Germline Epigenetic Regulation of KILLIN in Cowden and Cowden-like Syndrome, December 22/29, 2010, Bennett et al. 304 (24): 2724 — JAMA

Preliminary Communication
JAMA. 2010;304(24):2724-2731. doi: 10.1001/jama.2010.1877
Germline Epigenetic Regulation of KILLIN in Cowden and Cowden-like Syndrome
Kristi L. Bennett, PhD; Jessica Mester, MS, CGC; Charis Eng, MD, PhD
[+] Author Affiliations

Author Affiliations: Genomic Medicine Institute (Drs Bennett and Eng, and Ms Mester), Lerner Research Institute, Taussig Cancer Institute (Dr Eng), and the Stanley Shalom Zielony Nursing Institute (Dr Eng), Cleveland Clinic; and Department of Genetics and CASE Comprehensive Cancer Center, Case Western Reserve University School of Medicine (Dr Eng), Cleveland, Ohio.

Abstract

Context Germline loss-of-function phosphatase and tensin homolog gene (PTEN) mutations cause 80% of Cowden syndrome, a rare autosomal-dominant disorder (1 in 200 000 live births), characterized by high risks of breast, thyroid, and other cancers. 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% of the time, making molecular diagnosis, prediction, genetic counseling, and risk management challenging. Other mechanisms of loss of function such as hypermethylation, which should result in underexpression of PTEN or of KILLIN, a novel tumor suppressor transcribed in the opposite direction, may account for the remainder of Cowden syndrome and Cowden-like syndrome.

Objective
To determine whether germline methylation is found in Cowden syndrome or Cowden-like syndrome in individuals lacking germline PTEN mutations.

Design, Setting, and Participants
Nucleic acids from prospective nested series of 123 patients with Cowden syndrome or Cowden-like syndrome and 50 unaffected individuals without PTEN variants were analyzed for germline methylation and expression of PTEN and KILLIN at the Cleveland Clinic, August 2008-June 2010. Prevalence of component cancers between groups was compared using the Fisher exact test.

Main Outcome Measures
Frequency of germline methylation in PTEN mutation–negative Cowden syndrome and Cowden syndrome–like individuals. Prevalence of component cancers in methylation-positive and PTEN mutation–positive individuals.

Results
Of 123 patients with Cowden syndrome or Cowden-like syndrome, 45 (37%; 95% confidence interval [CI], 29%-45%) showed hypermethylation upstream of PTEN but no transcriptional repression. The germline methylation was found to transcriptionally down-regulate KILLIN by 250-fold (95% CI, 45-14 286; P = .007) and exclusively disrupted TP53 activation of KILLIN by 30% (95% CI, 7%-45%; P = .008). Demethylation treatment increased only KILLIN expression 4.88-fold (95% CI, 1.4-18.1; P = .05). Individuals with KILLIN -promoter methylation had a 3-fold increased prevalence of breast cancer (35/42 vs 24/64; P < .0001) and a greater than 2-fold increase of kidney cancer (4/45 vs 6/155; P = .004) over individuals with germline PTEN mutations.

Conclusions
Germline KILLIN methylation is common among patients with Cowden syndrome or Cowden-like syndrome and is associated with increased risks of breast and renal cancer over PTEN mutation–positive individuals. These observations need to be replicated.

KEYWORDS: BREAST NEOPLASMS, COWDEN SYNDROME, EPIGENESIS, GENETIC, GENES, TUMOR SUPPRESSOR, GENETIC PREDISPOSITION TO DISEASE, GERM-LINE MUTATION, HAMARTOMA, HAMARTOMA SYNDROME, MULTIPLE, KIDNEY NEOPLASMS, METHYLATION, DNA, NEOPLASMS, NEOPLASTIC SYNDROMES, HEREDITARY, PTEN, TENC1 PROTEIN, HUMAN.

open here please:
Germline Epigenetic Regulation of KILLIN in Cowden and Cowden-like Syndrome, December 22/29, 2010, Bennett et al. 304 (24): 2724 — JAMA




ONCOLOGÍA
Actualidad Ultimas noticias - JANOes
Hallan una alteración genética que favorece el riesgo de cáncer
JANO.es · 22 Diciembre 2010 09:12

Esta mutación favorece la aparición del síndrome de Cowden, un trastorno poco frecuente que se caracteriza por un alto riesgo de cáncer de mama, tiroides y otros tumores.



Investigadores de la Cleveland Clinic, en Estados Unidos, han identificado una nueva alteración genética que favorece la aparición del síndrome de Cowden, un trastorno poco frecuente que se caracteriza por un alto riesgo de cáncer de mama, tiroides y otros tumores.

Según informa en su último número el Journal of the American Medical Association (JAMA), esta enfermedad afecta a uno de cada 200.000 recién nacidos pero, en algunos casos, estos pacientes presentan una mutación en el gen supresor de tumores PTEN, que se asocia a un mayor riesgo de desarrollar varias neoplasias. Así, en ellos aumenta un 10% el riesgo de tener cáncer de tiroides a lo largo de su vida y hasta un 50% el riesgo de presentar cáncer de mama, informan los autores del estudio.

No obstante, se ha comprobado que la aparición de este trastorno puede estar provocada por esta alteración del PTEN o por el Killin, otro gen supresor de tumores cuya presencia conjunta también favorece la aparición del síndrome de Cowden.

El estudio incluyó el análisis de ácidos nucleicos de 123 pacientes con síndrome de Cowden y 50 personas no afectadas en los cuales se analizó la expresión del PTEN y el Killin durante casi dos años -de agosto de 2008 a junio de 2010-, a fin de comparar la prevalencia de cáncer en ambos casos. De este modo, se observó que los individuos con metilación de Killin presentaban una prevalencia tres veces mayor de cáncer de mama, al tiempo que se duplicaba el riesgo de presentar cáncer de riñón, en comparación con quienes presentaban mutaciones del PTEN.

"Al descubrir otro gen que predispone al cáncer, éste se deberá sumar al diagnóstico molecular", han asegurado los autores de la investigación, que proponen que en aquellos ciudadanos donde se detecte mutaciones del PTEN se incremente la vigilancia de la mama, del tiroides y también del riñón, en caso de que también haya metilación del gen Killin.


JAMA 2010; 304(24):2724-2731
Germline Epigenetic Regulation of KILLIN in Cowden and Cowden-like Syndrome, December 22/29, 2010, Bennett et al. 304 (24): 2724 — JAMA

Cleveland Clinic
Cleveland Clinic.

Actualidad Ultimas noticias - JANOes - Hallan una alteracion genetica que favorece el riesgo de cancer - JANO.es - ELSEVIER