeneity of the clinical PHTS manifestations within affected families. Furthermore, constitutive strong decrease of PTEN expression in colon normal mucosa could be associated with late onset of colorectal cancer.

Spatially distinct roles of class Ia PI3K isoforms in the development and maintenance of PTEN hamartoma tumor syndrome

PTEN hamartoma tumor syndrome (PHTS) comprises a collection of genetic disorders associated with germline mutations in the tumor suppressor gene PTEN. Therapeutic options and preventative measures for PHTS are limited. Using both genetically engineered mouse models and pharmacological PI3K isoform-selective inhibitors, we found that the roles of PI3K isoforms are spatially distinct in the skin: While p110α is responsible for the sustained survival of suprabasal cells of the epidermis in the absence of PTEN, p110β is important for the hyperproliferation of basal cells in PHTS. Furthermore, we identified a differential expression pattern of p110α and p110β in basal and suprabasal keratinocytes as well as differential PI3K regulation by upstream signals in the basal and suprabasal compartments of the epidermis, providing a potential molecular mechanism underlying the specific roles of PI3K isoforms in the epidermis. Finally, we demonstrate that combined inhibition of both PI3K isoforms prevents the development of PHTS and also reverses skin hamartomas that have reached advanced stages in mice. Together, these results not only advance our overall understanding of the diverse roles of PI3K isoforms, but also have the potential for meaningful translation via the clinical utilization of PI3K inhibitors for both prevention and therapy in PHTS patients.

A novel PTEN gene promoter mutation and untypical Cowden syndrome.

Cowden syndrome (CS), an autosomal dominant disorder, is one of a spectrum of clinical disorders that have been linked to germline mutations in the phosphatase and tensin homolog (PTEN) gene. Although 70-80% of patients with CS have an identifiable germline PTEN mutation, the clinical diagnosis presents many challenges because of the phenotypic and genotypic variations. In the present study, we sequenced the exons and the promoter of PTEN gene, mutations and variations in the promoter and exons were identified, and a PTEN protein expression negative region was determined by immunohistochemistry (IHC). In conclusion, a novel promoter mutation we found in PTEN gene may turn off PTEN protein expression occasionally, leading to the disorder of PTEN and untypical CS manifestations.

Germline PTEN Mutation Cowden Syndrome: An Underappreciated Form of Hereditary Kidney Cancer

Cowden syndrome is a hereditary cancer syndrome associated with a germline mutation in PTEN. Patients are predisposed to multiple malignancies including renal cell carcinoma. Patients with Cowden syndrome were evaluated as part of a clinical protocol. Those with a history of renal cell carcinoma underwent review of clinical features, tumor characteristics and family history. Renal tumors were evaluated for loss of heterozygosity. Among 24 patients with Cowden syndrome 4 were identified with renal cell carcinoma (16.7%). Three patients had solitary tumors, 2 with papillary type I histology and 1 with clear cell histology. The fourth patient had bilateral, synchronous chromophobe tumors. No patients had a prior family history of renal cell carcinoma. All patients with renal cell carcinoma had dermatologic manifestations of Cowden syndrome and had macrocephaly. Loss of heterozygosity at the PTEN mutation was identified in 4 tumors (80%). No genotype-phenotype association was found, as the same mutation was identified in different renal cell carcinoma histologies. Renal cell carcinoma is an underappreciated feature of Cowden syndrome. As most patients lack a prior family history or a distinctive renal cell carcinoma histology, recognition of the associated nonrenal features should target referral for genetic counseling. PTEN loss of heterozygosity is common in Cowden syndrome renal tumors. Because loss of PTEN can activate mTOR and mTOR inhibitors are Food and Drug Administration approved to treat renal cell carcinoma, these agents have clinical potential in renal cell carcinoma associated with Cowden syndrome.

