EPIGENETIC ALTERETION OF KILLIN GENE INCREASES CANCER RISK IN COWDEN SYNDROME

December 21, 2010 — Promoter methylation of the novel gene KILLIN in Cowden syndrome (CS) and Cowden-like syndrome (CLS) is associated with an increased incidence of breast and renal cancers, a new study has found.

Kristi L. Bennett, PhD, from the Case Western Reserve University School of Medicine and Genomic Medicine Institute at the Cleveland Clinic in Ohio, and colleagues reported their findings in the December 22/29 issue of the Journal of the American Medical Association.

"CS is extremely difficult to diagnose, and so it is underdiagnosed and has dire implications for the risk of future cancers," Charis Eng, MD, PhD, corresponding author, told Medscape Medical News.

"As caregivers, we are called upon to rule out CS, but more than 90% of CS patients do not have the major defining genetic mutation (ie, PTEN mutation)," he said. "Therefore, this study adds to the knowledge of the genetic etiology of CS and CLS."

According to the researchers, "many individuals in the general population share 1 or more features of [CS] but may not have [CS,] and may not even harbor alterations in any predisposition gene."

Epigenetic regulation in the form of PTEN hypermethylation has been recognized as a means of PTEN downregulation in a subset of malignancies and may also play a role in CS and CLS, the authors suggest.

In the current study, the researchers sought to determine whether germline methylation of the common PTEN/KILLIN promoter was present in patients with PTEN mutation–negative CS and CLS. They also aimed to determine the functional consequence of such methylation.

A total of 2000 patients with CS or CLS were recruited; of those, 400 had no pathogenic germline alterations in PTEN. Among those, 123 patients without SDHB/D variations (a variant that also gives rise to CS or CLS) also were identified. These 123 patients consisted of 48 participants with CS, 75 patients with CLS, and 50 unaffected individuals.

Of the patients with CS and CLS, 42% and 33%, respectively, were found to have germline hypermethylation in the PTEN/KILLIN promoter region.

Compared with individuals with germline PTEN mutations, those with KILLIN-promoter methylation had a 3-fold increased prevalence of breast cancer (P < .0001) and a greater than 2-fold increase of kidney cancer (P = .004).

"While individuals with PTEN mutations have an up to 28% lifetime risk of female breast cancer (vs 12% in the general population) and 10% lifetime risk of thyroid cancer (vs <1% in general population), individuals with KILLIN mutations have a particularly high risk of breast cancer and kidney cancers," Dr. Eng explained . "Knowing these ahead of time will help physicians personalize clinical screening in a gene-specific manner."

According to Dr. Eng, patients with CS and CSL are difficult to recognize, so it is important for clinicians to be mindful of red flags, including larger head size than normal and colon, breast, thyroid, and kidney cancers.

Given the limitations of small sample size and preliminary nature of the design, the authors write, "the assumption that KILLIN surveillance will improve the diagnosis of [CS] and [CLS] may be overly optimistic until further validation in a larger patient set can be performed."

With that said, "these findings provide a potential genetic answer for those CS (and CLS) patients and families that have the syndrome but who do not have germline mutations of the known genes that are associated with CS," editorialist Ben Ho Park, MD, PhD, from the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University in Baltimore, Maryland, told Medscape Medical News.

"Potentially, this study would add KILLIN to the list of genes to be tested for in patients and families who are diagnosed with CS/CLS," Dr. Park stated.

However, Dr. Park reinforces, more work on KILLIN is needed before it can be definitively assigned as a gene implicated in CS/CLS; specifically, studying the relationship between KILLIN alterations and disease phenotype is warranted.

This study was supported, in part, by the Breast Cancer Research Foundation, the William Randolph Hearst Foundations, and the National Cancer Institute. study authors have disclosed no relevant financial relationships. Dr. Park has received consultancy and research funding from GlaxoSmithKline and Horizon Discovery.

JAMA. 2010;304:2724-2731.