Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, United States of America.
Department of Pathology, Case Western Reserve University, Cleveland, Ohio, United States of America.
PLoS Genet. 2018 Apr 23;14(4):e1007352. doi: 10.1371/journal.pgen.1007352. eCollection 2018 Apr.
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.
患有特征为种系 PTEN 突变的遗传性癌症综合征的患者（称为 PTEN 错构瘤肿瘤综合征，PHTS）受益于基于 PTEN 的癌症风险评估和临床管理。PTEN 野生型患者（约 50%）仍然存在发生某些癌症的风险增加。在这些患者中，尚未探讨其他已知癌症易感性基因的种系突变的存在，这对不同的医疗管理有影响。我们对无 PTEN 突变的具有 Cowden/Cowden 样（CS/CS 样）和 Bannayan-Riley-Ruvalcaba 综合征（BRRS）特征的新发患者进行了为期 4 年的多中心前瞻性研究。进行了外显子组测序和靶向分析，包括来自美国医学遗传学与基因组学学院（ACMG）的 59 种临床可操作基因和 24 种与遗传性癌症综合征相关的额外基因。在 87 名（8%）CS/CS 样和 BRRS 患者中的 7 名中发现了致病性或可能致病性的癌症易感性基因改变，包括 MUTYH、RET、TSC2、BRCA1、BRCA2、ERCC2 和 HRAS。我们在 7 名（71.4%）患者中的 5 名中发现了与确定基因相关的经典表型。与未发现变异的患者相比，变异阳性患者的第二恶性肿瘤存在更为丰富（OR=6.101，95%CI 1.143-35.98，p=0.035）。与 The Cancer Genome Atlas（TCGA）相比，我们还比较了种系变异谱和频率，包括 6 例与 PHTS 相关的明显散发性癌症。尽管总体种系变异的患病率相当，但与 TCGA 相比，我们患者的突变基因谱不同。有趣的是，我们还发现我们的患者中存在大量不确定意义的变异（VUS）的显著富集（OR=2.3，95%CI 1.5-3.5，p=0.0002）。我们的数据表明，仅一小部分 PTEN 野生型 CS/CS 样和 BRRS 患者可归因于某些已知癌症相关基因的种系变异。因此，存在其他更可能的非经典癌症相关基因的改变是合理的，反映了这些异质性遗传性癌症综合征的复杂性。
