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Abstract：
OBJECTIVE: The objective of this study was to assess the frequency of potential germline pathogenic variants that may contribute to risk of development of adult granulosa cell tumors (AGCT) given the paucity of germline testing guidelines for these patients.
METHODS: This was a retrospective cross-sectional study analyzing comprehensive genomic profiling (CGP) results of AGCT with the FOXL2 p.C134W mutation submitted to Foundation Medicine between 2012 and 2022. Cases with a potential germline pathogenic variant were identified by filtering single nucleotide variants and short indels by variant allele frequency (VAF) and presence in ClinVar for select cancer susceptibility genes. Odds ratios for AGCT risk were calculated compared to a healthy population.
RESULTS: Prior to analysis, 595 patients were screened and 516 with a somatic FOXL2 p.C134W mutation were included. Potential germline pathogenic variants in a DNA repair-related gene (ATM, BRCA1, BRCA2, CHEK2, PALB2, PMS2, RAD51C, or RAD51D) were found in 6.6% of FOXL2-mutated AGCT. Potential germline pathogenic CHEK2 variants were found in 3.5% (18/516) of AGCT patients, a rate that was 2.8-fold higher than Genome Aggregation Database non-cancer subjects (95% CI 1.8-4.6, p < 0.001). The founder variants p.I157T (38.9%, 7/18) and p.T367fs*15 (c.1100delC; 27.8%, 5/18) were most commonly observed. CHEK2 VAF indicated frequent loss of the wildtype copy of the gene.
CONCLUSIONS: These results support ongoing utilization of genomic tumor profiling and confirmatory germline testing for potential germline pathogenic variants. Further prospective investigation into the biology of germline variants in this population is warranted.
METHODS: This was a retrospective cross-sectional study analyzing comprehensive genomic profiling (CGP) results of AGCT with the FOXL2 p.C134W mutation submitted to Foundation Medicine between 2012 and 2022. Cases with a potential germline pathogenic variant were identified by filtering single nucleotide variants and short indels by variant allele frequency (VAF) and presence in ClinVar for select cancer susceptibility genes. Odds ratios for AGCT risk were calculated compared to a healthy population.
RESULTS: Prior to analysis, 595 patients were screened and 516 with a somatic FOXL2 p.C134W mutation were included. Potential germline pathogenic variants in a DNA repair-related gene (ATM, BRCA1, BRCA2, CHEK2, PALB2, PMS2, RAD51C, or RAD51D) were found in 6.6% of FOXL2-mutated AGCT. Potential germline pathogenic CHEK2 variants were found in 3.5% (18/516) of AGCT patients, a rate that was 2.8-fold higher than Genome Aggregation Database non-cancer subjects (95% CI 1.8-4.6, p < 0.001). The founder variants p.I157T (38.9%, 7/18) and p.T367fs*15 (c.1100delC; 27.8%, 5/18) were most commonly observed. CHEK2 VAF indicated frequent loss of the wildtype copy of the gene.
CONCLUSIONS: These results support ongoing utilization of genomic tumor profiling and confirmatory germline testing for potential germline pathogenic variants. Further prospective investigation into the biology of germline variants in this population is warranted.
摘要：
目的：本研究的目的是评估可能导致成人颗粒细胞瘤（AGCT）发展风险的潜在种系致病变异的频率，因为这些患者缺乏种系检测指南。
方法：这是一项回顾性的横断面研究，分析了2012年至2022年提交给FoundationMedicine的具有FOXL2p.C134W突变的AGCT的综合基因组分析（CGP）结果。通过根据变异等位基因频率（VAF）和ClinVar中的存在过滤单核苷酸变异和短插入缺失来鉴定具有潜在种系致病性变异的病例，以选择癌症易感基因。与健康人群相比，计算了AGCT风险的几率。
结果：在分析之前，筛选了595例患者，其中包括516例体细胞FOXL2p.C134W突变。DNA修复相关基因（ATM，BRCA1,BRCA2,CHEK2,PALB2,PMS2,RAD51C,或RAD51D）在6.6%的FOXL2突变的AGCT中发现。在3.5%（18/516）的AGCT患者中发现了潜在的种系致病性CHEK2变异，该比率比基因组聚集数据库非癌症受试者高2.8倍(95%CI1.8-4.6,p<0.001)。创始人变体p.I157T(38.9%，7/18）和p.T367fs*15（c.1100delC；27.8%，5/18）是最常见的观察到的。CHEK2VAF表明该基因的野生型拷贝频繁丢失。
结论：这些结果支持正在进行的基因组肿瘤分析和验证性种系检测，用于潜在的种系致病变异。有必要对该人群中种系变异的生物学进行进一步的前瞻性研究。
方法：这是一项回顾性的横断面研究，分析了2012年至2022年提交给FoundationMedicine的具有FOXL2p.C134W突变的AGCT的综合基因组分析（CGP）结果。通过根据变异等位基因频率（VAF）和ClinVar中的存在过滤单核苷酸变异和短插入缺失来鉴定具有潜在种系致病性变异的病例，以选择癌症易感基因。与健康人群相比，计算了AGCT风险的几率。
结果：在分析之前，筛选了595例患者，其中包括516例体细胞FOXL2p.C134W突变。DNA修复相关基因（ATM，BRCA1,BRCA2,CHEK2,PALB2,PMS2,RAD51C,或RAD51D）在6.6%的FOXL2突变的AGCT中发现。在3.5%（18/516）的AGCT患者中发现了潜在的种系致病性CHEK2变异，该比率比基因组聚集数据库非癌症受试者高2.8倍(95%CI1.8-4.6,p<0.001)。创始人变体p.I157T(38.9%，7/18）和p.T367fs*15（c.1100delC；27.8%，5/18）是最常见的观察到的。CHEK2VAF表明该基因的野生型拷贝频繁丢失。
结论：这些结果支持正在进行的基因组肿瘤分析和验证性种系检测，用于潜在的种系致病变异。有必要对该人群中种系变异的生物学进行进一步的前瞻性研究。
