PTEN Promoter Silencing and Cowden Syndrome

Abstract

THE PHOSPHATASE AND TENSIN HOMOLOG GENE (PTEN) (RefSeq NM_000314) is a tumor suppressor located on the human chromosome 10q arm and is an important mediator of carcinogenesis in a variety of human malignancies. By the strictest definition, a tumor suppressor is a gene whose loss confers an increased lifetime risk of developing tumors. The most illustrative examples of genes that fulfill this criterion are those associated with familial cancer syndromes whereby heritable inactivation of 1 allele and subsequent increased tumor risk is passed along to each generation in an autosomaldominant fashion. Using this as a framework, PTEN is a bona fide tumor suppressor gene in that heritable germline mutations have been described in Cowden syndrome (CS), giving rise to a number of human tumors and cancers, most notably thyroid and breast cancers. As is the paradigm of tumor suppressor genes, affected patients with CS inherit 1 mutant inactive copy of PTEN from either parent, and the ensuing loss of the second allele results in tumor formation with subsequent genetic events that eventually lead to cancer. Although there are notable exceptions to this model, most heritable cancer syndromes are believed to adhere to this pattern. Although anomalies within a specific gene often account for the majority of a given familial cancer syndrome, there are striking examples in which a pedigree matches the syndrome, yet no mutations are found in the affected individuals. Such perplexing cases have led to the identification of additional genes that can account for a significant fraction in these cases. For example, germline mutations of the TP53 gene account for the majority of families with LiFraumeni syndrome, a heritable cancer syndrome hallmarked by a number of different cancers, including breast cancers, sarcomas, and leukemias. However, in families diagnosed with Li-Fraumeni syndrome without a TP53 mutation, germline mutations in the cell cycle checkpoint gene CHK2 can account for a considerable proportion of these familial cases. Similarly, patients with CS generally have been found to have germline mutations in PTEN, but in a substantial number of these families no PTEN mutations have been found. Along the same lines of CHK2 mutations and Li-Fraumeni syndrome, germline mutations in the succinate dehydrogenase subunits SDHB-D have been previously described in patients with PTEN wild-type CS as well as individuals who have features of CS but do not meet diagnostic criteria: patients who are said to have Cowdenlike syndrome (CLS). Despite the discovery of germline mutations in these genes, there remains a sizeable number of patients with CS and CLS who lack mutations in known genes. The study by Bennett et al in this issue of JAMA offers an intriguing explanation for some of these families with PTEN wild-type CS and CLS. It has previously been described that epigenetic inactivation of genes via hypermethylation of their promoters, of other DNA modifications, such as histone deacetylation, or both, can silence tumor suppressor genes. Indeed, silencing of tumor suppressor genes in sporadic cancers by epigenetic regulation is a welldocumented event, and in the case of specific tumor suppressor genes appears to be the more common mechanism of inactivation rather than gene mutation. In some cases, this can occur in the germline, and therefore these epigenetic changes, or “epimutations,” can then be passed to subsequent generations and predispose those individuals to an increased risk of certain cancers. This was the basis of the starting point for Bennett et al wherein they examined the peripheral lymphocytes derived from patients with CS and CLS for hypermethylation of the PTEN promoter. Perhaps not unexpectedly, the investigators did discover, in a significant fraction of these patients, PTEN promoter hypermethylation. However, rather unexpectedly, gene silencing of PTEN was not found, suggesting that methylation of the PTEN promoter did not alter or regulate expression of this tumor suppressor gene. Further study by Bennett el al led to the analysis of a relatively new gene called KILLIN. KILLIN has only recently been identified, and relatively little is known regarding its function or role in human cancers. KILLIN was originally identified as a TP53 regulated inhibitor of DNA synthesis, and