Cowden syndrome pathophysiology
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vamsikrishna Gunnam M.B.B.S [2]
Overview
It is thought that cowden syndrome is the result caused by phosphatase and tensin homolog (PTEN) gene mutations. Cowden syndrome follows autosomal dominant pattern of inheritance.
Pathophysiology
Physiology
The normal physiology of PTEN gene can be understood as follows:
- Location of PTEN gene tracks back to 10q22-23 chromosome.[1]
- PTEN gene is an tumor suppressor gene.
- PTEN gene whose function affects in the following:[2]
- Cell cycle progression
- Cell proliferation
- Chemotaxis
- Apoptosis
- Aging
- Muscle contractility
- DNA damage response
- Angiogenesis and
- Cell polarity
Genetics
Pathogenesis
- Cowden syndrome is transmitted in autosomal dominant pattern.[3]
- Genes involved in the pathogenesis of cowden syndrome include:[4]
- Mutations in the PTEN gene leads to oncogenesis, and somatic mutations
- Phosphatase and tensin homolog (PTEN) gene plays an important role in the following:[5][6][7]
- Phosphoinositide-3-kinase (PI3K)-AKT pathway and
- Rapamycin (mTOR) signaling pathways
- PTEN track backs to 10q23 which encodes and plays a significant role in the following:[8][9][10]
- Effects G1 cell cycle arrest and apoptosis
- Cellular proliferation and
- Migration
- Apoptosis
- Other gene mutations involved in the pathogenesis of cowden syndrome include:
Associated Conditions
Conditions associated with cowden syndrome include:[17][18][19]
- Breast cancer- 85% increases the risk
- Thyroid cancer- 35% increases the risk
- Endometrial cancer- 28% increases the risk
- Colorectal cancer- 9% increases the risk
- Kidney cancer- 35% increases the risk
- Melanoma- 6% increases the risk
- Bannayan-Riley-Ruvalcaba syndrome
Gross Pathology
On gross pathology, thyroid in cowden syndrome shows the following features: [20]
- Scattered foci of adipose tissue
- Lymphocytic thyroiditis
Microscopic Pathology
- On microscopic histopathological analysis, non dysplastic epithelium, dilated glands, expanded stroma are characteristic findings of colon polyps in cowden syndrome.[21][22]
- On microscopic histopathological analysis, C-cell hyperplasia, yellow-tan, lack gelatinous colloid, small follicles and positivity in the endothelial cells found in thyroid pathology in cowden syndrome.[23][24][25]
References
- ↑ Nelen MR, Padberg GW, Peeters EA, Lin AY, van den Helm B, Frants RR, Coulon V, Goldstein AM, van Reen MM, Easton DF, Eeles RA, Hodgsen S, Mulvihill JJ, Murday VA, Tucker MA, Mariman EC, Starink TM, Ponder BA, Ropers HH, Kremer H, Longy M, Eng C (May 1996). "Localization of the gene for Cowden disease to chromosome 10q22-23". Nat. Genet. 13 (1): 114–6. doi:10.1038/ng0596-114. PMID 8673088.
- ↑ Keniry M, Parsons R (September 2008). "The role of PTEN signaling perturbations in cancer and in targeted therapy". Oncogene. 27 (41): 5477–85. doi:10.1038/onc.2008.248. PMID 18794882.
- ↑ Eng, C. (2000). "Will the real Cowden syndrome please stand up: revised diagnostic criteria". Journal of Medical Genetics. 37 (11): 828–830. doi:10.1136/jmg.37.11.828. ISSN 1468-6244.
- ↑ Pilarski, R.; Burt, R.; Kohlman, W.; Pho, L.; Shannon, K. M.; Swisher, E. (2013). "Cowden Syndrome and the PTEN Hamartoma Tumor Syndrome: Systematic Review and Revised Diagnostic Criteria". JNCI Journal of the National Cancer Institute. 105 (21): 1607–1616. doi:10.1093/jnci/djt277. ISSN 0027-8874.
- ↑ Sansal I, Sellers WR (July 2004). "The biology and clinical relevance of the PTEN tumor suppressor pathway". J. Clin. Oncol. 22 (14): 2954–63. doi:10.1200/JCO.2004.02.141. PMID 15254063.
- ↑ Krymskaya VP, Goncharova EA (February 2009). "PI3K/mTORC1 activation in hamartoma syndromes: therapeutic prospects". Cell Cycle. 8 (3): 403–13. doi:10.4161/cc.8.3.7555. PMID 19177005.
- ↑ Nelen MR, Padberg GW, Peeters EA, Lin AY, van den Helm B, Frants RR, Coulon V, Goldstein AM, van Reen MM, Easton DF, Eeles RA, Hodgsen S, Mulvihill JJ, Murday VA, Tucker MA, Mariman EC, Starink TM, Ponder BA, Ropers HH, Kremer H, Longy M, Eng C (May 1996). "Localization of the gene for Cowden disease to chromosome 10q22-23". Nat. Genet. 13 (1): 114–6. doi:10.1038/ng0596-114. PMID 8673088.
- ↑ Stambolic V, Suzuki A, de la Pompa JL, Brothers GM, Mirtsos C, Sasaki T, Ruland J, Penninger JM, Siderovski DP, Mak TW (October 1998). "Negative regulation of PKB/Akt-dependent cell survival by the tumor suppressor PTEN". Cell. 95 (1): 29–39. PMID 9778245.
- ↑ Nelen MR, Padberg GW, Peeters EA, Lin AY, van den Helm B, Frants RR, Coulon V, Goldstein AM, van Reen MM, Easton DF, Eeles RA, Hodgsen S, Mulvihill JJ, Murday VA, Tucker MA, Mariman EC, Starink TM, Ponder BA, Ropers HH, Kremer H, Longy M, Eng C (May 1996). "Localization of the gene for Cowden disease to chromosome 10q22-23". Nat. Genet. 13 (1): 114–6. doi:10.1038/ng0596-114. PMID 8673088.