Biochemical screening and PTEN mutation analysis in individuals with autism spectrum disorders and macrocephaly

Unlike some other childhood neurodevelopmental disorders, no diagnostic biochemical marker has been identified in all individuals with an autism spectrum disorder (ASD). This deficit likely results from genetic heterogeneity among the population. Therefore, we evaluated a subset of individuals with ASDs, specifically, individuals with or without macrocephaly in the presence or absence of PTEN mutations. We sought to determine if amino or organic acid markers could be used to identify individuals with ASDs with or without macrocephaly in the presence or absence of PTEN mutations, and to establish the degree of macrocephaly in individuals with ASDs and PTEN mutation. Urine, blood and occipital-frontal circumference (OFC) measurements were collected from 69 individuals meeting DSM-IV-TR criteria. Urine and plasma samples were subjected to amino and organic acid analyses. PTEN was Sanger-sequenced from germline genomic DNA. Germline PTEN mutations were identified in 27% (6/22) of the macrocephalic ASD population. All six PTEN mutation-positive individuals were macrocephalic with average OFC+4.35 standard deviations (SDs) above the mean. No common biochemical abnormalities were identified in macrocephalic ASD individuals with or without PTEN mutations. In contrast, among the collective ASD population, elevation of urine aspartic acid (87%; 54/62), plasma taurine (69%; 46/67) and reduction of plasma cystine (72%; 46/64) were observed. PTEN sequencing should be carried out for all individuals with ASDs and macrocephaly with OFC ≥2SDs above the mean. A proportion of individuals with ASDs may have an underlying disorder in sulfur amino acid metabolism.

A pilot study of sirolimus (S) in subjects with Cowden syndrome (CS) with germ-line mutations in PTEN.

2532 Background: CS is characterized by germline PTEN mutations. Because tumors from CS patients show increased activation of the PI3K/Akt/mTOR pathway, mTOR inhibitor such as S might have activity in such patients. Methods: Eligibility: subjects with germline PTEN mutation who meet international diagnostic criteria for CS, age 18, ECOG PS 0-2, and adequate organ function. Subjects were treated with a 56-day course of daily oral S (2 mg). Objective: Inhibition of the mTOR pathway in benign skin/GI lesion, as assessed by IHC (P-AKT, Total S6, P-S6, P-4E-BP1, score 0-4), changes in benign or malignant tumor by CT/MRI/PET, digital dermoscopy/endoscopy, and changes in cerebellar testing by modified SARA (Neurology 2006). Protocol was amended to allow up to 20 subjects. Results: A total of 18 pts/16 families were enrolled. Median age 42 (range 19-69). Male/Female: 9/9. Involvement in skin, thyroid, GI polyps, breast, CNS, and all of the five organs was observed in 18, 15, 13, 8, 18, 5 subjects, respectively. 7 had h/o malignancies: 3 renal cell, 4 breast, 3 thyroid, 4 others. 3 cerebellar gangliocytomas and 2 others were measurable by CT or MRI. PTEN mutations: 6 families in Exon 1-2, 1 in Exon 4, 9 in Exon 5-8. All but one (D24H) were truncating mutations. 11 of 16 pts who completed a 56-day course reported subjective improvement in energy, mood, focus or skin lesion. Pts with Ex6-8 mutation (n=4) had a median SUV decrease of 29.4%. Regression of skin and GI lesions was observed by dermoscopy or endoscopy. Cerebellar evaluation showed a significant improvement in a total SARA score at 1 month (n=9, p=0.034). 3 pts were treated for only 28 days due to voluntary withdrawal. IHC analysis in skin and GI benign lesions showed a decrease in average P-S6K, P-S6, Total S6, P-S6/Total S6 in response to S. P-S6K/Total S6 ratios at d14 and d56 were significantly lower than at baseline (p=0.0026, 0.0391, respectively). The most common AEs (all grades &gt;25%) were LFTs/Hb (39%), fatigue/hypercholesterolemia (28%). Grade 3 AEs: 1 pt hypophosphatemia/lymphopenia. Conclusions: A 56-day course of S was well tolerated in subjects with CS and was associated with improvement in symptoms, skin/GI lesions, cerebellar function and decreased mTOR signaling. Clinical trial information: NCT00971789.

Second malignant neoplasms (SMN) in Cowden syndrome patients with underlying germline PTEN mutations.

