Germline PTEN promoter mutations and deletions in Cowden/Bannayan-Riley-Ruvalcaba syndrome result in aberrant PTEN protein and dysregulation of the phosphoinositol-3-kinase/Akt pathway

Xiao Ping Zhou, Kristin A. Waite, Robert Pilarski, Heather Hampel, Magali J. Fernandez, Cindy Bos, Majed Dasouki, Gerald L. Feldman, Lois A. Greenberg, Jennifer Ivanovich, Ellen Matloff, Annette Patterson, Mary Ella Pierpont, Donna Russo, Najah T. Nassif, Charis Eng

Research output: Contribution to journalArticlepeer-review

243 Scopus citations


Germline intragenic mutations in PTEN are associated with 80% of patients with Cowden syndrome (CS) and 60% of patients with Bannayan-Riley-Ruvalcaba syndrome (BRRS). The underlying genetic causes remain to be determined in a considerable proportion of classic CS and BRRS without a polymerase chain reaction (PCR)-detectable PTEN mutation. We hypothesized that gross gene deletions and mutations in the PTEN promoter might alternatively account for a subset of apparently mutation-negative patients with CS and BRRS. Using real time and multiplex PCR techniques, we identified three germline hemizygous PTEN deletions in 122 apparently mutation-negative patients with classic CS (N=95) or BRRS (N=27). Fine mapping suggested that one deletion encompassed the whole gene and the other two included exon 1 and encompassed exons 1-5 of PTEN, respectively. Two patients with the deletion were diagnosed with BRRS, and one patient with the deletion was diagnosed with BRRS/CS overlap (features of both). Thus 3 (11%) of 27 patients with BRRS or BRRS/CS-overlap had PTEN deletions. Analysis of the PTEN promoter revealed nine cases (7.4%) harboring heterozygous germline mutations. All nine had classic CS, representing almost 10% of all subjects with CS. Eight had breast cancers and/or benign breast tumors but, otherwise, oligo-organ involvement. PTEN protein analysis, from one deletion-positive and five PTEN-promoter-mutation-positive samples, revealed a 50% reduction in protein and multiple bands of immunoreactive protein, respectively. In contrast, control samples showed only the expected band. Further, an elevated level of phosphorylated Akt was detected in the five promoter-mutation-positive samples, compared with controls, indicating an absence of or marked reduction in functional PTEN. These data suggest that patients with BRRS and CS without PCR-detected intragenic PTEN mutations be offered clinical deletion analysis and promoter-mutation analysis, respectively.

Original languageEnglish (US)
Pages (from-to)404-411
Number of pages8
JournalAmerican Journal of Human Genetics
Issue number2
StatePublished - Aug 1 2003

Bibliographical note

Funding Information:
We are grateful to our patients and families and their clinicians, who have continued to participate in our research. We thank Susan Whitman and Tamara Vukosavljevic (Real-time PCR Core Facility at the Comprehensive Cancer Center, The Ohio State University), for their excellent technical support; and Micheala Aldred, for donating anonymous DNA samples from normal control subjects. This work is partially funded by the American Cancer Society (RSG-02-151-01-CCE to C.E.), Susan G. Komen Breast Cancer Research Foundation (BCTR 2000 462 to C.E.), and National Cancer Institute (P30CA16058 to The Ohio State University Comprehensive Cancer Center). C.E. is a recipient of the Doris Duke Distinguished Clinical Scientist Award.


Dive into the research topics of 'Germline PTEN promoter mutations and deletions in Cowden/Bannayan-Riley-Ruvalcaba syndrome result in aberrant PTEN protein and dysregulation of the phosphoinositol-3-kinase/Akt pathway'. Together they form a unique fingerprint.

Cite this