Cancer risks by sex and variant type in PTEN hamartoma tumor syndrome

Abstract

BACKGROUND PTEN Hamartoma Tumor Syndrome (PHTS) is a rare syndrome with a broad phenotypic spectrum, including increased risks of breast (BC, 67-78% at age 60), endometrial (EC, 19-28%) and thyroid cancer (TC, 6-38%). Current risks are likely overestimated due to ascertainment bias. We aimed to provide more accurate and personalized cancer risks. METHODS A European, adult PHTS cohort study with data from medical files, registries and/or questionnaires. Cancer risks and hazard ratios were assessed with Kaplan-Meier and Cox regression analyses, and standardized incidence ratios (SIR) were calculated. Bias correction consisted of excluding cancer index cases and incident case analyses. RESULTS 455 patients were included, including 50.5% index cases, 372 with prospective follow-up (median 6 year, IQR : 3-10), and 159/281 females and 39/174 males with cancer. By age 60, PHTS-related cancer risk was higher in females (68.4% to 86.3%) than males (16.4% to 20.8%). Female BC risks ranged from 54.3% (95%CI 43.0-66.4) to 75.8% (95%CI 60.7-88.4), with two-to-three-fold increased risks for PTEN truncating and about two-fold for phosphatase domain variants. EC risks ranged from 6.4% (95%CI 2.1-18.6) to 22.1% (95%CI 11.6-39.6), and TC risks from 8.9% (95%CI 5.1-15.3) to 20.5% (95%CI 11.3-35.4). Colorectal cancer, renal cancer and melanoma risks were each below 10.0%. CONCLUSION Females have a different breast cancer risk depending on their PTEN germline variant. PHTS patients are predominantly at risk of breast (females), endometrial and thyroid cancer. This should be the main focus of surveillance. These lower, more unbiased and personalized risks provide guidance for optimized cancer risk management.

PTEN hamartoma tumour syndrome: case report based on data from the Iranian hereditary colorectal cancer registry and literature review

“…Compared to previously reported rates [2,9,34,73,[75][76][77], recent literature suggests that PHTS patients may have an even higher risk of developing breast cancer (up to 80%) and endometrial cancer (up to 28%). In addition, these patients may develop a significant number of benign thyroid lesions (up to 60%) and thyroid cancer (over 10%) [34,78].…”

“…Compared to previously reported rates [2,9,34,73,[75][76][77], recent literature suggests that PHTS patients may have an even higher risk of developing breast cancer (up to 80%) and endometrial cancer (up to 28%). In addition, these patients may develop a significant number of benign thyroid lesions (up to 60%) and thyroid cancer (over 10%) [34,78]. Genetic and molecular studies of PHTS have revealed the presence of pathogenic variants in the PTEN/MMAC1 gene, located on chromosome 10 at position q 22-23, which is implicated in breast and thyroid cancer [73,[79][80][81][82].…”

“…These findings suggest that colon polyposis is an underreported characteristic in PHTS guidelines. Furthermore, evidence supports the elevated risk of colorectal cancer in PHTS patients [34,76,85,89,90]. However, the association between PHTS and gastrointestinal malignancies is still a controversial subject [40,78,[91][92][93][94][95].…”

“…PHTS is associated with a high prevalence of breast, thyroid, and endometrial neoplasias, which are the primary complications of the disease [ 34 , 73 ]. The lifetime risk of developing breast cancer in women with PHTS ranges from 54.3 to 75.8% [ 34 ]. Hence, women with PHTS are recommended to self-examine their breasts and undergo regular mammography [ 13 ].…”

“…The International Cowden Syndrome Consortium (ICSC) [ 9 , 10 ] recommends surveillance for additional manifestations of PHTS and potentially related malignancies, as outlined in Table 2 . Patients suspected of having PHTS are at increased risk of cancers of the breast, thyroid, colon and rectum necessitating further investigation [ 34 ]. Furthermore, the American Gastroenterology Association recommends annual comprehensive physical examination, thyroid ultrasound screening beginning at the time of diagnosis, endometrial suction biopsy starting at the age 30–35 and colonoscopy screening beginning at 35 years of age or 5–10 years before the initial documented case of colon cancer in the family [ 35 ].…”