1527 Background: Cowden syndrome (CS) patients with underlying germline PTEN mutations are at significantly increased risks of breast, thyroid, endometrial and renal cancers. Current estimates of lifetime cancer risks do not provide the majority of patients who present after their first cancer a meaningful gauge of their risk of a SMN. Quantification of the risk of a SMN will allow patients to be better informed and provide clinicians a much needed guide to finally address patients’ question of “how likely am I to have a second cancer and will it likely be the same primary?” Methods: We conducted a 5-year, multi-center prospective study of CS and CS-like patients, all of whom had comprehensive PTEN analysis done. Patients’ records were reviewed for prior history of invasive cancers. Invasive SMNs were confirmed by pathology reports or physician reports where possible. All metastatic disease, synchronous primary cancer at the same site and non-melanoma skin cancers were excluded. Incidences of SMNs were compared between patients with pathogenic PTEN mutations (PTENmut+) and wildtype PTEN (PTENwt). Standardized incidence ratios (SIR), cumulative incidences and excess absolute risks for SMNs were calculated comparing against SEER-derived data. Results: Of 2,792 CS/CS-like patients who present with 1 or more cancers, there were 100 (4%) PTENmut+patients. Compared with PTENwt CS/CS-like patients with SMNs (223/2039; 11%), PTENmut+cases (42/100; 42%) were more likely to develop SMNs (p&lt;0.0001). PTENmut+ cases were also younger at median age of SMN diagnosis (48yrs vs 54 yrs; p=0.30). PTENmut+ patients were 56-fold more likely to develop any SMN compared with the general population (95%CI 41-55); corresponding to an excess absolute risk of 731/10000 person years. Breast cancer was the most common SMN encountered in PTENmut+CS/CS-like patients (SIR 73; 95%CI 45-122) followed by endometrial (SIR 44; 95% CI 18-92), renal (SIR 47; 95% CI 15-113) and thyroid cancers (SIR 222; 95% CI 37-734). Conclusions: Our study shows that PTENmut+CS/CS-like patients are significantly more likely to present with a SMN compared to PTENwt CS/CS-like patients and the general population, and should be advised and surveillanced accordingly.

High cumulative risks of cancer in patients with PTEN hamartoma tumour syndrome

BackgroundPTEN hamartoma tumour syndrome (PHTS) encompasses several clinical syndromes with germline mutations in the PTEN tumour suppressor gene, including Cowden syndrome which is characterised by an increased risk of breast...

Cognitive characteristics of PTEN hamartoma tumor syndromes

We sought to characterize cognition in individuals with germline PTEN mutations (n = 23) as well as in PTEN mutation-negative individuals with classic Cowden syndrome or Bannayan-Riley-Ruvalcaba syndrome (n = 2). Twenty-five individuals completed a comprehensive neuropsychological evaluation. One sample t-tests and effect sizes were used to examine differences in participant test scores compared with normal controls. Composite scores were created for each patient within each of the cognitive domains assessed and classified as above average, average, or below average according to normative standards. χ(2) analyses compared these classifications to expected proportions in normal control samples. The mean intelligence quotient was in the average range, and the range of intellectual functioning was very wide (from extremely low to very superior). However, in a large subset of patients, scores were lower than expected on measures of motor functioning, executive functioning, and memory recall, suggesting disruption of frontal circuits in these participants. This is the first study to characterize cognition in individuals with PTEN mutations and associated syndromes using a comprehensive neuropsychological battery. Contrary to previous reports suggesting an association with intellectual disability, the mean intelligence quotient was average, and there was a broad range of intellectual abilities. Specific evidence of disruption of frontal circuits may have implications for treatment compliance and cancer surveillance, and further investigation is warranted.

