Novel PTEN mutations in patients with Cowden disease: absence of clear genotype–phenotype correlations

Abstract

Cowden disease (CD) is characterised by multiple hamartomas in a variety of tissues. The pathological hallmark is the presence of a number of trichilemmomas. Several neurological symptoms are also part of CD with megalencephaly and Lhermitte-Duclos disease (LDD) as the most important features. Early recognition of CD patients is important because of the increased risk of developing malignancies. Breast cancer is the most frequent malignancy, but also urogenital, digestive tract, and thyroid cancers are found with higher frequencies. CD was localised to chromosome 10q23 and the PTEN gene (also known as MMAC1 or TEP1) was shown to be involved. Germline mutations were identified in both familial and sporadic CD patients. We identified eight PTEN mutations, of which seven were novel, in 13 CD patients. Combined with previous data we have identified 17 independent CD mutations. Gross DNA alterations in CD patients were not detected. Genotype-phenotype relations are discussed. The only correlation suggested to exist is that missense mutations are not detected in LDD patients. However, larger numbers are needed to confirm this. Association of PTEN mutations and the occurrence of malignant breast disease found in an earlier study cannot be confirmed. Clinical features of five CD patients without a PTEN mutation in the coding sequence do not differ from CD patients with a PTEN mutation. Furthermore, it is likely that we have identified the majority of CD patients in the Netherlands. From this we estimate that CD has a prevalence of about 1 in 250 000 in the Dutch population with a low mutation frequency.

Microsatellite instability and the PTEN1 gene mutation in a subset of early onset gliomas carrying germline mutation or promoter methylation of the hMLH1 gene

“…This mutation resulted in in-frame deletion of lysine residue at position 62, a tensine homologous domain of PTEN1 protein. In-frame deletion of a single amino acid within the same domain was also reported in a patient of Cowden disease (Nelen et al, 1999). These ®ndings suggest that in-frame deletion observed in tumor 114 would be an inactivating mutation.…”

PTEN/MMAC1 is infrequently mutated in pT2 and pT3 carcinomas of the prostate

“…Mutations of PTEN/MMAC1 have been detected in some carcinomas of the breast, prostate, and endometrium, and in melanoma and glioblastoma Guldberg et al, 1997;Liu et al, 1997;Rasheed et al, 1997;Rhei et al, 1997;Risinger et al, 1997;Suzuki et al,1998;Tashiro et al,1997;Teng et al, 1997;Wang et al, 1997). In addition, mutation of PTEN/MMAC1 may be responsible for the development of Cowden disease Nelen et al, 1997;Tsou et al, 1997) and Bannayan-Zonana syndrome (Arch et al, 1997;Marsh et al, 1997). In a recent analysis of 60 localized prostate cancers and 20 lymph node metastases, Cairns et al reported that 3 of 11 (27%) localized tumors with LOH and 7 of 12 (58%) metastatic cancers with LOH had mutations or homozygous deletions of PTEN/MMAC1 .…”

MMAC1/PTEN inhibits cell growth and induces chemosensitivity to doxorubicin in human bladder cancer cells

“…MMAC1/PTEN/TEP1 has been identi®ed as a tumor suppressor gene mapped to chromosome 10q23 (Steck et al, 1997;Li and Sun, 1997;, and somatic mutations or deletions of MMAC1/PTEN have been found in bladder cancer as well as glioblastoma, melanoma, and cancers of the prostate, breast, endometrium, lung and thyroid (Steck et al, 1997;Wang et al, 1997;Gulberg et al, 1997;Cairns et al, 1997;Rhei et al, 1997;Tashiro et al, 1997;Kim et al, 1998;Dahia et al, 1997;Sano et al, 1999). Additionally, germ-like mutations of MMAC1/PTEN have been demonstrated in Cowden disease, Bannayan-Zonana syndrome related hamartoma, and familial cancer predisposition syndromes Starink et al, 1986;Nelen et al, 1997;Marsh et al, 1997). To date, however, the molecular and functional analyses of MMAC1/PTEN in bladder cancer have been very limited.…”