GERMLINE PTEN MUTATIONS IN COWDEN-SYNDROME-LIKE FAMILIES

Cowden syndrome (CS) or multiple hamartoma syndrome (MIM 158350) is an autosomal dominant disorder with an increased risk for breast and thy roid carcinoma. The diagnosis of CS, as operationally defined by the I nternational Cowden Consortium, is made when a patient, or family, has a combination of pathognomonic major and/or minor criteria. The CS ge ne has recently been identified as PTEN, which maps at 10q23.3 and enc odes a dual specificity phosphatase. PTEN appears to function as a tum our suppressor in CS, with between 13-80% of CS families harbouring ge rmline nonsense, missense,and frameshift mutations predicted to disrup t normal PTEN function. To date, only a small number of tumour suppres sor genes, including BRCA1, BRCA2, and p53, have been associated with familial breast or breast/ovarian cancer families. Given the involveme nt of PTEN in CS, we postulated that PTEN was a likely candidate to pl ay a role in families with a ''CS-like'' phenotype, but not classical CS. To answer these questions, we gathered a series of patients from f amilies who had features reminiscent of CS but did not meet the Consor tium Criteria. Using a combination of denaturing gradient gel electrop horesis (DGGE), temporal temperature gel electrophoresis (TTGE), and s equence analysis, we screened 64 unrelated CS-like subjects for germli ne mutations in PTEN. A single male with follicular thyroid carcinoma from one of these 64 (2%) CS-like families harboured a germline point mutation, c.209T-->C. This mutation occurred at the last nucleotide of exon 3 and within a region homologous to the cytoskeletal proteins te nsin and auxilin. We conclude that germline PTEN mutations play a rela tively minor role in CS-like families. In addition, our data would sug gest that, for the most part, the strict International Cowden Consorti um operational diagnostic criteria for CS are quite robust and should remain in place.