Prevalence of Germline PTEN, BMPR1A, SMAD4, STK11, and ENG Mutations in Patients With Moderate-Load Colorectal Polyps

Gastrointestinal polyposis is a common clinical problem, yet there is no consensus on how to best manage patients with moderate-load polyposis. Identifying genetic features of this disorder could improve management and especially surveillance of these patients. We sought to determine the prevalence of hamartomatous polyposis-associated mutations in the susceptibility genes PTEN, BMPR1A, SMAD4, ENG, and STK11 in individuals with ≥5 gastrointestinal polyps, including at least 1 hamartomatous or hyperplastic/serrated polyp. We performed a prospective, referral-based study of 603 patients (median age: 51 years; range, 2-89 years) enrolled from June 2006 through January 2012. Genomic DNA was extracted from peripheral lymphocytes and analyzed for specific mutations and large rearrangements in PTEN, BMPR1A, SMAD4, and STK11, as well as mutations in ENG. Recursive partitioning analysis was used to determine cutoffs for continuous variables. The prevalence of mutations was compared using Fisher's exact test. Logistic regression analyses were used to determine univariate and multivariate risk factors. Of 603 patients, 119 (20%) had a personal history of colorectal cancer and most (n = 461 [76%]) had <30 polyps. Seventy-seven patients (13%) were found to have polyposis-associated mutations, including 11 in ENG (1.8%), 13 in PTEN (2.2%), 13 in STK11 (2.2%), 20 in BMPR1A (3.3%), and 21 in SMAD4 (3.5%). Univariate clinical predictors for risk of having these mutations included age at presentation younger than 40 years (19% vs 10%; P = .008), a polyp burden of ≥30 (19% vs 11%; P = .014), and male sex (16% vs 10%; P = .03). Patients who had ≥1 ganglioneuroma (29% vs 2%; P < .001) or presented with polyps of ≥3 histologic types (20% vs 2%; P = .003) were more likely to have germline mutations in PTEN. Age younger than 40 years, male sex, and specific polyp histologies are significantly associated with risk of germline mutations in hamartomatous-polyposis associated genes. These associations could guide clinical decision making and further investigations.

PTEN mutations as a cause of constitutive insulin sensitivity and obesity in human beings

BackgroundEpidemiological evidence and genetic evidence link type 2 diabetes, obesity, and cancer. The tumour suppressor phosphatase and tensin homolog (PTEN) has roles in both cellular growth and metabolic signalling. Germline PTEN mutations cause Cowden syndrome, a cancer predisposition syndrome, providing an opportunity to study the metabolic effects of PTEN haploinsufficiency in human beings. We investigated insulin sensitivity and beta-cell function in patients with Cowden syndrome. MethodsInsulin sensitivity and beta-cell function were assessed in 15 carriers of the PTEN mutation and 15 matched controls by oral glucose tolerance tests and hyperinsulinaemic euglycaemic clamps. Insulin signalling was measured in biopsies of muscle and adipose tissue with immunoblot. The effect of PTEN haploinsufficiency on obesity was assessed with anthropometric indices, dual-emission x-ray absorptiometry, and skinfold thickness in patients and controls. FindingsAll measures of insulin resistance were lower in mutation carriers, including fasting plasma insulin (mean 29 pmol/L [range 9–99] vs 74 [22–185], p=0·001). This was confirmed by hyperinsulinaemic euglycaemic clamps, which showed glucose infusion rates twice as high in patients as in controls (p=0·009). This higher insulin sensitivity was explained by enhanced insulin signalling through the PI3K-AKT pathway, evidenced by increased AKT phosphorylation in both muscle and adipose tissue. PTEN mutation carriers were obese compared with population-based controls (mean BMI 32 kg/m2 [range 23–42] vs 26 [15–48], p<0·001). Increased body mass in patients with Cowden syndrome was due to augmented adiposity without corresponding changes in fat distribution. InterpretationPTEN haploinsufficiency is the first description of a monogenic cause of profound insulin sensitivity. The constitutive insulin sensitisation is apparently obesogenic. This study demonstrates a potential divergent effect on diabetes and cancer risk, with PTEN mutations increasing risk of obesity and cancer but decreasing risk of type 2 diabetes via enhanced insulin sensitivity. FundingUK Medical Research Council and Wellcome Trust.

