Mutation spectrum and genotype-phenotype analyses in Cowden disease and Bannayan-Zonana syndrome, two hamartoma syndromes with germline PTEN mutation

Debbie J. Marsh, Valérie Coulon, Kathryn L. Lunetta, Philippe Rocca-Serra, Patricia L.M. Dahia, Zimu Zheng, Danny Liaw, Stacey Caron, Bernadette Duboué, Albert Y. Lin, Anne Louise Richardson, Jean Marie Bonnetblanc, Jean Marie Bressieux, Agnés Cabarrot-Moreau, Agnés Chompret, Liliane Demange, Rosalind A. Eeles, Alan M. Yahanda, Eric R. Fearon, Jean Pierre FrickerRobert J. Gorlin, Shirley V. Hodgson, Susan Huson, Didier Lacombe, Frédéric LePrat, Sylvie Odent, Claude Toulouse, Olufunmilayo I. Olopade, Hagay Sobol, Sigrid Tishler, C. Geoffrey Woods, Bruce G. Robinson, H. Christian Weber, Ramon Parsons, Monica Peacocke, Michel Longy, Charis Eng*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

570 Scopus citations


The tumour suppressor gene PTEN, which maps to 10q23.3 and encodes a 403 amino acid dual specificity phosphatase (protein tyrosine phosphatase; PTPase), was shown recently to play a broad role in human malignancy. Somatic PTEN deletions and mutations were observed in sporadic breast, brain, prostate and kidney cancer cell lines and in several primary tumours such as endometrial carcinomas, malignant melanoma and thyroid tumours. In addition, PTEN was identified as the susceptibility gene for two hamartoma syndromes: Cowden disease (CD; MIM 158350) and Bannayan-Zonana (BZS) or Ruvalcaba-Riley-Smith syndrome (MIM 153480). Constitutive DNA from 37 CD families and seven BZS families was screened for germline PTEN mutations. PTEN mutations were identified in 30 of 37 (81%) CD families, including missense and nonsense point mutations, deletions, insertions, a deletion/insertion and splice site mutations. These mutations were scattered over the entire length of PTEN, with the exception of the first, fourth and last exons. A 'hot spot' for PTEN mutation in CD was identified in exon 5 that contains the PTPase core motif, with 13 of 30 (43%) CD mutations identified in this exon. Seven of 30 (23%) were within the core motif, the majority (five of seven) of which were missense mutations, possibly pointing to the functional significance of this region. Germline PTEN mutations were identified in four of seven (57%) BZS families studied. Interestingly, none of these mutations was observed in the PTPase core motif. It is also worthy of note that a single nonsense point mutation, R233X, was observed in the germline DNA from two unrelated CD families and one BZS family. Genotype-phenotype studies were not performed on this small group of BZS families. However, genotype-phenotype analysis in the group of CD families revealed two possible associations worthy of follow-up in independent analyses. The first was an association noted in the group of CD families with breast disease. A correlation was observed between the presence/absence of a PTEN mutation acid the type of breast involvement (unaffected versus benign versus malignant). Specifically and more directly, an association was also observed between the presence of a PTEN mutation and malignant breast disease. Secondly, there appeared to be an interdependent association between mutations upstream and within the PTPase core motif, the core motif containing the majority of missense mutations, and the involvement of all major organ systems (central nervous system, thyroid, breast, skin and gastrointestinal tract). However, these observations would need to be confirmed by studying a larger number of CD families.

Original languageEnglish
Pages (from-to)507-515
Number of pages9
JournalHuman Molecular Genetics
Issue number3
StatePublished - Mar 1998
Externally publishedYes


Dive into the research topics of 'Mutation spectrum and genotype-phenotype analyses in Cowden disease and Bannayan-Zonana syndrome, two hamartoma syndromes with germline PTEN mutation'. Together they form a unique fingerprint.

Cite this