Unexpected cancer-predisposition gene variants in Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome patients without underlying germline PTEN mutations

摘要

Patients with heritable cancer syndromes characterized by germline PTEN mutations (termed PTEN hamartoma tumor syndrome, PHTS) benefit from PTEN -enabled cancer risk assessment and clinical management. PTEN- wildtype patients (~50%) remain at increased risk of developing certain cancers. Existence of germline mutations in other known cancer susceptibility genes has not been explored in these patients, with implications for different medical management. We conducted a 4-year multicenter prospective study of incident patients with features of Cowden/Cowden-like (CS/CS-like) and Bannayan-Riley-Ruvalcaba syndromes (BRRS) without PTEN mutations. Exome sequencing and targeted analysis were performed including 59 clinically actionable genes from the American College of Medical Genetics and Genomics (ACMG) and 24 additional genes associated with inherited cancer syndromes. Pathogenic or likely pathogenic cancer susceptibility gene alterations were found in 7 of the 87 (8%) CS/CS-like and BRRS patients and included MUTYH , RET , TSC2 , BRCA1 , BRCA2 , ERCC2 and HRAS . We found classic phenotypes associated with the identified genes in 5 of the 7 (71.4%) patients. Variant positive patients were enriched for the presence of second malignant neoplasms compared to patients without identified variants (OR = 6.101, 95% CI 1.143–35.98, p = 0.035). Germline variant spectrum and frequencies were compared to The Cancer Genome Atlas (TCGA), including 6 apparently sporadic cancers associated with PHTS. With comparable overall prevalence of germline variants, the spectrum of mutated genes was different in our patients compared to TCGA. Intriguingly, we also found notable enrichment of variants of uncertain significance (VUS) in our patients (OR = 2.3, 95% CI 1.5–3.5, p = 0.0002). Our data suggest that only a small subset of PTEN- wildtype CS/CS-like and BRRS patients could be accounted for by germline variants in some of the known cancer-related genes. Thus, the existence of alterations in other and more likely non-classic cancer-associated genes is plausible, reflecting the complexity of these heterogeneous hereditary cancer syndromes. Author summary In the US, there are 12 million individuals living with heritable cancer, with its burden of morbidity and mortality. Heritable cancers occur when an individual is born with particular genetic errors (germline mutations). Because many germline mutations are known to cause specific cancers, knowing which patient has mutations in what gene allows for the practice of preventative, proactive, rather than reactive, medicine. However, the challenge is that many patients with classic symptoms test negative for mutations in genes known to be associated with the diagnosed clinical syndrome. This is true for Cowden (CS) and Bannayan-Riley-Ruvalcaba (BRRS) syndromes, whereby only a subset of patients have germline mutations in PTEN . Due to advances in biomedical research, we now know that there are multiple cancer-related genes besides PTEN . Importantly, these genes had not been examined in CS and BRRS patients. Here, we identify such variants in 8% of these patients, with the majority showing clinical features known to be associated with the mutated genes. These findings suggest potentially different clinical management, guided by the specific genes identified. More importantly, the remaining patients who tested negative for the known studied cancer-associated genes suggest yet-to-be discovered genes responsible for CS/BRRS.