Management of Reproductive Health in Cowden Syndrome Complicated by Endometrial Polyps and Breast Cancer

Cowden syndrome is an autosomal-dominant condition associated with mutations in the tumor suppressor gene PTEN. Gynecologic malignancies are common with a 5-10% risk of endometrial cancer and 25-50% risk of breast cancer.A 37-year-old woman with a history of breast cancer, other neoplasms, and multiple skin lesions was diagnosed with Cowden syndrome after a germline PTEN mutation was identified. The endometrium had high glucose uptake on positron emission tomography scan and was irregularly thickened on ultrasonography; biopsy revealed endometrial polyps and simple hyperplasia. Fifteen months later, hysteroscopy again confirmed numerous benign endometrial polyps.Recurrent, multiple endometrial polyps portend a high risk of endometrial cancer in women with Cowden syndrome. Monitoring for malignancy and consideration of hysterectomy after childbearing is completed is warranted.

Endometrial cancer in a 14‐year‐old girl with Cowden syndrome: A case report

The appearance of endometrial cancer in adolescence is uncommon and warrants investigation for an hereditary cancer syndrome. Cowden syndrome is an autosomal dominant cancer syndrome associated with a germline PTEN mutation and increased risk of breast, thyroid, endometrial and colon cancer. In this report we present a case of a 14-year-old nulligravid female diagnosed with grade 1 endometrial adenocarcinoma. She subsequently developed fibrocystic breast disease and colon polyps and was diagnosed with Cowden syndrome at age 20. We therefore recommend formal evaluation for Cowden syndrome to be considered when endometrial cancer is diagnosed in adolescence.

Primary lung adenocarcinoma occurring in a PTEN related syndrome (Cowden's disease): Routine EGFR sequencing also highlights two rare somatic mutations S768I and V769L

Cowden's syndrome is a rare autosomal dominant disorder that has been linked to germline mutations in the phosphatase and TENsin homolog (PTEN) gene. PTEN is a tumour suppressor gene that negatively regulates the PI3K–AKT–mTOR pathway. Cowden's syndrome is a multi-system disease with increased risks for a number of malignancies but very rarely for lung cancer.A systematic follow-up chest CT scan was performed to a 42 year's old female, light smoker. It showed a 20mm opacity of the left upper pulmonary lobe. Differential diagnose with benign tumours (such as hamartoma) was carefully searched. Procedures led to the diagnosis of a primitive lung adenocarcinoma. EGFR sequencing shows two rare somatic mutations (S768I and V769L).Lack of expression of PTEN is a non-sufficient condition leads to lung cancer formation alone. Nevertheless, it increases cell oncogenic potential. PTEN lacking in non small cell lung cancer is a frequent issue. It could be an alternative mechanism of non-efficacy of EGFR-TKI in cells with a sensitizing EGFR mutation.This case report, a very rare entity: a patient with a PTEN germline mutation and a lung adenocarcinoma harbouring two concomitant rare somatic mutations of EGFR. This observation comforts PTENs role in lung oncogenesis.

Germline PIK3CA and AKT1 Mutations in Cowden and Cowden-like Syndromes

Cowden syndrome (CS) is a difficult-to-recognize multiple hamartoma syndrome with high risks of breast, thyroid, and other cancers. Germline mutations in PTEN on 10q23 were found to cause 85% of CS when accrued from tertiary academic centers, but prospective accrual from the community over the last 12 years has revealed a 25% PTEN mutation frequency. PTEN is the phosphatase that has been implicated in a heritable cancer syndrome and subsequently in multiple sporadic cancers and developmental processes. PTEN antagonizes the AKT1/PI3K signaling pathway and has roles in cell cycle, migration, cell polarity, and apoptosis. We report that 8 of 91 (8.8%) unrelated CS individuals without germline PTEN mutations carried 10 germline PIK3CA mutations (7 missense, 1 nonsense, and 2 indels) and 2 (2.2%) AKT1 mutations. These mutations result in significantly increased P-Thr308-AKT and increased cellular PIP3. Our observations suggest that PIK3CA and AKT1 are CS susceptibility genes.