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PTEN & Cowden Syndrome Yi-An Chiang

PTEN & Cowden Syndrome Yi-An Chiang. Outline. Cowden Syndrome PTEN Mouse Models PTEN & Cowden syndrome. Cowden Syndrome. CS was first reported in 1963 An autosomal dominant disorder 1 in 200,000 to 1 in 250,000

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PTEN & Cowden Syndrome Yi-An Chiang

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  1. PTEN & Cowden SyndromeYi-An Chiang

  2. Outline • Cowden Syndrome • PTEN • Mouse Models • PTEN & Cowden syndrome

  3. Cowden Syndrome • CS was first reported in 1963 • An autosomal dominant disorder • 1 in 200,000 to 1 in 250,000 • An inherited multi-system disease manifested by macrocephaly, multiple hamartomas, papillomas, mucocutaneous lesions and a predisposition for developing carcinoma of the breast, thyroid and endometrium.

  4. Clinical Manifestations… Butler et. Al., 2005

  5. Bussaglia et. Al, 2002; Schreibman et. Al., 2005. • Bussaglia, 2002

  6. PTEN Gene: Background Information • PTEN= Phosphatase and tensin homolog • Location of PTEN gene: chromosome 10q23 (a chromosomal region subjects to frequent LOH). • PTEN gene is composed of 9 exons and encodes a polypeptide of 403 amino acids.

  7. Structure of PTEN

  8. PTEN: Different Roles • As a protein phosphatase: dephosphorylate protein substrates. • As a lipid phosphatase: removes the phosphate from phosphatidylinositol 3,4,5-triphosphate (PIP3)  regulates the action of the phosphatidylinositol 3-kinase (PI3K).

  9. PTEN: Different Roles • As a tumor suppressor: PTEN is a critical negative regulator of the PI3K pathway through its lipid phosphatase activity.

  10. PTEN: Different Roles • Different locations, different ways of maintaining genomic stability  A hallmark of cancers! • PTEN at nucleus: novel functions discovered  Nuclear PTEN in maintenance of chromosomal stability has been demonstrated in both mouse and human systems: • PTEN interacts with centromeres • PTEN may be necessary for DNA repair

  11. In Mouse Models… • Mice with a complete null mutation of PTEN  Early embryonic lethality  PTEN is essential for normal embryogenesis • Half of PTEN+/– mice die within 1 year of birth. • PTEN+/- survivors develop a broad range of tumors, including mammary, thyroid, endometrial and prostate cancers, as well as T-cell lymphomas.  PTEN is a powerful and distinct tumor suppressor.

  12. In mice, PTEN deficiency causes increases in cell proliferation, apoptotic resistance, centromeric instability, and DNA double-strand breaks. • All of these defects enhance an animal's susceptibility to carcinogens and the occurrence of secondary genetic or epigenetic alterations that can lead to cancer development.

  13. PTEN & CS • Germline mutation of one allele of PTEN results in hereditary cancer predisposition. • Mutations are scattered along the entire gene. • Loss of function of the PTEN gene are found in approximately 80% of patients with CS: 1. Missense mutation: mostly occurs in exon 5 of PTEN encoding the core motif of the phosphate domain. 2. Loss of heterozygosity (LOH): loss of wield-type allele.

  14. CS & PTEN Mutation

  15. CS and Cancers • Cowden syndrome patients are at increased risk to develop breast, thyroid, and endometrial cancer. • The lifetime risk of: - breast cancer in women with CS is estimated to be as high as 50%, as compared to 11% within the general population. - thyroid cancer in both genders is estimated to approach10%, as compared to less than 1% in the general population. - Endometrial cancer is more frequent in women with CS with an estimated risk of 5–10% as compared to <2.5% in the general population • Other malignancies have anecdotally been reported to be increased with CS.

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