Parkville Familial Cancer Centre, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, Victoria, Australia.
Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
J Med Genet. 2023 Feb;60(2):112-118. doi: 10.1136/jmedgenet-2021-108399. Epub 2022 Apr 8.
is the most important contributor to familial breast cancer after and . Large genomic rearrangements (LGRs) in and are routinely assessed in clinical testing and are a significant contributor to the yield of actionable findings. In contrast, the contribution of LGRs in has not been systematically studied.
We performed targeted sequencing and real-time qPCR validation to identify LGRs in in 5770 unrelated patients with familial breast cancer and 5741 cancer-free control women from the same Australian population.
Seven large deletions ranging in size from 0.96 kbp to 18.07 kbp involving were identified in seven cases, while no LGRs were identified in any of the controls. Six LGRs were considered pathogenic as they included one or more exons of and disrupted the WD40 domain at the C terminal end of the PALB2 protein while one LGR only involved a partial region of intron 10 and was considered a variant of unknown significance. Altogether, pathogenic LGRs identified in this study accounted for 10.3% (6 of 58) of the pathogenic variants detected among the 5770 families with familial breast cancer.
Our data show that a clinically important proportion of pathogenic mutations in Australian patients with familial breast cancer are LGRs. Such observations have provided strong support for inclusion of LGRs in routine clinical genetic testing.
在 BRCA1 和 BRCA2 之后， 是家族性乳腺癌最重要的贡献者。BRCA1 和 BRCA2 中的大片段基因重排（LGRs）在临床检测中通常进行评估，是产生可操作发现的重要因素。相比之下， 中 LGRs 的贡献尚未得到系统研究。
我们对来自同一澳大利亚人群的 5770 名患有家族性乳腺癌的无关联患者和 5741 名无癌症对照女性进行了靶向测序和实时 qPCR 验证，以鉴定 LGRs 在 中的情况。
在 7 例患者中鉴定出了 7 个大小从 0.96 kbp 到 18.07 kbp 不等的 大片段缺失，而在任何对照中均未鉴定出 LGRs。6 个 LGRs 被认为是致病性的，因为它们包含一个或多个 的外显子，并破坏了 PALB2 蛋白 C 末端的 WD40 结构域，而一个 LGR 仅涉及内含子 10 的部分区域，被认为是意义不明的变异。总的来说，在这项研究中鉴定出的致病性 LGRs 占 5770 个家族性乳腺癌家庭中检测到的致病性 变异的 10.3%（6 个中的 6 个）。
我们的数据表明，在澳大利亚患有家族性乳腺癌的患者中，BRCA1 和 BRCA2 中的致病性突变中有相当大的比例是 LGRs。这些观察结果为将 LGRs 纳入常规临床遗传检测提供了有力支持。
