Second malignant neoplasms in patients with Cowden syndrome with underlying germline PTEN mutations.
OBJECTIVE
Patients with Cowden syndrome (CS) with underlying germline PTEN mutations are at increased risk of breast, thyroid, endometrial, and renal cancers. To our knowledge, risk of subsequent cancers in these patients has not been previously explored or quantified.


METHODS
We conducted a 7-year multicenter prospective study (2005 to 2012) of patients with CS or CS-like disease, all of whom underwent comprehensive PTEN mutational analysis. Second malignant neoplasms (SMNs) were ascertained by medical records and confirmed by pathology reports. Standardized incidence ratios (SIRs) for all SMNs combined and for breast, thyroid, endometrial, and renal cancers were calculated.


RESULTS
Of the 2,912 adult patients included in our analysis, 2,024 had an invasive cancer history. Germline pathogenic PTEN mutations (PTEN mutation positive) were identified in 114 patients (5.6%). Of these 114 patients, 46 (40%) had an SMN. Median age of SMN diagnosis was 50 years (range, 21 to 71 years). Median interval between primary cancer and SMN was 5 years (range, <1 to 35 years). Of the 51 PTEN mutation-positive patients who presented with primary breast cancer, 11 (22%) had a subsequent new primary breast cancer and 10-year second breast cancer cumulative risk of 29% (95% CI, 15.3 to 43.7). Risk of SMNs compared with that of the general population was significantly elevated for all cancers (SIR, 7.74; 95% CI, 5.84 to 10.07), specifically for breast (SIR, 8.92; 95% CI, 5.85 to 13.07), thyroid (SIR, 5.83; 95% CI, 3.01 to 10.18), and endometrial SMNs (SIR, 14.08.07; 95% CI, 7.10 to 27.21).


CONCLUSIONS
Patients with CS with germline PTEN mutations are at higher risk for SMNs compared with the general population. Prophylactic mastectomy should be considered on an individual basis given the significant risk of subsequent breast cancer.
Joanne Ngeow, Kim Stanuch, Jessica L. Mester, and Charis Eng, Cleveland Clinic; and Jill S. Barnholtz-Sloan and Charis Eng, Case Western Reserve University, Cleveland, OH.
Joanne
J
Ngeow
Joanne Ngeow, Kim Stanuch, Jessica L. Mester, and Charis Eng, Cleveland Clinic; and Jill S. Barnholtz-Sloan and Charis Eng, Case Western Reserve University, Cleveland, OH.
Kim
K
Stanuch
Joanne Ngeow, Kim Stanuch, Jessica L. Mester, and Charis Eng, Cleveland Clinic; and Jill S. Barnholtz-Sloan and Charis Eng, Case Western Reserve University, Cleveland, OH.
Jessica L
JL
Mester
Joanne Ngeow, Kim Stanuch, Jessica L. Mester, and Charis Eng, Cleveland Clinic; and Jill S. Barnholtz-Sloan and Charis Eng, Case Western Reserve University, Cleveland, OH.
Jill S
JS
Barnholtz-Sloan
Joanne Ngeow, Kim Stanuch, Jessica L. Mester, and Charis Eng, Cleveland Clinic; and Jill S. Barnholtz-Sloan and Charis Eng, Case Western Reserve University, Cleveland, OH. engc@ccf.org.
Charis
C
Eng
D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D004252:DNA Mutational Analysis; D005260:Female; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006223:Hamartoma Syndrome, Multiple / Q000201:enzymology / Q000473:pathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D016609:Neoplasms, Second Primary / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D051059:PTEN Phosphohydrolase / Q000235:genetics* / Q000378:metabolism; D011446:Prospective Studies; D012307:Risk Factors; D055815:Young Adult
D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human