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.
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/CSLpatients 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.
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Authors: Günter Emons; Eric Steiner; Dirk Vordermark; Christoph Uleer; Nina Bock; Kerstin Paradies; Olaf Ortmann; Stefan Aretz; Peter Mallmann; Christian Kurzeder; Volker Hagen; Birgitt van Oorschot; Stefan Höcht; Petra Feyer; Gerlinde Egerer; Michael Friedrich; Wolfgang Cremer; Franz-Josef Prott; Lars-Christian Horn; Heinrich Prömpeler; Jan Langrehr; Steffen Leinung; Matthias W Beckmann; Rainer Kimmig; Anne Letsch; Michael Reinhardt; Bernd Alt-Epping; Ludwig Kiesel; Jan Menke; Marion Gebhardt; Verena Steinke-Lange; Nils Rahner; Werner Lichtenegger; Alain Zeimet; Volker Hanf; Joachim Weis; Michael Mueller; Ulla Henscher; Rita K Schmutzler; Alfons Meindl; Felix Hilpert; Joan Elisabeth Panke; Vratislav Strnad; Christiane Niehues; Timm Dauelsberg; Peter Niehoff; Doris Mayr; Dieter Grab; Michael Kreißl; Ralf Witteler; Annemarie Schorsch; Alexander Mustea; Edgar Petru; Jutta Hübner; Anne Derke Rose; Edward Wight; Reina Tholen; Gerd J Bauerschmitz; Markus Fleisch; Ingolf Juhasz-Boess; Lax Sigurd; Ingo Runnebaum; Clemens Tempfer; Monika J Nothacker; Susanne Blödt; Markus Follmann; Thomas Langer; Heike Raatz; Simone Wesselmann; Saskia Erdogan Journal: Geburtshilfe Frauenheilkd Date: 2018-10-19 Impact factor: 2.915