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

Abstract

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 Human Molecular Genetics, 1998, Vol. 7, No. 3 508 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 and 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.

Intragenic PTEN/MMAC1 Loss of Heterozygosity in Conventional (Clear-Cell) Renal Cell Carcinoma is Associated with Poor Patient Prognosis

“…These results are in keeping with findings that heterozygous PTEN/MMAC1ϩ/Ϫ animals display hyperplastic and dysplastic lesions in many organs in the absence of PTEN/MMAC1 mutations of the remaining allele (27). Studies in humans with Cowden syndrome, who carry heterozygote PTEN/MMAC1 germline mutations, have also shown that in a number of cases, the tumors do not have detectable PTEN/MMAC1 locus LOH (28), indicating that somatic deletion of the wild-type allele has not occurred. Similarly, heterozygous loss of PTEN/ MMAC1 in mouse thyroid and prostate leads to an increase in the proliferative indices of these tissues, again raising the possibility that heterozygous loss alone of PTEN/MMAC1 may play a role in tumor development and progression (27).…”

PTEN promoter is methylated in a proportion of invasive breast cancers

“…32,33 Although definitive studies are lacking in breast cancer, that this may occur in humans is suggested by the fact that heterozygous inactivation of PTEN results in 3 dominantly inherited disorders: Cowden syndrome (associated with a predisposition to thyroid and breast cancers), Bannayan-Zonana syndrome and Lhermitte-Duclos syndrome. [3][4][5] Of course, this more likely suggests that it is easier to mutate the second allele once the first allele is lost.…”

“…2 Germline mutations have been reported in Cowden syndrome and Bannayan-Zonana syndrome, 2 dominantly inherited conditions causing predisposition to a variety of cancers including breast cancer. [3][4][5] Homozygous somatic mutations have also been recorded in a high percentage of human tumors, common among which are glioblastoma multiforme 6 -8 and endometrial cancer. 9 -11 Genetic, functional and animal modeling studies have substantiated the tumor-suppressor function of PTEN.…”

Associations between congenital malformations and childhood cancer. A register-based case-control study

“…1994. and more recently with Cowden disease and a aermline mutation in the tumour suppressor gene PTEN (Marsh et al 1998). …”