Eid Michal, Trizuljak Jakub, Taslerova Renata, Gryc Martin, Vlazny Jakub, Vilmanova Sara, Jelinkova Martina, Homolova Alena, Tucek Stepan, Hlavsa Jan, Grolich Tomas, Kala Zdenek, Kral Zdenek, Slaby Ondrej
Department of Internal Medicine, Hematology and Oncology, University Hospital Brno, Faculty of Medicine, Masaryk University, Brno, Czech Republic.
Department of Pathology, University Hospital Brno, Faculty of Medicine, Masaryk University, Brno, Czech Republic.
Mutagenesis. 2025 Mar 15;40(1):20-29. doi: 10.1093/mutage/geae014.
Multidisciplinary molecular tumor boards (MTB) are already well established in many comprehensive cancer centers and play an important role in the individual treatment planning for cancer patients. Comprehensive genomic profiling of tumor tissue based on next-generation sequencing is currently performed for diagnostic and mainly predictive testing. If somatic genomic variants are identified, which are suspected to be pathogenic germline variants (PGVs), MTB propose genetic counseling and germline DNA testing. Commonly used comprehensive genomic profiling approaches of tumor tissue do not include a matched germline DNA control. Therefore, the detection of PGVs could be only predicted based on the content of tumor cells (CTC) in selected tumor area (%) and variant allele frequency score (%). For conclusion, the role of a medical geneticist is essential in these cases. The overall prevalence of PGVs in patients with pancreatic ductal adenocarcinoma (PDAC) and colorectal cancer (CRC) is approximately 10%. In this single-center study, we present 37 patients with PDAC and 48 patients with CRC who were presented at MTB and tested using the large combined DNA/RNA sequencing panel. Content of tumor cells and variant allele frequency scores were evaluated in all tested patients. In case of suspicion of PGV and no previous genetic testing based on the standard guidelines, genetic counseling was recommended regardless of age, sex, and family history. In the PDAC subgroup, five patients were recommended by MTB for genetic counseling based on suspicious genetic findings. Based on a medical geneticist's decision, germline DNA sequencing was performed in four of these cases, and all of them tested positive for PGV in the following genes: ATM, ATM, BRCA1, and BRCA2. In the CRC subgroup, no PGV was confirmed in the two patients genetically tested based on the MTB recommendations. Furthermore, we present data from our center's registry of patients with PDAC and CRC who underwent genetic counseling and germline DNA testing based on the standard screening criteria. Our data confirm that comprehensive genomic profiling of tumor tissue can identify patients with hereditary forms of PDAC, who could remain unidentified by standard screening for hereditary forms of cancer.
多学科分子肿瘤委员会（MTB）在许多综合癌症中心已得到充分确立，并在癌症患者的个体化治疗规划中发挥着重要作用。基于下一代测序的肿瘤组织综合基因组分析目前用于诊断，主要是预测性检测。如果识别出体细胞基因组变异，怀疑其为致病性种系变异（PGV），MTB会建议进行遗传咨询和种系DNA检测。常用的肿瘤组织综合基因组分析方法不包括匹配的种系DNA对照。因此，只能根据选定肿瘤区域中肿瘤细胞的含量（%）和变异等位基因频率评分（%）来预测PGV的检测。总之，在这些情况下，医学遗传学家的作用至关重要。胰腺导管腺癌（PDAC）和结直肠癌（CRC）患者中PGV的总体患病率约为10%。在这项单中心研究中，我们介绍了37例PDAC患者和48例CRC患者，他们在MTB接受评估并使用大型联合DNA/RNA测序面板进行检测。对所有检测患者的肿瘤细胞含量和变异等位基因频率评分进行了评估。如果怀疑有PGV且此前未根据标准指南进行基因检测，则无论年龄、性别和家族史如何，均建议进行遗传咨询。在PDAC亚组中，MTB根据可疑的基因发现建议5例患者进行遗传咨询。根据医学遗传学家的决定，其中4例进行了种系DNA测序，所有这些患者在以下基因中PGV检测均呈阳性：ATM、BRCA1和BRCA2。在CRC亚组中，根据MTB建议进行基因检测的2例患者未确认有PGV。此外，我们还展示了来自我们中心PDAC和CRC患者登记处的数据，这些患者根据标准筛查标准接受了遗传咨询和种系DNA检测。我们的数据证实，肿瘤组织的综合基因组分析可以识别出遗传性PDAC患者，而这些患者可能无法通过遗传性癌症的标准筛查被发现。
