Higher Cancer Risk For Those With Cowden Syndrome Due To Gene Mutation

Higher Cancer Risk For Those With Cowden Syndrome Due To Gene Mutation
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Main Category: Genetics
Also Included In: Cancer / Oncology; Breast Cancer; Endocrinology
Article Date: 22 Dec 2010 - 10:00 PST


A gene mutation found in patients with Cowden syndrome dramatically increases their lifetime risk of developing cancer, researchers from the Cleveland Clinic, USA, revealed in the journal JAMA (Journal of the American Medical Association). Most individuals with Cowden syndrome have a mutation in the tumor suppressor PTEN gene, as do a small percentage of those with Cowden-like syndrome.

Cowden syndrome, also known as Cowden disease and multiple hamartoma syndrome, is an inherited disorder in which many hamartomas (non-cancerous growths) are formed. The growths develop in the skin, thyroid, colon, breast, intestines, as well as in the inside of the mouth. Patients have a much higher risk of developing cancer, especially breast, thyroid and colon cancers.

The genetic mutations are linked to a 10% lifetime risk of developing thyroid cancer, and a 50% risk for female breast cancer.

The authors wrote:

"A large heterogeneous group of individuals with Cowden-like syndrome, who have various combinations of Cowden syndrome features but who do not meet Cowden syndrome diagnostic criteria, have PTEN mutations less than 10 percent of the time, making molecular diagnosis, prediction, genetic counseling, and risk management challenging."

The researchers say that PTEN or KILLIN may be underexpressed. KILLIN is another tumor-suppressor gene located right next to PTEN.

The authors said:

"In the context of a difficult-to-recognize syndrome, identification of additional cancer predisposition genes would facilitate molecular diagnosis, genotype-specific predictive testing of family members who are as yet clinically unaffected, genetic counseling, and medical management."

Because of its similar function to PTEN, Charis Eng, M.D., Ph.D. and team set out to determine whether KILLIN was also a (cancer) predisposition gene in individuals with Cowden syndrome or Cowden-like syndrome.

They carried out analyses of nucleic acids from 123 individuals who had either Cowden syndrome or Cowden-like syndrome, and 50 healthy people without the PTEN variants. They were all genetically screened for expression of PTEN and KILLIN from August 2008 to June 2010. The investigators compared rates of cancer between the groups.

They found that KILLIN is a predisposition gene for patients with Cowden and Cowden-like syndromes. Those with KILLIN-promoter methylation (turns gene off) were three times as likely to develop breast cancer (35/42 compared to 24/64), twice as likely to develop kidney cancer (4/45 compared to 6/155) than those with germline (the cell line from which egg or sperm cells [gametes] are derived) PTEN mutations.

The authors wrote:

By discovering another cancer predisposition gene, we have added to the sensitivity of molecular diagnosis and predictive testing becomes possible. Importantly, genetic counseling and gene-informed risk assessment and management become evidence based.

The current national practice guidelines for individuals with PTEN germline mutations includes heightened surveillance of the female breasts and thyroid, but do not have awareness of renal cancer risk. If our observations of 2- to 3-fold increased risks of renal and/or breast cancer with KILLIN germline methylation over those of PTEN mutation holds, then extra vigilance for the organs at risk, breast and kidneys, is warranted. The KILLIN-associated breast cancer risks would parallel those conferred by germline BRCAl/2 mutations.

If these data can be and must be replicated independently, then a hypothetical schema for prioritizing gene testing could be as follows: (1) individuals with classic Cowden syndrome should be offered PTEN testing first; (2) those found not to have germline PTEN mutations should then be offered KILLIN epigenetic [affects expression of genes without mutation] analysis, in the setting of genetic counseling; and (3) individuals with classic Cowden syndrome without germline PTEN mutation (80 percent are mutation-positive) and without KILLIN epigenetic inactivation (half of the 20 percent should have KILLIN epigenetic inactivation) should then be offered SDHB/D [a type of genes] testing (10 percent of the 20 percent should have SDHB/D mutation). Altogether, therefore, PTEN, KILLIN, and SDHB/D should then account for 92 percent of all classic Cowden syndrome.

Accompanying Editorial - PTEN Promoter Silencing and Cowden Syndrome
Jelovac, M.D., and Ben Ho Park, M.D., Ph.D., of the Johns Hopkins University School of Medicine, Baltimore, say that this study's findings should be cautiously viewed as a foundation for subsequent studies which could further prove what the role of KILLIN is in Cowden syndrome and Cowden-like syndrome.

They wrote:

"In addition, the findings by Bennett et al propose a new model whereby heritable epigenetic regulation in neighboring genes could account for a number of familial cancer syndromes where no germline mutations have been found. If true, the results of this work could have even greater significance for researchers and physicians and, most importantly, for the families and patients affected by this often devastating group of disorders."

▲ "Germline Epigenetic Regulation of KILLIN in Cowden and Cowden-like Syndrome"
[Germline Epigenetic Regulation of KILLIN in Cowden and Cowden-like Syndrome, December 22/29, 2010, Bennett et al. 304 (24): 2724 — JAMA]
Kristi L. Bennett, PhD; Jessica Mester, MS, CGC; Charis Eng, MD, PhD
JAMA. 2010;304(24):2724-2731. doi: 10.1001/jama.2010.1877

Written by Christian Nordqvist
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Higher Cancer Risk For Those With Cowden Syndrome Due To Gene Mutation