What is Cowden Syndrome?
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Cowden Syndrome, also known as Cowden's Disease and multiple hamartoma syndrome, is an often underdiagnosed condition, affecting every 1 in 200,000 people. Characterized by its hamartomas, which are benign growths that appear on the skin, patients with the condition also have an increased lifetime risk of developing different cancers.
A usually autosomal dominantly inherited condition, Cowden syndrome can also arise from de novo PTEN mutations (Dragoo et al., 2021). According to that Dragoo research, 80% of patients had identifiable PTEN mutations. In the mutation PTEN is downregulated, resulting in tumor formation not being prevented. Due to this, Cowden is often grouped with other hamartoma causing conditions, like Bannayan-Rile-Ruvalcaba and Proteus-like syndrome, the grouping being recognized as "PTEN hamartoma syndromes" (Yehia et al., 2018). That term has also been shortened to PTHS. |
Manifestations and Symptoms
84% of patients of CS also suffer from Macrocephaly (Jelsig et al., 2014). ASD has also been reported. Lhermitte-Duclos disease is apart of the diagnostic criterion as well.
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Along with their increased susceptibility of developing thyroid cancer, 2/3rds of CS patients have thyroid disorders (Yehia et al., 2018)
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As the most observable symptom, skin lesions and hamartomas develop by adolescence. At birth or childhood, pigmented spots are also common.
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In terms of gastrointestinal effects, polyps are very common, usually the hamartomatous subtype of polyps. These are found in high numbers.
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Like with the thyroid, CS patients are at an increased risk of developing breast cancer. however it seems to only increase diagnosis of female breast cancer.
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Again with a similarity to the other cancers, endometrial cancer risk is increased for CS-diagnosed females under the age of 50.
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The PTEN Gene and CS
The PTEN gene has been recognized as a tumor-repressing gene since its discovery in 1997 (Wang et al., 1997). Although there have been others who meet clinical criteria for CS without having a PTEN mutation, those patients were found to have other mutations in SDHB, SDHC, and SDHD which resulted in second-hit mutations, compounding in heterozygous loss of PTEN (Dragoo, et al., 2021). On the inverse of this acknowledgment, PTEN has also been tied to non-hamartoma causing conditions like autism spectrum disorder (ASD) and macrocephaly mutations (Yehia et al., 2019).
The PTEN gene is known to be located on human's 10th chromosome, on band 10q23.31. PTEN acts primarily as a phosphatase to dephosphorylate PIP3, creating PIP2. That process results in the inhibition of the Akt pathway, which regulates things like cell growth and survival. In addition to this, the believed interaction for CS, the weak protein phosphatase is vital for PTEN's role as a tumor suppressant. It may specifically be involved in the prevention of rapid growth and division (Chu and Tarnawksi, 2004). As one of the most commonly lost tumor suppressors in cancer patients (Chen et al., 2005), the gene's connection to CS patient cancer prognosis is important to find.
The PTEN gene is known to be located on human's 10th chromosome, on band 10q23.31. PTEN acts primarily as a phosphatase to dephosphorylate PIP3, creating PIP2. That process results in the inhibition of the Akt pathway, which regulates things like cell growth and survival. In addition to this, the believed interaction for CS, the weak protein phosphatase is vital for PTEN's role as a tumor suppressant. It may specifically be involved in the prevention of rapid growth and division (Chu and Tarnawksi, 2004). As one of the most commonly lost tumor suppressors in cancer patients (Chen et al., 2005), the gene's connection to CS patient cancer prognosis is important to find.
