Dominguez-Valentin Mev, Evans D Gareth R, Nakken Sigve, Tubeuf Hélène, Vodak Daniel, Ekstrøm Per Olaf, Nissen Anke M, Morak Monika, Holinski-Feder Elke, Martins Alexandra, Møller Pål, Hovig Eivind
1Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.
2Department of Genetic Medicine, The University of Manchester, Manchester Academic Health Science Centre, St. Mary's Hospital, Manchester, UK.
Hered Cancer Clin Pract. 2018 Jan 15;16:4. doi: 10.1186/s13053-018-0086-0. eCollection 2018.
In kindreds carrying variants, some women in these families will develop cancer despite testing negative for the family's pathogenic variant. These families may have additional genetic variants, which not only may increase the susceptibility of the families' but also be capable of causing cancer in the absence of the variants. We aimed to identify novel genetic variants in prospectively detected breast cancer (BC) or gynecological cancer cases tested negative for their families' pathogenic variant ( or ).
Women with BC or gynecological cancer who had tested negative for or variants were included. Forty-four cancer susceptibility genes were screened for genetic variation through a targeted amplicon-based sequencing assay. Protein- and RNA splicing-dedicated in silico analyses were performed for all variants of unknown significance (VUS). Variants predicted as the ones most likely affecting pre-mRNA splicing were experimentally analyzed in a minigene assay.
We identified 48 women who were tested negative for their family's ( = 13) or ( = 35) variants. Pathogenic variants in the and genes were found in 10% (5/48) of the cases, of whom 15% (2/13) were from and 9% (3/35) from families. Out of the 26 unique VUS, 3 (12%) were predicted to affect RNA splicing ( c.721G > A, c.764A > G and c.815C > T). However, by using a minigene, assay we here show that c.721G > A does not cause a splicing defect, similarly to what has been recently reported for the c.764A > G. The c.815C > T was previously described as causing partial exon skipping and it was identified in this work together with the c.9382C > T (p.R3128X).
All women in breast or breast/ovarian cancer kindreds would benefit from being offered genetic testing irrespective of which causative genetic variants have been demonstrated in their relatives.
在携带特定变异的家族中，尽管一些女性针对家族致病变异检测呈阴性，但这些家族中的部分女性仍会患癌。这些家族可能存在其他遗传变异，这不仅可能增加家族成员的易感性，而且在不存在特定变异的情况下也可能引发癌症。我们旨在在前瞻性检测的乳腺癌（BC）或妇科癌症病例中识别新的遗传变异，这些病例针对家族致病变异（特定基因或其他基因）检测呈阴性。
纳入针对特定基因或其他基因变异检测呈阴性的BC或妇科癌症女性患者。通过基于靶向扩增子的测序分析，对44个癌症易感基因进行遗传变异筛查。对所有意义未明的变异（VUS）进行蛋白质和RNA剪接专用的计算机分析。对预测最有可能影响前体mRNA剪接的变异，在微型基因分析中进行实验分析。
我们鉴定出48名女性，她们针对家族特定基因（特定基因1，n = 13）或其他基因（特定基因2，n = 35）变异检测呈阴性。在10%（5/48）的病例中发现特定基因1和特定基因2中的致病变异，其中15%（2/13）来自特定基因1家族，9%（3/35）来自特定基因2家族。在26个独特的VUS中，3个（12%）被预测会影响RNA剪接（特定基因1的c.721G>A、特定基因2的c.764A>G和特定基因3的c.815C>T）。然而，通过微型基因分析，我们在此表明，与最近报道的特定基因2的c.764A>G情况类似，特定基因1的c.
