Agaoglu Nihat B, Bychkovsky Brittany L, Horton Carolyn, Lo Min-Tzu, Polfus Linda, Carraway Cassidy, Hemyari Parichehr, Young Colin, Richardson Marcy E, Scheib Rochelle, Garber Judy E, Rana Huma Q
Division of Cancer Genetics and Prevention, Dana-Farber Cancer Institute, Boston, MA.
Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.
Genet Med Open. 2024 Feb 14;2:101829. doi: 10.1016/j.gimo.2024.101829. eCollection 2024.
As panel testing expands, more individuals with double pathogenic variants (DPVs) in cancer susceptibility genes are likely to be identified. Little is known about the effects of DPVs on cancer phenotype, although this information is crucial for genetic counseling and risk management. We sought to describe the cancer phenotype among individuals with DPVs in cancer susceptibility genes.
A retrospective study of individuals with DPVs identified through a single testing laboratory from 2012 to 2017 was conducted. DPV combinations were enumerated. For DPV gene combinations that occurred >10 times, cancer histories of individuals with DPVs were compared with cancer histories of controls with a single PV matched by gene.
Among 644 individuals with DPVs, combinations that included the , , , , and genes occurred >10 times. There were 8883 matched controls for a single PV in these genes. The median age of first cancer diagnosis was younger with (43), compared with (47, = .016) or (47, = .015) alone. Similar findings were observed when comparing age at first breast cancer (BC) for the with single-gene controls. Individuals with 2 PVs also were younger at first cancer diagnosis (40) compared with single PV controls (47, = .0038). This difference was not driven by age at first BC diagnosis among females.
Individuals with + or 2 PVs have a greater cancer burden than single gene controls. These findings can be used to counsel individuals with DPVs and their families and inform cancer screening recommendations.
随着基因组合检测的扩大，可能会发现更多癌症易感基因中存在双致病变体（DPV）的个体。尽管这些信息对于遗传咨询和风险管理至关重要，但关于DPV对癌症表型的影响却知之甚少。我们试图描述癌症易感基因中存在DPV的个体的癌症表型。
对2012年至2017年通过单一检测实验室鉴定出的携带DPV的个体进行回顾性研究。列举了DPV组合。对于出现次数超过10次的DPV基因组合，将携带DPV的个体的癌症病史与基因匹配的单一致病变体（PV）对照的癌症病史进行比较。
在644例携带DPV的个体中，包含、、、和基因的组合出现次数超过10次。这些基因中单个PV有8883例匹配对照。首次癌症诊断的中位年龄，携带的个体（43岁）比单独携带（47岁，P = 0.016）或（47岁，P = 0.015）的个体更年轻。在比较携带与单基因对照的首次乳腺癌（BC）诊断年龄时也观察到类似结果。与单基因PV对照（47岁，P = 0.0038）相比，携带2个PV的个体首次癌症诊断时也更年轻（40岁）。这种差异不是由女性首次BC诊断年龄驱动的。
携带+或2个PV的个体比单基因对照有更大的癌症负担。这些发现可用于为携带DPV的个体及其家人提供咨询，并为癌症筛查建议提供参考。
