A Novel Phosphatase Gene on 10q23, MINNP, in Hereditary and Sporadic Breast Cancer
Abstract
PTEN is a tumor suppressor gene on 10q23 and encodes a dual specificity phosphatase. One of the major substrates for PTEN is phosphotidylinositol (3,4,5) triphosphate in the PI3 kinase pathway. When PTEN is dysfunctional or absent, P-Akt is high and hence, anti-apoptotic. PTEN is a major susceptibility gene for Cowden syndrome (CS), a hereditary disorder with a high risk of breast and thyroid cancer, and appears to be involved in a broad range of tumors. In addition, germline PTENmutations have been found in a developmental disorder, Bannayan-Riley-Ruvalcaba syndrome (BRR) as well. Previously not thought to be associated with cancer risk, BRR families and cases with germline PTEN mutations have recently been shown to be at risk for cancers and especially breast tumors. Between 10-80% (mean 60%) of CS families and 60% of BRR individuals have germline PTENmutations. Families that do not have germline PTEN mutations are not inconsistent with linkage to the l0q22-23 region. Thus, genes with related function to PTEN in the 10q21-q25 region are good candidates genes for PTENmutation negative CS, BRR and related sporadic tumors, e.g., those of the breast and thyroid. MINPP1 lies no more than 1 Mb upstream of PTEN and encodes an inositol polyphosphate phosphatase. In Year 2 of the award, we have found no germline intragenic MINPP1 mutations in 30 CS, 35 BRR and 15 CS-like. However, we have found at least 2 CS probands with germline deletions involving MINPP1 and PTEN, and 1 CS with a deletion involving part of PTEN. In addition, at least 2 CS probands without PTEN or MINPP1 alterations have been found to have germline BMPR1A mutations (this gene lies just upstream of MINPP). While we have not found somatic intragenic MINPP1 mutations in 50 sporadic breast cancers, we have found somatic deletions encompassing PTEN and MINPP1. More interestingly these deletions involve the neoplastic epithelium and/or the surrounding stroma.
Document Details
- Document Type
- Technical Report
- Publication Date
- Aug 01, 2002
- Accession Number
- ADA409758
Entities
People
- Charis Eng
Organizations
- Ohio State University