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KLLN epigenotype-phenotype associations in Cowden syndrome.

Nizialek EA, Mester JL, Dhiman VK, Smiraglia DJ, Eng C - Eur. J. Hum. Genet. (2015)

Bottom Line: Interestingly, KLLN-associated risk of thyroid cancer appears to be gender and PTEN status dependent.KLLN promoter methylation associated with different benign phenotypes dependent on PTEN status.Furthermore, increasing KLLN promoter methylation is associated with a greater phenotype burden in mutation-negative CS patients.

View Article: PubMed Central - PubMed

Affiliation: Genomic Medicine Institute, Cleveland Clinic, Cleveland, OH, USA.

ABSTRACT
Germline KLLN promoter hypermethylation was recently identified as a potential genetic etiology of the cancer predisposition syndrome, Cowden syndrome (CS), when no causal PTEN gene mutation was found. We screened for KLLN promoter methylation in a large prospective series of CS patients and determined the risk of benign and malignant CS features in patients with increased methylation both with and without a PTEN mutation/variant of unknown significance. In all, 1012 CS patients meeting relaxed International Cowden Consortium criteria including 261 PTEN mutation-positive CS patients, 187 PTEN variant-positive CS patients and 564 PTEN mutation-negative CS patients, as well as 111 population controls were assessed for germline KLLN promoter methylation by MassARRAY EpiTYPER analysis. KLLN promoter methylation was analyzed both as a continuous and a dichotomous variable in the calculation of phenotypic risks by stepwise logistic regression and Kaplan-Meier/standardized incidence ratio methods, respectively. Significantly increased KLLN promoter methylation was seen in CS individuals with and without a PTEN mutation/VUS compared with controls (P<0.001). Patients with high KLLN promoter methylation have increased risks of all CS-associated malignancies compared with the general population. Interestingly, KLLN-associated risk of thyroid cancer appears to be gender and PTEN status dependent. KLLN promoter methylation associated with different benign phenotypes dependent on PTEN status. Furthermore, increasing KLLN promoter methylation is associated with a greater phenotype burden in mutation-negative CS patients. Germline promoter hypermethylation of KLLN is associated with particular malignant and benign CS features, which is dependent on the PTEN mutation status.

No MeSH data available.


Related in: MedlinePlus

Kaplan–Meier curves for cumulative risk of thyroid cancer between patients with low compared with high KLLN promoter methylation. (a) An increased risk of thyroid cancer was observed in male patients with high KLLN promoter methylation for all cases and for PTEN mutation-negative cases. No significant differences in risk of thyroid cancer in males were observed for PTEN mutation-positive or PTEN VUS cases. (b) For females, no significant differences in thyroid cancer risk based on KLLN promoter methylation were seen for all cases, PTEN mutation-negative cases, or PTEN mutation-positive cases. A trend can be observed for increased risk for thyroid cancer with low KLLN methylation for all cases. For the PTEN VUS cases, there was a significant increase in thyroid cancer risk for females with low KLLN promoter methylation compared with high.
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fig2: Kaplan–Meier curves for cumulative risk of thyroid cancer between patients with low compared with high KLLN promoter methylation. (a) An increased risk of thyroid cancer was observed in male patients with high KLLN promoter methylation for all cases and for PTEN mutation-negative cases. No significant differences in risk of thyroid cancer in males were observed for PTEN mutation-positive or PTEN VUS cases. (b) For females, no significant differences in thyroid cancer risk based on KLLN promoter methylation were seen for all cases, PTEN mutation-negative cases, or PTEN mutation-positive cases. A trend can be observed for increased risk for thyroid cancer with low KLLN methylation for all cases. For the PTEN VUS cases, there was a significant increase in thyroid cancer risk for females with low KLLN promoter methylation compared with high.

Mentions: To analyze the relationship among KLLN promoter methylation status, PTEN mutation status, and age-adjusted risk of developing the most common CS-associated malignancies, specifically, breast, thyroid, endometrial, and renal carcinomas, KLLN promoter methylation was analyzed as a dichotomous variable (>32% methylated versus <32%). Of 1012 total patients, 197 (19.5%) have high KLLN promoter methylation. This is broken down as 76 of 564 (13.5%) PTEN mutation-negative, 81 of 260 (31.2%) PTEN mutation-positive, and 40 of 187 (21.4%) PTEN VUS cases. Only thyroid cancer showed significant differences in cumulative risk between CS/CSL patients with high KLLN promoter methylation and those with low KLLN promoter methylation (P=0.025; Figure 2 and Supplementary Figure 4). The association remained significant in the PTEN mutation-negative subgroup (P=0.023, Figure 2a). Additionally, there was a significant difference in the thyroid histologies of CS/CSL male patients with high KLLN promoter methylation compared with those with low methylation (P=0.039; Supplementary Figure 5). Of 17 male patients with thyroid cancer and low KLLN promoter methylation, 9 (53%) had papillary thyroid cancer compared with only 1 (5.9%) with follicular histology. In contrast, among the nine male patients with high KLLN promoter methylation and thyroid cancer, two (22%) had papillary thyroid cancer and three (33%) follicular thyroid cancer. For male patients with thyroid cancer, PTEN mutation status was not significantly different in those with high versus low KLLN promoter methylation.


