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 biologic insights on human germline PTEN mutations, and to better inform current surveillance recommendations on the basis of expert opinion.

Experimental design: 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 carried out.

Results: Elevated SIRs were found for carcinomas of the breast [25.4, 95% confidence interval (CI), 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), kidney (30.6, 17.8-49.4), and melanoma (8.5, 4.1-15.6). Estimated lifetime risks were, respectively, 85.2% (95% CI, 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, whereas 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.

Figure 1

Consolidated PTEN mutation spectrum. Distribution and number of substitutions (missense and/or nonsense), small insertion mutations, and small deletion mutations across the gene. In the top panel, blue bars represent missense mutations and red bars represent nonsense mutations. In the second panel, the blue arrowheads represent small insertions and the red arrowheads represent small deletions along the gene. Complex mutations (indels, splice-site mutations, and large deletions) and promoter mutations are not depicted. For both panels, frequencies of both the substitution mutations and the insertion/deletion mutations are shown on the left. The bar below corresponds to the multiple exons of the PTEN cDNA molecule, with exon 1 on the left to exon 9 on the right, allowing for matching of mutation to exon.

Figure 2

Age-related penetrance curves for (A) female breast cancer; (B) thyroid cancer; (C) endometrial cancer; (D) colorectal cancer; (E) kidney cancer; and (F) melanoma. The highest age-related penetrance is observed in female breast cancer, with an estimated 85% lifetime risk.

Figure 3

Schematic showing a flowchart of recommendations for the evaluation, workup and screening for a patient with a potential PTEN mutation.