Cancer risk and genotype–phenotype correlations in PTEN hamartoma tumor syndrome

Abstract

Patients with germline PTEN mutations are at high risk of developing benign and malignant tumours. We aimed to evaluate the cumulative risk of several types of cancer and of dysplastic cerebellar gangliocytoma (Lhermitte-Duclos disease, LDD). In addition, genotype-phenotype correlations in PTEN hamartoma tumour syndrome (PHTS) were assessed. Data on patients with PTEN mutations were collected from clinical genetic centres in Western Europe, Australia, and the USA. The cumulative risk of developing cancers of the breast, thyroid, endometrium, skin, kidneys, colorectum, and lungs, and also LDD was calculated by Kaplan-Meier methods. Associations between mutations and cancer were assessed by Chi square means. A total of 180 germline PTEN mutation carriers, 81 males (45%), from nine countries were included. The cumulative risk of developing any cancer and/or LDD at age 60 was 56% for males and 87% for females (p = 0.001). Females had significant higher risks of developing breast cancer, thyroid cancer, and LDD than males. The only genotype-phenotype correlation identified was a lower frequency of thyroid cancer in patients with missense mutations (p = 0.014). In conclusion, PHTS patients, particularly females, have a substantial risk of developing one or more tumours from a broad tumour spectrum. Major genotype-phenotype associations could not be identified.

Esophageal cancer in a family with hamartomatous tumors and germline PTEN frameshift and SMAD7 missense mutations

“…[6] The same registry reported a higher incidence of colorectal cancer among patients with PTEN frameshift mutations compared to missense or promoter mutations, while another registry reported lower rates of thyroid cancer in missense mutation patients. [7,10] The present family demonstrates clinical features consistent with these genotype-phenotype correlations, with thyroid cancer occurring in Patient II-2, and prominent colonic involvement in both affected patients. Although DNA from Parents I-1 and I-2 was not available for analysis, as they are alive and reportedly without symptoms, we speculate that the PTEN mutation arose de novo in Patient II-2.…”

“…[2–5] The autosomal-dominant and highly-penetrant PHTS conditions are characterized by a broad range of manifestations including macrocephaly, skin abnormalities, neurologic problems, and hamartomatous or ganglioneuromatous gastrointestinal polyposis. [6,7] Harmartomatous polyps of the stomach and colorectum define the related but distinct autosomal-dominant Juvenile Polyposis Syndrome (JPS), which results from germline mutations of SMAD4 or BMPR1A disrupting signaling through the bone morphogenetic protein (BMP)/SMAD4 pathway. [8,9]…”

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

“…There are no conclusively established genotype-cancer phenotype correlations (10). However, individuals with missense pathogenic variants in the PTEN gene may have a lower risk of thyroid cancer than other mutation types (11).…”

PTEN hamartoma tumour syndrome: early tumour development in children

“…Breast and thyroid carcinoma are found more frequently in adult patients with PHTS than in the general population 3. The cumulative cancer risk for all cancers seems to be higher in women with PHTS than in men (87% vs 56%) even when excluding female-only cancers 4. Children with PHTS often manifest macrocephaly, variable degrees of developmental delay/intellectual disability, autism spectrum disorders, pigmented penile macules in males, vascular anomalies and intestinal hamartomatous polyps 5.…”

“…A few studies have suggested that patients with missense PTEN mutations may have a lower risk of thyroid carcinoma,4 those with mutations in the promoter of the gene may have a higher risk of breast cancer3 and those with non-sense PTEN mutations may be at an increased risk of colorectal cancer, although these observations have not been confirmed.…”