Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome

  title={Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome},
  author={Danny Liaw and Deborah J. Marsh and Jing Li and Patricia L. M. Dahia and Steven I. Wang and Zimu Zheng and Shikha Bose and Katherine M. Call and Hui C. Tsou and Monica Peacoke and Charis Eng and Ramon Parsons},
  journal={Nature Genetics},
Cowden disease (CD) is an autosomal dominant cancer predisposition syndrome associated with an elevated risk for tumours of the breast, thyroid and skin1–2. Lhermitte-Duclos disease (LDD) cosegregates with a subset of CD families and is associated with macrocephaly, ataxia and dysplastic cerebellar gangliocytomatosis3–4. The common feature of these diseases is a predisposition to hamartomas, benign tumours containing differentiated but disorganized cells indigenous to the tissue of origin… 

Germline mutations in the PTEN/MMAC1 gene in patients with Cowden disease.

The PTEN/MMAC1 gene, encoding a putative protein tyrosine or dual-specificity phosphatase, is confirmed as the gene for Cowden disease by a refined localization of the gene to the interval between D 10S1761 and D10S541, which contains the PTEN-MMAC 1 gene and by mutation analysis in eight unrelated familial and 11 sporadic patients with Cowden Disease.

Germline PTEN mutations in Cowden syndrome-like families.

It is concluded that germline PTEN mutations play a relatively minor role in CS-like families, and the strict International Cowden Consortium operational diagnostic criteria for CS are quite robust and should remain in place.

Allelic imbalance, including deletion of PTEN/MMAC1, at the Cowden disease locus on 10q22‐23, in hamartomas from patients with cowden syndrome and germline PTEN mutation

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.

Somatic mutations of the PTEN tumor suppressor gene in sporadic follicular thyroid tumors

The findings suggest that the PTEN tumor suppressor gene is occasionally inactivated in sporadic follicular thyroid tumors.

A novel germline mutation of the PTEN/MMAC1 gene in a patient with Cowden disease.

A new, different germline mutation is reported here in a woman with CD treated for breast cancer metastases, which was predicted to result in termination at the corresponding codon, thus leading to the truncation of encoded PTEN protein.

Inherited mutations in PTEN that are associated with breast cancer, cowden disease, and juvenile polyposis.

Germ-line PTEN mutations predispose to breast cancer in association with CD, although the signs of CD may be subtle, and mutant transcripts appeared unstable in RNA from normal tissues from three families.

A novel mutation of the PTEN gene in a Japanese patient with Cowden syndrome and bilateral breast cancer.

Somatic deletions and mutations in the Cowden disease gene, PTEN, in sporadic thyroid tumors.

It is concluded that a subset of thyroid tumors have somatic deletions of the PTEN gene, predominantly the benign forms, and that small intragenic mutations of PTEN are infrequent in thyroid tumors.

Absence of PTEN germ-line mutations in men with a potential inherited predisposition to prostate cancer.

  • K. CooneyH. Tsou M. Peacocke
  • Medicine, Biology
    Clinical cancer research : an official journal of the American Association for Cancer Research
  • 1999
DNA was isolated from whole blood of 11 prostate cancer patients from 10 unrelated families to test the hypothesis that germ-line mutations in the PTEN are unlikely to contribute in a significant way to the inherited predisposition to prostate cancer.

No evidence for germline PTEN mutations in families with breast and brain tumours

It is unlikely that PTEN is a significant BRCA predisposing locus, however, one might ask whether breast cancer cases resulting from germline PTEN mutation could occur without any mammary histological feature of Cowden disease.



Localization of the gene for Cowden disease to chromosome 10q22–23

Cowden disease (CD) (MIM 158350), or multiple hamartoma syndrome, is a rare autosomal dominant familial cancer syndrome with a high risk of breast cancer and central nervous system manifestations of CD were emphasized only recently.

Differential loss of heterozygosity in the region of the Cowden locus within 10q22-23 in follicular thyroid adenomas and carcinomas.

Examination of sporadic thyroid tumors for loss of heterozygosity (LOH) of microsatellite markers in the 20-cM region within and flanking the Cowden critical interval may provide evidence against a stepwise progression from atypical adenomas to carcinomas.

The relationship between specific RET proto-oncogene mutations and disease phenotype in multiple endocrine neoplasia type 2. International RET mutation consortium analysis.

It is suggested that genotype-phenotype correlations do exist and, if made reliably absolute, could prove useful in the future in clinical management with respect to screening, surveillance, and prophylaxis, as well as provide insight into the genetic effects of particular mutations.

Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers

The results identify a strong candidate tumour suppressor gene at chromosome 10q23.3, whose loss of function appears to be associated with the oncogenesis of multiple human cancers.

Cowden disease: gene marker studies and measurements of epidermal growth factor.

Excess circulating EGF in body fluids from CD patients and controls is not responsible for the manifestations of the syndrome and alterations in growth factors or their receptors may play a role in CD.

The Cowden syndrome: a clinical and genetic study in 21 patients

An analysis of the findings in 21 patients with the Cowden syndrome or the multiple hamartoma syndrome finds craniomegaly (high head circumference) was found to be the most common extracutaneous manifestation, while the incidence of thyroid abnormalities was similar to that reported previously.

Cowden syndrome and Lhermitte-Duclos disease in a family: a single genetic syndrome with pleiotropy?

Single strand conformational polymorphism analysis failed to show any germline p53 mutations as a cause of the syndrome in this three generation family with Cowden syndrome and Lhermitte-Duclos disease.

PTEN, a Putative Protein Tyrosine Phosphatase Gene Mutated in Human Brain, Breast, and Prostate Cancer

Mapping of homozygous deletions on human chromosome 10q23 has led to the isolation of a candidate tumor suppressor gene, PTEN, that appears to be mutated at considerable frequency in human cancers.

Discussion: Genetics of multiple primary tumors. A clinical etiologic approach illustrated by three patients

It is suggested that, in future studies of multiple tumors, epidemiologists consider not just malignancies, but all forms of neoplasia, both in the patient and in the family.

Lhermitte‐duclos disease and cowden disease: A single phakomatosis

The occurrence of these two rare disorders in single patients is more than a coincidence, and the clinical findings in the combined condition establishes it as a new phakomatosis.