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PTEN, KLLN mutations provide insight into Cowden disease-related endometrial cancer
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Clinical predictors such as younger age and a higher PTEN Cleveland Clinic score were associated with the presence of germline PTEN and KLLN mutations in patients with endometrial cancer, as well as Cowden or Cowden-like disease, according to study results.
Patients with endometrial cancer who harbor these mutations may be appropriate candidates for high-risk cancer surveillance and prophylactic surgery of the uterus, researchers wrote.
Charis Eng
“Endometrial cancer is the one of the most common gynecologic cancer in the western world,” researcher Charis Eng, MD, PhD, department chair of the Genomic Medicine Institute at Cleveland Clinic’s Lerner Research Institute and a HemOnc Today Editorial Board member, told HemOnc Today. “In this study, we wanted to determine the frequency of inherited gene mutations in patients with endometrial cancer and some features of Cowden and Cowden-like disease.”
Eng and colleagues evaluated data from 371 patients (median age, 54 years) with endometrial cancer as well as Cowden or Cowden-like disease.
“Cowden and Cowden-like [disease] are cancer predisposition disorders caused by alterations in one of at least four genes: PTEN, SDHB, SDHD and KLLN,” Eng said. “As such, these individuals need to be recognized and referred to genetics professionals for gene-informed precision health care. Cowden and Cowden-like [disease] have clinical features that can be found commonly, and so [they] are difficult for non-genetics caregivers to recognize. We also wanted to determine if the patients with mutation in the different genes manifested differently.”
Overall, 7% of patients had a germline pathogenic PTEN mutation, 9.8% harbored the germline SDHB-D variation and 10.5% of patients harbored germline KLLN promoter methylation.
Germline PTEN mutations were significantly more common in patients aged younger than 30 years (OR = 6.1; 95% CI, 1.4-26.2) and those aged 30 to 50 years (OR = 4.4; 95% CI, 1.7-11.2). These mutations also were more common in patients who had macrocephaly (OR = 14.4; 95% CI, 5.6-37.6), those with a PTEN protein level within the lowest vs. highest quartile (OR = 5.1; 95% CI, 1.1-24.6), and those who also had renal cancer (OR = 5.7; 95% CI, 1.86-17.55).
Patients with a higher PTEN Cleveland Clinic score — a risk assessment tool that relies on several factors, including head circumference and various aspects of medical history, to estimate an individual’s risk for harboring a PTEN mutation — also was associated with the presence of germline PTEN mutations (OR for each increment = 1.35; 95% CI, 1.2-1.5).
Younger age (OR for each year younger = 1.25; 95% CI, 1.04-1.5) and a higher PTEN Cleveland Clinic score (OR for each increment = 1.03; 95% CI, 0.99-1.07) were clinical predictors of KLLN promoter methylation. Overall, patients who harbored germline KLLN promoter methylation were 8 years younger than patients who did not (mean age, 44 years vs. 52 years; P = .018).
Researchers did not identify clinical predictors for SHDB-D variation.
“Clinical predictors for finding a mutation that can alert the treating clinician to refer the patient to a genetic professional include early age of onset of endometrial cancer (younger than 50 years) and a big head size,” Eng said. “We would love for an independent group to validate our study.”
These findings also may help inform treatment decisions of oncologists who treat patients with endometrial cancer, the researchers wrote.
“High-risk cancer surveillance and prophylactic surgery of the uterus may be considered for KLLN [promoter methylation -positive] patients similarly to those with PTEN mutations,” Eng and colleagues wrote. – by Alexandra Todak
For more information:
Charis Eng, MD, PhD, can be reached at engc@ccf.org.
Disclosure: The researchers report no relevant financial disclosures.
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