MUTATION SPECTRUM AND GENOTYPE-PHENOTYPE ANALYSES IN COWDEN-DISEASE AND BANNAYAN-ZONANA-SYNDROME, 2 HAMARTOMA SYNDROMES WITH GERMLINE PTEN MUTATION

The tumour suppressor gene PTEN, which maps to 10q23.3 and encodes a 4 03 amino acid dual specificity phosphatase (protein tyrosine phosphata se: PTPase), was shown recently to play a broad role in human malignan cy. Somatic PTEN deletions and mutations were observed in sporadic bre ast, brain, prostate and kidney cancer cell lines and in several prima ry tumours such as endometrial carcinomas, malignant melanoma and thyr oid tumours. In addition, PTEN was identified as the susceptibility ge ne for two hamartoma syndromes: Cowden disease (CD; MIM 158350) anti B annayan-Zonana (BZS) or Ruvalcaba-Riley-Smith syndrome (MIM 153480). C onstitutive DNA from 37 CD families and seven BZS families was screene d 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 mutation s, These mutations were scattered over the entire length of PTEN with the exception of the first, fourth and last exons. A 'hot spot' for; P TEN 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 se ven) of which were missense mutations, possibly pointing to the functi onal significance of this region, Germline PTEN mutations were identif ied int four of seven (57%) BZS families studied, interestingly, none of these mutations was observed in the PTPase core motif. II is also w orthy of note that a single nonsense point mutation, R233X, was observ ed in the germline DNA from two unrelated CD families and one BZS fami ly Genotype-phenotype studies were not performed on this small group o f BZS families, However genotype-phenotype analysis in the group of CD families revealed two possible associations worthy of follow-up in in dependent analyses, The first was an association noted in the group of CD families with breast disease. A correlation was observed between t he presence/absence of a PTEN mutation and the type of breast involvem emt (unaffected versus benign versus malignant), Specifically and more directly an association was also observed between the presence of a P TEN mutation and malignant breast disease, Secondly, there appeared to be an interdependent association between mutations upstream and withi n the PTPase core motif, the core motif containing the majority of mis sense mutations, and the involvement of all major organ systems (centr al nervous system, thyroid, breast, skin and gastrointestinal tract). However, these observations would need to be confirmed by studying a l arger number of CD families.