KLLN epigenotype-phenotype associations in Cowden syndrome.

Nizialek EA, Mester JL, Dhiman VK, Smiraglia DJ, Eng C - Eur. J. Hum. Genet. (2015)

Kaplan–Meier curves for cumulative risk of thyroid cancer between patients with low compared with high KLLN promoter methylation. (a) An increased risk of thyroid cancer was observed in male patients with high KLLN promoter methylation for all cases and for PTEN mutation-negative cases. No significant differences in risk of thyroid cancer in males were observed for PTEN mutation-positive or PTEN VUS cases. (b) For females, no significant differences in thyroid cancer risk based on KLLN promoter methylation were seen for all cases, PTEN mutation-negative cases, or PTEN mutation-positive cases. A trend can be observed for increased risk for thyroid cancer with low KLLN methylation for all cases. For the PTEN VUS cases, there was a significant increase in thyroid cancer risk for females with low KLLN promoter methylation compared with high.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4613489&req=5

fig2: Kaplan–Meier curves for cumulative risk of thyroid cancer between patients with low compared with high KLLN promoter methylation. (a) An increased risk of thyroid cancer was observed in male patients with high KLLN promoter methylation for all cases and for PTEN mutation-negative cases. No significant differences in risk of thyroid cancer in males were observed for PTEN mutation-positive or PTEN VUS cases. (b) For females, no significant differences in thyroid cancer risk based on KLLN promoter methylation were seen for all cases, PTEN mutation-negative cases, or PTEN mutation-positive cases. A trend can be observed for increased risk for thyroid cancer with low KLLN methylation for all cases. For the PTEN VUS cases, there was a significant increase in thyroid cancer risk for females with low KLLN promoter methylation compared with high.
Mentions: To analyze the relationship among KLLN promoter methylation status, PTEN mutation status, and age-adjusted risk of developing the most common CS-associated malignancies, specifically, breast, thyroid, endometrial, and renal carcinomas, KLLN promoter methylation was analyzed as a dichotomous variable (>32% methylated versus <32%). Of 1012 total patients, 197 (19.5%) have high KLLN promoter methylation. This is broken down as 76 of 564 (13.5%) PTEN mutation-negative, 81 of 260 (31.2%) PTEN mutation-positive, and 40 of 187 (21.4%) PTEN VUS cases. Only thyroid cancer showed significant differences in cumulative risk between CS/CSL patients with high KLLN promoter methylation and those with low KLLN promoter methylation (P=0.025; Figure 2 and Supplementary Figure 4). The association remained significant in the PTEN mutation-negative subgroup (P=0.023, Figure 2a). Additionally, there was a significant difference in the thyroid histologies of CS/CSL male patients with high KLLN promoter methylation compared with those with low methylation (P=0.039; Supplementary Figure 5). Of 17 male patients with thyroid cancer and low KLLN promoter methylation, 9 (53%) had papillary thyroid cancer compared with only 1 (5.9%) with follicular histology. In contrast, among the nine male patients with high KLLN promoter methylation and thyroid cancer, two (22%) had papillary thyroid cancer and three (33%) follicular thyroid cancer. For male patients with thyroid cancer, PTEN mutation status was not significantly different in those with high versus low KLLN promoter methylation.

Bottom Line: Interestingly, KLLN-associated risk of thyroid cancer appears to be gender and PTEN status dependent.KLLN promoter methylation associated with different benign phenotypes dependent on PTEN status.Furthermore, increasing KLLN promoter methylation is associated with a greater phenotype burden in mutation-negative CS patients.

View Article: PubMed Central - PubMed

Affiliation: Genomic Medicine Institute, Cleveland Clinic, Cleveland, OH, USA.

ABSTRACT
Germline KLLN promoter hypermethylation was recently identified as a potential genetic etiology of the cancer predisposition syndrome, Cowden syndrome (CS), when no causal PTEN gene mutation was found. We screened for KLLN promoter methylation in a large prospective series of CS patients and determined the risk of benign and malignant CS features in patients with increased methylation both with and without a PTEN mutation/variant of unknown significance. In all, 1012 CS patients meeting relaxed International Cowden Consortium criteria including 261 PTEN mutation-positive CS patients, 187 PTEN variant-positive CS patients and 564 PTEN mutation-negative CS patients, as well as 111 population controls were assessed for germline KLLN promoter methylation by MassARRAY EpiTYPER analysis. KLLN promoter methylation was analyzed both as a continuous and a dichotomous variable in the calculation of phenotypic risks by stepwise logistic regression and Kaplan-Meier/standardized incidence ratio methods, respectively. Significantly increased KLLN promoter methylation was seen in CS individuals with and without a PTEN mutation/VUS compared with controls (P<0.001). Patients with high KLLN promoter methylation have increased risks of all CS-associated malignancies compared with the general population. Interestingly, KLLN-associated risk of thyroid cancer appears to be gender and PTEN status dependent. KLLN promoter methylation associated with different benign phenotypes dependent on PTEN status. Furthermore, increasing KLLN promoter methylation is associated with a greater phenotype burden in mutation-negative CS patients. Germline promoter hypermethylation of KLLN is associated with particular malignant and benign CS features, which is dependent on the PTEN mutation status.

No MeSH data available.


Related in: MedlinePlus