Allelic imbalance, including deletion ofPTEN/MMAC1, at the Cowden disease locus on 10q22-23, in hamartomas from patients with cowden syndrome and germlinePTEN mutation

Abstract

Cowden disease (CD) is a rare, autosomal dominant inherited cancer syndrome characterized by multiple benign and malignant lesions in a wide spectrum of tissues. While individuals with CD have an increased risk of breast and thyroid neoplasms, the primary features of CD are hamartomas. The gene for CD has been mapped by linkage analysis to a 6 cM region on the long arm of chromosome 10 at 10q22‐23. Loss of heterozygosity (LOH) studies of sporadic follicular thyroid adenomas and carcinomas, both component tumors of CD, have suggested that the putative susceptibility gene for CD is a tumor suppressor gene. Somatic missense and nonsense mutations have recently been identified in breast, prostate, and brain tumor cell lines in a gene encoding a dual specificity phosphatase, PTEN/MMAC1, mapped at 10q23.3. Furthermore, germline PTEN/MMAC1 mutations are associated with CD. In the present study, 20 hamartomas from 11 individuals belonging to ten unrelated families with CD have been examined for LOH of markers flanking and within PTEN/MMAC1. Eight of these ten families have germline PTEN/MMAC1 mutations. LOH involving microsatellite markers within the CD interval, and including PTEN/MMAC1, was identified in two fibroadenomas of the breast, a thyroid adenoma, and a pulmonary hamartoma belonging to 3 of 11 (27%) of these patients. The wild‐type allele was lost in these hamartomas. Semi‐quantitative PCR performed on RNA from hamartomas from three different tissues from a CD patient suggested substantial reduction of PTEN/MMAC1 RNA levels in all of these tissues. The LOH identified in samples from individuals with CD and the suggestion of allelic loss and reduced transcription in hamartomas from a CD patient provide evidence that PTEN/MMAC1 functions as a tumor suppressor in CD. Genes Chromosomes Cancer 21:61–69, 1998. © 1998 Wiley‐Liss, Inc.

Where Birt–Hogg–Dubé meets Cowden Syndrome: mirrored genetic defects in two cases of syndromic oncocytic tumours

“…17 A small reduction of PTEN expression is sufficient to trigger tumour formation in mice, and heterozygosity of PTEN is generally maintained in malignancies developed by CS patients. 18 FLCN, on the other hand, has been thus far considered a canonical TSG, the two alleles of which are inactivated in tumour cells by LOH or somatic mutations. 19 Somatic 'second hit' FLCN mutations or LOH on chromosome 17p are, in fact, indentified in the vast majority of BHD-associated renal tumours.…”

Analysis of the 10q23 chromosomal region and the PTEN gene in human sporadic breast carcinoma

“…Clearly, the existence of such candidate genes, which are lost in the samples studied here, remains to be determined. Analysis of LOH in a variety of tumours has suggested that multiple discrete regions of chromosome 10 loss may occur in a single tumour or tumour type (Parmiter et al, 1988;Karlbom et al, 1993;Herbst et al, 1994;Peiffer et al, 1995;Albarosa et al, 1996;Ittmann, 1996;Trybus et al, 1996;Zedenius et al, 1996;Marsh et al 1998b). The precise physical localization of such deleted regions with respect to one another and the number of tumoursuppressor genes they represent has been difficult to determine, in part because of the variety of markers used in the different studies.…”

GSK3β mediates suppression of cyclin D2 expression by tumor suppressor PTEN

“…Germ-line mutations of PTEN cause three autosomal dominant disorders, Cowden disease, Lhermitte-Duclos disease and Bannayan-Zonana syndrome, all of which form benign tumors in a variety of tissues with increased risk for cancer development Nelen et al, 1997;Marsh et al, 1998). PTEN is also essential for embryonic development: Its inactivation by gene targeted disruption in mouse resulted in early embryonic lethality, and Pten þ /À mice showed hyperplastic-dysplastic changes in many tissues (Di Cristofano et al, 1998).…”