Lifetime Cancer Risks in Individuals with Germline PTEN Mutations

Abstract

Purpose Age-adjusted cancer incidence and age-related penetrance studies have helped guide cancer risk assessment and management. PTEN Hamartoma-Tumor Syndrome (PHTS) is a term encompassing subsets of several clinical syndromes with germline mutations in the PTEN tumor suppressor gene. We conducted the first prospective study to clarify corresponding cancer risks to shed biological insights on human germline PTEN mutations, and to better inform current surveillance recommendations based on expert opinion. Methods A series of 3,399 individuals meeting relaxed International Cowden Consortium PHTS criteria were prospectively recruited; 368 individuals were found to have deleterious germline PTEN mutations. Age-adjusted standardized incidence ratio (SIR) calculations and genotype-phenotype analyses were performed. Results Elevated SIRs were found for carcinomas of the breast (25.4, 95%C.I. 19.8-32.0), thyroid (51.1, 38.1-67.1), endometrium (42.9, 28.1-62.8), colorectum (10.3, 5.6-17.4), and kidney (30.6, 17.8-49.4), and melanoma (8.5, 4.1–15.6). Estimated lifetime risks were, respectively, 85.2% (95%C.I. 71.4%-99.1%), 35.2% (19.7%-50.7%), 28.2% (17.1%-39.3%), 9.0% (3.8-%14.1%), 33.6% (10.4%–56.9%) and 6% (1.6%-9.4%). Promoter mutations were associated with breast cancer, while colorectal cancer was associated with nonsense mutations. Conclusion Lifetime risks for a variety of cancers, now extending to colorectal cancer, kidney cancer and melanoma, are increased in patients with PTEN mutations. The genotype-phenotype associations here may provide new insights on PTEN structure and function. We propose a comprehensive approach to surveillance of patients with PTEN mutations.

S3-Leitlinie – Kolorektales Karzinom

“…Beim Cowden-Syndrom [388] ist insbesondere das Risiko für Mamma-und Schilddrüsenkarzinome erhöht. Das Risiko für kolorektale Karzinome scheint nach neueren Daten mit einem Lebenszeitrisiko von 28 % ebenfalls erhöht zu sein [389]. Weiterhin wurden erhöhte Risiken für Karzinome des Endometriums und der Nieren sowie für Melanome beschrieben.…”

PTEN, DICER1, FH, and Their Associated Tumor Susceptibility Syndromes: Clinical Features, Genetics, and Surveillance Recommendations in Childhood

“…4). In addition, there are significant lifetime risks for malignancy in affected individuals, including breast, endometrial, and colorectal cancer, renal cell carcinoma, and melanoma, with thyroid cancer representing the predominant risk in childhood (5). An overall prevalence for PHTS has not been established, but the prevalence of CS has been estimated to be at least one in 200,000 (6).…”

“…Epithelial differentiated thyroid cancer (DTC) occurs in as many as one third of patients with PHTS (5). It can be preceded by multinodular goiter.…”

“…The risk starts in childhood, with the earliest reported case occurring at 7 years of age (8). As many as 5% of individuals with PHTS under 20 years of age will develop DTC (5). Other PHTS-related cancers have rarely been reported in children (5,9).…”

“…As many as 5% of individuals with PHTS under 20 years of age will develop DTC (5). Other PHTS-related cancers have rarely been reported in children (5,9). There are no conclusively established genotype-cancer phenotype correlations (10).…”