A review on age-related cancer risks in PTEN hamartoma tumor syndrome

Abstract

Patients with PTEN hamartoma tumor syndrome (PHTS, comprising Cowden, Bannayan-Riley-Ruvalcaba, and Proteus-like syndromes) are at increased risk of developing cancer due to pathogenic PTEN germline variants. This review summarizes age-, sex-, and type-specific malignant cancer risks for PHTS patients, which is urgently needed for clinical management. A PubMed literature search for Standardized Incidence Ratios or Cumulative Lifetime cancer risks (CLTRs) resulted in nine cohort studies comprising four independent PHTS cohorts, including mainly index cases and prevalent cancer cases. The median age at diagnosis was 36 years. Reported CLTRs for any cancer varied from 81% to 90%. The tumor spectrum included female breast cancer (CLTRs including sex-specific estimates at age 60-70: 67% to 85%), endometrium cancer (19% to 28%), thyroid cancer (6% to 38%), renal cancer (2% to 24%), colorectal cancer (9% to 32%), and melanoma (0% to 6%). Although these estimates provide guidance for clinical care, discrepancies between studies, sample sizes, retrospective designs, strongly ascertained cases, and lack of pediatric research emphasizes that data should be interpreted with great caution. Therefore, more accurate and more personalized age-, sex-, and cancer-specific risk estimates are needed to enable counseling of all PHTS patients irrespective of ascertainment, and improvement of cancer surveillance guidelines.

Keywords: Hamartoma syndrome, multiple; PTEN Phosphohydrolase; germ-line mutation; neoplasms; neoplastic syndromes, hereditary; risk.

FIGURE 1

Standardized Incidence Ratios per cancer type in PHTS patients. The Standardized Incidence Ratio (SIR) is presented with corresponding 95% Confidence Interval (95%CI) on the x‐axis. Shapes represent different studies and colors different sexes. The vertical dashed line represents SIR = 1.0. SIRs are presented for (A) any cancer, (B) female breast cancer, (C) endometrial cancer, (D) thyroid cancer, (E) renal cancer, (F) colorectal cancer, (G) melanoma [Colour figure can be viewed at wileyonlinelibrary.com]

FIGURE 2

Cumulative Lifetime Risks per cancer type in PHTS patients. The Cumulative Lifetime Risk (CLTR) is presented in percentages per age‐group with corresponding 95% Confidence Interval (95%CI) on the y‐axis. Shapes represent different studies and colors different sexes. CLTRs are presented for (A) any cancer (Nieuwenhuis et al. [2014] and Riegert‐Johnson et al. included Lhermitte‐Duclos Disease), ⁵ , ¹³ (B) female breast cancer, (C) endometrial cancer, (D) thyroid cancer, (E) renal cancer, (F) colorectal cancer, (G) melanoma [Colour figure can be viewed at wileyonlinelibrary.com]