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

The tumour suppressor gene PTEN , which maps to 10q23.3 and encodes a 403amino 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 tumourssuch as endometrial carcinomas, malignant melanoma and thyroid tumours. Inaddition, PTEN was identified as the susceptibility gene for two hamartomasyndromes: Cowden disease (CD; MIM 158350) and Bannayan-Zonana (BZS) orRuvalcaba-Riley-Smith syndrome (MIM 153480). Constitutive DNA from 37 CDfamilies and seven BZS families was screened for germline PTEN mutations.PTEN mutations were identified in 30 of 37 (81%) CD families, includingmissense and nonsense point mutations, deletions, insertions, adeletion/insertion and splice site mutations. These mutations werescattered 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 identifiedin exon 5 that contains the PTPase core motif, with 13 of 30 (43%) CDmutations identified in this exon. Seven of 30 (23%) were within the coremotif, the majority (five of seven) of which were missense mutations,possibly pointing to the functional significance of this region. GermlinePTEN mutations were identified in four of seven (57%) BZS families studied.Interestingly, none of these mutations was observed in the PTPase coremotif. It is also worthy of note that a single nonsense point mutation,R233X, was observed in the germline DNA from two unrelated CD families andone BZS family. Genotype-phenotype studies were not performed on this smallgroup of BZS families. However, genotype-phenotype analysis inthe group ofCD families revealed two possible associations worthy of follow-up inindependent analyses. The first was an association noted in the group of CDfamilies with breast disease. A correlation was observed between thepresence/absence of a PTEN mutation and the type of breast involvement(unaffected versus benign versus malignant). Specifically and moredirectly, an association was also observed between the presence of a PTENmutation and malignant breast disease. Secondly, there appeared to be aninterdependent association between mutations upstream and within the PTPasecore 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, theseobservations would need to be confirmed by studying a larger number of CDfamilies.