A Novel Germline Mutation of the PTEN/MMAC1 Gene in a Patient with Cowden Disease

Abstract

Cowden disease (CD) is a rare autosomal dominant familial tumor syndrome with a high risk of breast cancer and to a lesser extent thyroid neoplasms. Breast cancers develop in 25–50% of women and thyroid cancers in 3–10% of all affected individuals. Other clinical features include multiple hamartomas of the skin, oral mucosa, breast, thyroid, and intestinal epithelium. The most characteristic lesions are multiple facial trichilemnomas, acral keratosis and multiple oral papillomas, occurring in 99% of CD patients (1–4). Lhermitte-Duclos disease (LDD), characterized by a dysplastic gangliocytoma of the cerebellum, leading to progressive cerebellar syndrome and frequent hydrocephaly, is now established as a component of CD (5–8). Megencephaly/macrocephaly is present in 38% of CD patients and 80% of LDD patients (4, 6, 7). CNS tumors, both malignant and benign, may also be components of CD. The CD susceptibility gene has been mapped on chromosome 10q22–23 (9). Subsequently, PTEN/MMAC1, a nine exons gene coding a dual specificity phosphatase with homology to tensin and auxilin, mutated in a wide array of cancer, was recently identified in this region (10, 11). Up until now, 37 different germline mutations of PTEN/MMAC1 have been found in patients with CD (12–16). A new, different germline mutation is reported here in a woman with CD treated for breast cancer metastases. In March 1993, a 48-year-old woman was referred to our Neurology Department for dural metastases, revealed by seizures, right hemiparesis and frontal syndrome. She had a history of multiple tumors and hamartomas. A bilateral breast cancer was discovered in 1975 and treated by radiotherapy and chemotherapy. Two benign thyroid nodules were resected in 1989. At the same time an exophthalmy revealed a retro-orbital tumor which was identified as a carcinoma of unknown origin and treated with radiotherapy. In 1992 a tumor was discovered in the superior part of the right kidney as well as multiple angiomas of the liver. The diagnosis of CD was retained, because of macrocephaly, cutaneous trichilemnomas and typical papillomatosis of the tongue and the lip. A cutaneous angioma and a lipoma were noted. There was no sign of LhermitteDuclos disease on the MRI. The patient’s father presented macrocephaly and cutaneous lesions but her two brothers had no signs of CD. Her son had macrocephaly and typical papillomas of the lip. The patient was treated with cranial radiotherapy and then chemotherapy every month (cisplatin-5FU, carboplatine-VP16). Because of poor quality of life and absence of clinical response, despite radiological stabilization, the treatment was discontinued after one year and the patient died four months later. Constitutional DNA was extracted from peripheral lymphocytes. DGGE (denaturing gradient gel electrophoresis) analysis failed to show any germline p53 mutations. The nine exons and splice junctions of the PTEN/MMAC1 gene were screened for mutations by DGGE (Zhou et al., manuscript in preparation). The primers were chosen among the intron sequences to avoid co-amplification of the Pten/Mmac pseudogene. An abnormal DGGE profile was seen on exon 7. (Fig. 1) Sequencing identified a C to T base transition at the first base of codon 214 (Q214X). This base transition (CAG to TAG) was predicted to result in termination at the corresponding codon, thus leading to the truncation of encoded PTEN protein. Germline PTEN mutations have already been reported in CD patients and in two other hamartomatous conditions that overlap clinically with CD, the Bannayan-