Germline PTEN, SDHB-D, and KLLN alterations in endometrial cancer patients with Cowden and Cowden-like syndromes: an international, multicenter, prospective study.
BACKGROUND
Endometrial cancer has been recognized only recently as a major component of Cowden syndrome (CS). Germline alterations in phosphatase and tensin homolog (PTEN; PTEN_mut+), succinate dehydrogenase B/C/D (SDHB-D; SDHx_var+), and killin (KLLN_Me+) cause CS and Cowden syndrome-like (CSL) phenotypes. This study was aimed at identifying the prevalence and clinicopathologic predictors of germline PTEN_mut+, SDHx_var+, and KLLN_Me+ in CS/CSL patients presenting with endometrial cancer.


METHODS
PTEN and SDHB-D mutation and KLLN promoter methylation analyses were performed for 371 prospectively enrolled patients (2005-2011). PTEN protein was analyzed from patient-derived lymphoblast lines. The PTEN Cleveland Clinic (CC) score is a weighted, regression-based risk calculator giving the a priori risk for PTEN_mut+. Demographic and clinicopathologic features were correlated with the specific gene.


RESULTS
Germline PTEN_mut+, SDHx_var+, and KLLN_Me+ were found in 7%, 9.8%, and 10.5% of informative samples, respectively. Predictors of PTEN_mut+ included an age ≤ 50 years (odds ratio [OR] for an age < 30 years, 6.1 [P = .015]; OR for an age of 30-50 years, 4.4 [P = .001]), macrocephaly (OR, 14.4; P < .001), a higher CC score (OR for a 1-U increment, 1.35; P < .001), a PTEN protein level within the lowest quartile (OR, 5.1; P = .039), and coexisting renal cancer (OR, 5.7; P = .002). KLLN_Me+ patients were on average 8 years younger than KLLN_Me- patients (44 vs 52 years, P = .018). Predictors of KLLN_Me+ were a younger age and a higher CC score. On the other hand, no clinical predictors of SDH_var+ were found.


CONCLUSIONS
Clinical predictors of PTEN and KLLN alterations, but not SDHx_var+, were identified. These predictors should alert the treating physician to potential heritable risk and the need for referral to genetic professionals. High-risk cancer surveillance and prophylactic surgery of the uterus may be considered for KLLN_Me+ patients similarly to PTEN_mut+ patients.
Section of Gynecologic Oncology/ObGyn and Women's Health Institute, Cleveland Clinic, Cleveland, Ohio.
Haider
H
Mahdi
Jessica L
JL
Mester
Emily A
EA
Nizialek
Joanne
J
Ngeow
Chad
C
Michener
Charis
C
Eng
D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D002478:Cells, Cultured; D019175:DNA Methylation; D016889:Endometrial Neoplasms / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D006223:Hamartoma Syndrome, Multiple / Q000235:genetics*; D006801:Humans; D008875:Middle Aged; D028361:Mitochondrial Diseases / Q000235:genetics*; D009154:Mutation; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D011401:Promoter Regions, Genetic; D011446:Prospective Studies; D013385:Succinate Dehydrogenase / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D055815:Young Adult
C554482:KLLN protein, human; D025521:Tumor Suppressor Proteins; C108095:SDHB protein, human; D013385:Succinate Dehydrogenase; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human
Cowden syndrome; Cowden-like syndrome; endometrial cancer; killin (KLLN); phosphatase and tensin homolog (PTEN); succinate dehydrogenase B/D (SDHB-D)