- ↑ Keniry M, Parsons R (September 2008). "The role of PTEN signaling perturbations in cancer and in targeted therapy". Oncogene. 27 (41): 5477–85. doi:10.1038/onc.2008.248. PMID 18794882.
- ↑ Bennett KL, Mester J, Eng C (December 2010). "Germline epigenetic regulation of KILLIN in Cowden and Cowden-like syndrome". JAMA. 304 (24): 2724–31. doi:10.1001/jama.2010.1877. PMID 21177507.
- ↑ Cho YJ, Liang P (April 2008). "Killin is a p53-regulated nuclear inhibitor of DNA synthesis". Proc. Natl. Acad. Sci. U.S.A. 105 (14): 5396–401. doi:10.1073/pnas.0705410105. PMC 2291080. PMID 18385383.
- ↑ Ni Y, Zbuk KM, Sadler T, Patocs A, Lobo G, Edelman E, Platzer P, Orloff MS, Waite KA, Eng C (August 2008). "Germline mutations and variants in the succinate dehydrogenase genes in Cowden and Cowden-like syndromes". Am. J. Hum. Genet. 83 (2): 261–8. doi:10.1016/j.ajhg.2008.07.011. PMC 2495063. PMID 18678321.
- ↑ Orloff MS, He X, Peterson C, Chen F, Chen JL, Mester JL, Eng C (January 2013). "Germline PIK3CA and AKT1 mutations in Cowden and Cowden-like syndromes". Am. J. Hum. Genet. 92 (1): 76–80. doi:10.1016/j.ajhg.2012.10.021. PMC 3542473. PMID 23246288.
- ↑ Yehia L, Niazi F, Ni Y, Ngeow J, Sankunny M, Liu Z, Wei W, Mester JL, Keri RA, Zhang B, Eng C (November 2015). "Germline Heterozygous Variants in SEC23B Are Associated with Cowden Syndrome and Enriched in Apparently Sporadic Thyroid Cancer". Am. J. Hum. Genet. 97 (5): 661–76. doi:10.1016/j.ajhg.2015.10.001. PMC 4667132. PMID 26522472.
- ↑ Colby S, Yehia L, Niazi F, Chen J, Ni Y, Mester JL, Eng C (November 2016). "Exome sequencing reveals germline gain-of-function EGFR mutation in an adult with Lhermitte-Duclos disease". Cold Spring Harb Mol Case Stud. 2 (6): a001230. doi:10.1101/mcs.a001230. PMC 5111001. PMID 27900366.
- ↑ Tan MH, Mester JL, Ngeow J, Rybicki LA, Orloff MS, Eng C (January 2012). "Lifetime cancer risks in individuals with germline PTEN mutations". Clin. Cancer Res. 18 (2): 400–7. doi:10.1158/1078-0432.CCR-11-2283. PMC 3261579. PMID 22252256.
- ↑ Bubien V, Bonnet F, Brouste V, Hoppe S, Barouk-Simonet E, David A, Edery P, Bottani A, Layet V, Caron O, Gilbert-Dussardier B, Delnatte C, Dugast C, Fricker JP, Bonneau D, Sevenet N, Longy M, Caux F (April 2013). "High cumulative risks of cancer in patients with PTEN hamartoma tumour syndrome". J. Med. Genet. 50 (4): 255–63. doi:10.1136/jmedgenet-2012-101339. PMID 23335809.
- ↑ Mester JL, Moore RA, Eng C (2013). "PTEN germline mutations in patients initially tested for other hereditary cancer syndromes: would use of risk assessment tools reduce genetic testing?". Oncologist. 18 (10): 1083–90. doi:10.1634/theoncologist.2013-0174. PMC 3805149. PMID 24037976.
- ↑ Cameselle-Teijeiro, José; Fachal, Carmen; Cabezas-Agrícola, José M.; Alfonsín-Barreiro, Natividad; Abdulkader, Ihab; Vega-Gliemmo, Ana; Hermo, José Antonio (2015). "Thyroid Pathology Findings in Cowden Syndrome". American Journal of Clinical Pathology. 144 (2): 322–328. doi:10.1309/AJCP84INGJUVTBME. ISSN 0002-9173.
- ↑ Son EJ, Nosé V (2012). "Familial follicular cell-derived thyroid carcinoma". Front Endocrinol (Lausanne). 3: 61. doi:10.3389/fendo.2012.00061. PMC 3356064. PMID 22654876.
- ↑ Dotto J, Nosé V (November 2008). "Familial thyroid carcinoma: a diagnostic algorithm". Adv Anat Pathol. 15 (6): 332–49. doi:10.1097/PAP.0b013e31818a64af. PMID 18948764.
- ↑ Barletta JA, Bellizzi AM, Hornick JL (October 2011). "Immunohistochemical staining of thyroidectomy specimens for PTEN can aid in the identification of patients with Cowden syndrome". Am. J. Surg. Pathol. 35 (10): 1505–11. doi:10.1097/PAS.0b013e31822fbc7d. PMID 21921783.
- ↑ Nosé V (April 2011). "Familial thyroid cancer: a review". Mod. Pathol. 24 Suppl 2: S19–33. doi:10.1038/modpathol.2010.147. PMID 21455198.
- ↑ Son EJ, Nosé V (2012). "Familial follicular cell-derived thyroid carcinoma". Front Endocrinol (Lausanne). 3: 61. doi:10.3389/fendo.2012.00061. PMC 3356064. PMID 22654876.
- ↑ "Immunohistochemistry for PTEN".