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Abstract：
BACKGROUND: Multigene panel testing by next-generation sequencing (MGP-NGS) enables the detection of germline pathogenic or likely pathogenic variants (PVs/LPVs) in genes beyond those associated with a certain cancer phenotype. Opportunistic genetic screening based on MGP-NGS in patients with suspicion of hereditary cancer reveals these incidental findings (IFs).
METHODS: MGP-NGS was performed in patients who fulfilled the clinical criteria to undergo genetic testing according to the Catalan Health Service guidelines. Variants were classified following the American College of Medical Genetics and Genomics-Association for Molecular Pathology guidelines and the Cancer Variant Interpretation Group UK guidelines.
RESULTS: IFs were identified in 10 (1.22%) of the 817 patients who underwent MGP-NGS. The mean age at cancer diagnosis was 49.4±9.5 years. Three IFs (30.0%) were detected in PMS2, two (20.0%) in ATM and TP53 and one (10.0%) in MSH6, NTHL1 and VHL. Seven (70.0%) IFs were single-nucleotide substitutions, two (20.0%) were deletions and one (10.0%) was a duplication. Three (30.0) IFs were located in intronic regions, three (30.3%) were nonsense, two (20.0%) were frameshift and two (20.0%) were missense variations. Six (60.0%) IFs were classified as PVs and four (40.0%) as LPVs.
CONCLUSIONS: Opportunistic genetic screening increased the diagnostic yield by 1.22% in our cohort. Most of the identified IFs were present in clinically actionable genes (n=7; 70.0%), providing these families with an opportunity to join cancer early detection programmes, as well as secondary cancer prevention. IFs might facilitate the diagnosis of asymptomatic individuals and the early management of cancer once it develops.
METHODS: MGP-NGS was performed in patients who fulfilled the clinical criteria to undergo genetic testing according to the Catalan Health Service guidelines. Variants were classified following the American College of Medical Genetics and Genomics-Association for Molecular Pathology guidelines and the Cancer Variant Interpretation Group UK guidelines.
RESULTS: IFs were identified in 10 (1.22%) of the 817 patients who underwent MGP-NGS. The mean age at cancer diagnosis was 49.4±9.5 years. Three IFs (30.0%) were detected in PMS2, two (20.0%) in ATM and TP53 and one (10.0%) in MSH6, NTHL1 and VHL. Seven (70.0%) IFs were single-nucleotide substitutions, two (20.0%) were deletions and one (10.0%) was a duplication. Three (30.0) IFs were located in intronic regions, three (30.3%) were nonsense, two (20.0%) were frameshift and two (20.0%) were missense variations. Six (60.0%) IFs were classified as PVs and four (40.0%) as LPVs.
CONCLUSIONS: Opportunistic genetic screening increased the diagnostic yield by 1.22% in our cohort. Most of the identified IFs were present in clinically actionable genes (n=7; 70.0%), providing these families with an opportunity to join cancer early detection programmes, as well as secondary cancer prevention. IFs might facilitate the diagnosis of asymptomatic individuals and the early management of cancer once it develops.
摘要：
背景：通过下一代测序（MGP-NGS）进行的多基因组测试能够检测与某些癌症表型相关的基因中的种系致病性或可能的致病性变体（PV/LPV）。在怀疑遗传性癌症的患者中，基于MGP-NGS的机会遗传筛查揭示了这些偶然发现（IFs）。
方法：MGP-NGS在符合根据加泰罗尼亚卫生服务指南进行基因检测的临床标准的患者中进行。根据美国医学遗传学和基因组学协会分子病理学指南和英国癌症变异解释小组指南对变异进行分类。
结果：在817例接受MGP-NGS治疗的患者中，有10例（1.22%）出现了IFs。癌症诊断的平均年龄为49.4±9.5岁。在PMS2中检测到三个IF（30.0％），在ATM和TP53中检测到两个（20.0％），在MSH6，NTHL1和VHL中检测到一个（10.0％）。七个(70.0%)IFs为单核苷酸取代，两个（20.0%）是缺失，一个（10.0%）是重复。三个(30.0个)IFs位于内含子区域，三个(30.3%)是胡说八道，两个（20.0％）是移码，两个（20.0％）是错义变异。六个（60.0％）IFs被分类为PV，四个（40.0％）被分类为LPV。
结论：在我们的队列中，机会遗传筛查使诊断率提高了1.22%。大多数已鉴定的IFs存在于临床可操作的基因中（n=7；70.0％），为这些家庭提供加入癌症早期检测计划的机会，以及二级癌症预防。一旦癌症发展，IFs可能有助于无症状个体的诊断和癌症的早期治疗。
方法：MGP-NGS在符合根据加泰罗尼亚卫生服务指南进行基因检测的临床标准的患者中进行。根据美国医学遗传学和基因组学协会分子病理学指南和英国癌症变异解释小组指南对变异进行分类。
结果：在817例接受MGP-NGS治疗的患者中，有10例（1.22%）出现了IFs。癌症诊断的平均年龄为49.4±9.5岁。在PMS2中检测到三个IF（30.0％），在ATM和TP53中检测到两个（20.0％），在MSH6，NTHL1和VHL中检测到一个（10.0％）。七个(70.0%)IFs为单核苷酸取代，两个（20.0%）是缺失，一个（10.0%）是重复。三个(30.0个)IFs位于内含子区域，三个(30.3%)是胡说八道，两个（20.0％）是移码，两个（20.0％）是错义变异。六个（60.0％）IFs被分类为PV，四个（40.0％）被分类为LPV。
结论：在我们的队列中，机会遗传筛查使诊断率提高了1.22%。大多数已鉴定的IFs存在于临床可操作的基因中（n=7；70.0％），为这些家庭提供加入癌症早期检测计划的机会，以及二级癌症预防。一旦癌症发展，IFs可能有助于无症状个体的诊断和癌症的早期治疗。