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References
D. Dragoo, A. Taher, V.K. Wong, A, Elsaiey, N, Consul, H.S, Mahmoud, B. Mujtaba, N. Stanietzky, K.M. Elsayes. PTEN Hamartoma Tumor Syndrome/Cowden Syndrome: Genomics, Oncogenesis, and Imaging Review for Associated Lesions and Malignancy. Cancers 13(13) June 22, 2021. https://doi.org/10.3390/cancers13133120
L. Yehia, Y. Ni, K. Sesock, F. Niazo, B. Fletcher, H.J.L. Chen, T. LaFramboise, C. Eng, Unexpected cancer-predispotions gene variants in Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome patients without underlying germline PTEN mutations. PLOS Genetics April 23, 2018.
https://doi.org/10.1371/journal.pgen.1007352
A.M., Jelsig, N. Qvist, K. Brusgaard, C.B. Nielsen, T.P. Hansen, L.B. Ousager. Hamartomatous polyposis syndromes: A review. Orphanet Journal of Rare Diseases 9 (101) July 15, 2014.
https://doi.org/10.1186/1750-1172-9-101
S.I. Wang, J. Puc, J. Li, J.N. Bruce, P. Cairns, D. Sidransky, R. Parsons. Somatic mutations of PTEN in glioblastoma multiforme. Cancer Res 57: 4183–4186. 1997
L. Yehia, E. Keel, C. Eng. The Clinical Spectrum of PTEN Mutations. Annual Review of Medicine 71(103-116) August 21, 2019
https://doi.org/10.1146/annurev-med-052218-125823
E.C. Chu and A.S. Tarnawski PTEN regulatory functions in tumor suppression and cell biology Med Sci Monit 10(10) October 1, 2004
RA235-241 ID: 11797
Z. Chen, L.C. Trotman, D. Shaffer, H.K. Lin, Z.A. Dotan, M. Niki, J.A. Koutcher, H.I. Scher, T. Ludwig, W. Gerald, C. Cordon-Cardo, P.P. Pandolfi. Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis Nature 436(725-730) August 4, 2005
https://doi.org/10.1038/nature03918
A. Sueta, M. Takeno, L. Goto-Yamaguchi, M. Tomiguchi, T. Inao, M. Yamamoto-Ibusuki, Y. Yamamoto. A progressive and refractory case of breast cancer with Cowden syndrome World Journal of Surgical Oncology 20(279) September 3, 2022
https://doi.org/10.1186/s12957-022-02745-5
L. Yehia, Y. Ni, K. Sesock, F. Niazo, B. Fletcher, H.J.L. Chen, T. LaFramboise, C. Eng, Unexpected cancer-predispotions gene variants in Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome patients without underlying germline PTEN mutations. PLOS Genetics April 23, 2018.
https://doi.org/10.1371/journal.pgen.1007352
A.M., Jelsig, N. Qvist, K. Brusgaard, C.B. Nielsen, T.P. Hansen, L.B. Ousager. Hamartomatous polyposis syndromes: A review. Orphanet Journal of Rare Diseases 9 (101) July 15, 2014.
https://doi.org/10.1186/1750-1172-9-101
S.I. Wang, J. Puc, J. Li, J.N. Bruce, P. Cairns, D. Sidransky, R. Parsons. Somatic mutations of PTEN in glioblastoma multiforme. Cancer Res 57: 4183–4186. 1997
L. Yehia, E. Keel, C. Eng. The Clinical Spectrum of PTEN Mutations. Annual Review of Medicine 71(103-116) August 21, 2019
https://doi.org/10.1146/annurev-med-052218-125823
E.C. Chu and A.S. Tarnawski PTEN regulatory functions in tumor suppression and cell biology Med Sci Monit 10(10) October 1, 2004
RA235-241 ID: 11797
Z. Chen, L.C. Trotman, D. Shaffer, H.K. Lin, Z.A. Dotan, M. Niki, J.A. Koutcher, H.I. Scher, T. Ludwig, W. Gerald, C. Cordon-Cardo, P.P. Pandolfi. Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis Nature 436(725-730) August 4, 2005
https://doi.org/10.1038/nature03918
A. Sueta, M. Takeno, L. Goto-Yamaguchi, M. Tomiguchi, T. Inao, M. Yamamoto-Ibusuki, Y. Yamamoto. A progressive and refractory case of breast cancer with Cowden syndrome World Journal of Surgical Oncology 20(279) September 3, 2022
https://doi.org/10.1186/s12957-022-02745-5