East Anglian Medical Genetics Service, Cambridge University Hospitals NHS Trust, Cambridge, UK.
Academic Department of Medical Genetics, NIHR Cambridge Biomedical Research Centre, University of Cambridge, Box 238, Level 6 Addenbrooke's Treatment Centre, Cambridge Biomedical Campus, Cambridge, CB2 0QQ, UK.
Breast Cancer Res Treat. 2019 Apr;174(3):553-560. doi: 10.1007/s10549-018-05096-6. Epub 2019 Jan 4.
The identification of new hereditary breast cancer genes is an area of highly active research. In 2015, two independent studies provided initial evidence for a novel breast cancer susceptibility gene, RECQL, a DNA helicase which plays an important role in the DNA damage response. Several subsequent studies in independent patient cohorts have provided further data on RECQL variant frequency in additional populations, some of which have brought in to question the increased breast cancer risk associated with RECQL mutations.
The initial reports present findings from whole exome sequencing of high-risk familial breast cancer cases in the French-Canadian, Polish and Han Chinese populations and estimate the carrier frequency of pathogenic RECQL mutations in high-risk breast cancer patients who have previously tested negative for BRCA1 and BRCA2 mutations to be approximately 1-2%. Proposed founder mutations were identified in French-Canadian and Polish populations. Functional studies support loss of function of the helicase activity of RECQL for some of the reported pathogenic mutations. An additional study in a cohort of Southern Chinese high-risk breast cancer patients estimated the frequency of pathogenic RECQL mutations to be 0.54%. A possible Chinese founder mutation was identified, but only a small number of controls were sequenced. Subsequent case-control studies screening for the Polish founder mutation in patients from Germany and Belarus did not find any evidence for increased breast cancer risk for this variant. An Australian case-control study also failed to identify an increased risk of breast cancer associated with RECQL loss of function variants.
RECQL plays an important role in DNA repair, and is a plausible candidate breast cancer susceptibility gene. Initial studies showed evidence of an association between variants in this gene and an increased breast cancer risk in three separate populations, and identified founder mutations with significantly increased odds ratios. However, several subsequent studies have failed to support the association. With the limited and conflicting evidence available, there remains debate as to whether there is an increased breast cancer risk in individuals carrying RECQL loss of function variants. Further studies are required to better quantify the risks associated with RECQL variants and the current evidence base is not sufficient to justify routine inclusion of RECQL on breast cancer gene panels in clinical use. Management of patients in whom RECQL variants have been identified should be based on clinician assessment, in the context of the family history. Further studies are required to better quantify the risks to RECQL mutation carriers and may also guide management and potential therapeutic targeting for patients.
新的遗传性乳腺癌基因的鉴定是一个非常活跃的研究领域。2015 年，两项独立的研究为一种新的乳腺癌易感基因 RECQL 提供了初步证据，RECQL 是一种 DNA 解旋酶，在 DNA 损伤反应中发挥重要作用。随后在独立的患者队列中进行的几项研究提供了更多关于 RECQL 变异在其他人群中的频率的数据，其中一些研究对与 RECQL 突变相关的乳腺癌风险增加提出了质疑。
最初的报告介绍了在法裔加拿大、波兰和汉族高危家族性乳腺癌病例的全外显子组测序结果，并估计先前 BRCA1 和 BRCA2 突变检测阴性的高危乳腺癌患者中致病性 RECQL 突变的携带者频率约为 1-2%。在法裔加拿大和波兰人群中发现了假定的起始突变。功能研究支持报告的一些致病性突变导致解旋酶活性丧失。在中国南部高危乳腺癌患者队列中的一项额外研究估计，致病性 RECQL 突变的频率为 0.54%。鉴定出一个可能的中国起始突变，但仅对少数对照进行了测序。随后在德国和白俄罗斯的患者中筛查波兰起始突变的病例对照研究没有发现该变体与乳腺癌风险增加有关的任何证据。一项澳大利亚病例对照研究也未能确定 RECQL 功能缺失变异与乳腺癌风险增加相关。
RECQL 在 DNA 修复中发挥重要作用，是一个合理的乳腺癌易感基因候选基因。最初的研究表明，该基因中的变异与三个不同人群中的乳腺癌风险增加之间存在关联，并确定了起始突变，其优势比显著增加。然而，随后的几项研究未能支持这种关联。由于现有证据有限且存在争议，携带 RECQL 功能缺失变异的个体是否存在乳腺癌风险增加仍存在争议。需要进一步的研究来更好地量化与 RECQL 变异相关的风险，并且目前的证据基础不足以证明在临床使用中常规将 RECQL 纳入乳腺癌基因面板是合理的。在临床实践中，应根据家族史，由临床医生对 RECQL 变异患者进行评估并进行管理。需要进一步的研究来更好地量化 RECQL 突变携带者的风险，也可能为患者的管理和潜在治疗靶向提供指导。
