Cowden Syndrome is one of several PTEN Hamartoma Tumor Syndromes caused by heterozygous germline mutations in the PTEN gene. Symptoms include learning disability, macrocephaly, skin papules on the face and mucous membranes, intestinal and colonic polyps, uterine fibroids, lipomas, and increased susceptibility to thyroid, breast and endometrial cancers. Two studies, published in 2012 and 2013 suggest that renal cell carcinomas (RCC) may also be a low risk symptom of Cowden Syndrome, and as such, PTEN mutations might be an underappreciated cause of hereditary kidney cancers.
Mester et al. (2012) analysed a cohort of 219 patients with germline PTEN mutations, 9 of whom (4.1%) had a medical history of RCC, and Shuch et al. (2013) investigated a cohort of 24 Cowden Syndrome patients – with confirmed PTEN mutations – 4 of whom (16.7%) had a medical history of RCC. Overall, the prevalence of RCC in patients carrying a PTEN mutation was 5.3% (13/243), and all patients who developed RCC had symptoms consistent with Cowden Syndrome. The increased prevalence of RCC found in the Shuch et al. cohort is likely to be because this cohort was a carefully selected group of patients with particularly prominent symptoms of Cowden Syndrome, whereas the Mester cohort was selected solely on the basis of their PTEN mutation status.
Of the 13 Cowden Syndrome patients with RCC described in these two studies, six had type I papillary RCCs; two had type IIB papillary RCCs; three had chromophobe RCC, two of whom presented with bilateral tumours; one had a clear cell RCC; and tumour histology was not available for one patient. Immunohistochemical staining (Mester et al., 2012) and loss of heterozygosity (LOH) analysis (Shuch et al., 2013) showed that PTEN expression was lost in all but two of the tumour samples analysed. Interestingly, the clear cell RCC tumour showed both LOH of PTEN and had also acquired a somatic truncating mutation in one VHL allele.
Homozygous deletion of both PTEN and VHL has been previously shown to cause liver hemangioblastomas and kidney cysts in mice (Chen et al., 2010; Frew et al., 2008), and compound heterozygosity of PTEN and FLCN has been reported to cause oncocytic tumour growth specifically in the context of Cowden and BHD Syndromes (Pradella et al., 2013). Furthermore, mutations in SDHB and SDHD, which catalyse the step preceding that catalysed by FH in the citric acid cycle, can cause both Familial Paraganglioma Syndrome – another heritable kidney cancer syndrome – and a Cowden-like Syndrome (Ni et al., 2008). Taken together, there is evidence that PTEN interacts genetically with a number of known kidney cancer genes to cause disease.
Loss of PTEN increases PI3K signalling, leading to mTORC1 hyperactivity via dysregulation of the AKT-TSC1/2 signalling axis (Salmena et al., 2008). Dysregulation of mTOR signalling and of HIF1a translation are common features of hereditary kidney cancer syndromes, and as such many known kidney cancer proteins, such as TSC1/2, FLCN, FH, VHL, SDHB, SDHD and TFE3, converge on this pathway (Shuch et al., 2013).
Clinically, Cowden Syndrome has some symptoms that overlap with other kidney cancer susceptibility syndromes in addition to RCC: learning disability, lipomas, fibromas and other types of hamartomas, as in TSC; uterine fibroids, as in HLRCC; colon polyps which are an unconfirmed symptom of BHD; and skin papules as is seen in all three syndromes.
From the above evidence, it seems that there is significant overlap in the clinical symptoms, genetics and molecular biology of Cowden Syndrome with many of the kidney cancer syndromes, including BHD, TSC, HLRCC and VHL. Thus, clinicians should be aware of Cowden Syndrome as a differential diagnosis in patients with kidney cancer, especially if the patient has additional syndromic symptoms.
- Chen S, Sanford CA, Sun J, Choi V, Van Dyke T, Samulski RJ, & Rathmell WK (2010). VHL and PTEN loss coordinate to promote mouse liver vascular lesions. Angiogenesis, 13 (1), 59-69 PMID: 20221685
- Frew IJ, Thoma CR, Georgiev S, Minola A, Hitz M, Montani M, Moch H, & Krek W (2008). pVHL and PTEN tumour suppressor proteins cooperatively suppress kidney cyst formation. The EMBO journal, 27 (12), 1747-57 PMID: 18497742
- Mester JL, Zhou M, Prescott N, & Eng C (2012). Papillary renal cell carcinoma is associated with PTEN hamartoma tumor syndrome. Urology, 79 (5), 11870-7 PMID: 22381246
- Ni Y, Zbuk KM, Sadler T, Patocs A, Lobo G, Edelman E, Platzer P, Orloff MS, Waite KA, & Eng C (2008). Germline mutations and variants in the succinate dehydrogenase genes in Cowden and Cowden-like syndromes. American journal of human genetics, 83 (2), 261-8 PMID: 18678321
- Pradella LM, Lang M, Kurelac I, Mariani E, Guerra F, Zuntini R, Tallini G, MacKay A, Reis-Filho JS, Seri M, Turchetti D, & Gasparre G (2013). Where Birt-Hogg-Dubé meets Cowden syndrome: mirrored genetic defects in two cases of syndromic oncocytic tumours. European journal of human genetics : EJHG, 21 (10), 1169-72 PMID: 23386036
- Salmena L, Carracedo A, & Pandolfi PP (2008). Tenets of PTEN tumor suppression. Cell, 133 (3), 403-14 PMID: 18455982
- Shuch B, Ricketts CJ, Vocke CD, Komiya T, Middelton LA, Kauffman EC, Merino MJ, Metwalli AR, Dennis P, & Linehan WM (2013). Germline PTEN mutation Cowden syndrome: an underappreciated form of hereditary kidney cancer. The Journal of urology, 190 (6), 1990-8 PMID: 23764071
www.bhdsyndrome.org – the primary online resource for anyone interested in BHD Syndrome.