BRCA1和BRCA2基因突变的携带者是乳腺癌高风险人群，但这些突变只涉及10%~15%遗传性乳腺癌，其他与遗传性乳腺癌有关的基因有待发现。3月9日，在第10届欧洲乳腺癌会议上（EBCC-10），香港大学临床医学副教授兼遗传性及高风险乳腺癌和卵巢癌项目主任AVA Kwong报告了一种中国乳腺癌高危人群的基因突变——RECQL突变。

　　AVA Kwong和她的团队对1114例香港遗传性乳癌家族资料库的患者进行了遗传检测。她们的家族史表明她们患乳腺癌的风险高，但他们的四个常见癌症基因突变（BRCA1和BRCA2、TP53、PTEN）检测均为阴性。

　　AVA Kwong指出：“我们决定检测RECQL突变，RECQL突变最近被确定与乳腺癌风险增加有关，我们发现，华南患者组的0.54%的女性有RECQL突变，北京患者组有2% 的RECQL突变。这种程度的发生率意味着RECQL突变足够重要，可纳入有乳腺癌家族史的中国妇女的基因检测项目。我们需要做进一步的工作，以确定其是否为始祖突变（founder mutations）。

　　当一个新成立的殖民地很小，它的始祖基因可强烈地影响到未来人口的遗传构成。例如，据了解德系犹太人有三个始祖BRCA突变。中国海外移民的规模提示，RECQL突变最可能普遍存在于亚洲以外国家。在2010年，生活在美国的中国人近350万人，在英国有40万以上。

　　在香港患者的研究组，我们确定了两个潜在的复发性突变，我们应开展更多工作确认其基因是始祖基因。”

　　目前，乳腺癌筛查引发越来越多的争议，能识别和筛选高风险妇女变得越来越重要。然而，在开发有效的筛选项目之前，我们应更好地理解这些基因突变的确切临床意义。当然，我们也应该注重可采取治疗和预防策略的突变。

　　RECQL突变与肝癌、胰腺癌和头颈癌的所有人群的预后不良相关，在本研究中，RECQL突变与患者家属的心血管疾病相关。

　　AVA Kwong： “然而，香港这组基因突变携带者的心血管疾病也很常见，这是另一个值得进一步研究的内容，目前的数字还不足以得出明确结论。我们不认为RECQL突变是中国人群特有的。因为RecQ与RECQL突变已在其他种族人群发现，比如RecQ与RECQL突变与乳腺癌的关系在波兰和魁北克人群中发现。我们以前针对其他乳腺癌相关突变的工作使我们相信，位点（loci）的确因种族不同而不同。我们BRCA 1和BRCA 2研究发现，中国研究组40%的BRCA突变是新突变。我们希望我们的工作能使高风险妇女的筛查方案更有针对性，并推动研发专门针对携带特定基因突变的患者的新药”

　　本次会议的主席、葡萄牙里斯本Champalimaud临床中心主任Fatima Cardos指出：“这是一项有趣的研究，如果能被进一步研究证实，可能会使RECQL突变加入有乳腺癌家庭史的高风险人群的乳腺癌基因筛查项目。”

研究摘要

RECQL as a novel breast cancer susceptibility gene in Chinese breast cancer patients

A. Kwong， J. Chen， I.W.Y. Cheuk， M.T. Siu， C.H. Au， F.B.F. Law， D.N. Ho， B.K. Ip， A.T.C. Wong， V.Y. Shin， T.L. Chan， E.S.K. Ma， S.A. Narod

Background: Breast cancer is the most common cancer in women worldwide and in Asia. High penetrance breast cancer susceptibility genes， BRCA1 and BRCA2， attributed to 10–15% of familial breast cancer. Other high penetrance genes， for example， TP53， PTEN and CDH1， also showed to be bona fide breast cancer susceptibility genes. Several moderate-and low-penetrance genes including ATM， CHEK2， PALB2， RAD50 have also been found to be associated with breast cancer risk and account for 5% of familial breast cancer. Recently， RECQL germline mutation has been identified to be associated with increased risk of breast cancer. However， the genetic contribution in the Chinese population remains undetermined.

Methods: A total of 1114 patients with breast cancer patients (BRCA， TP53 and PTEN negative) were selected from the Hong Kong Hereditary Breast Cancer Family Registry and underwent genetic testing for RECQL mutation. 88 normal controls were also included in the study. DNA was extracted from peripheral blood samples from patients and controls. RECQL full gene sequencing using targeted next generation sequencing was carried out by MiSeq (Illumina) and further validated by Sanger sequencing. Sequencing data were analyzed by our in-house developed fully automatic bioinformatics pipeline including BWA-MEM and variant callers， SAMtools and GATL.

Results: We have identified six germline RECQL mutations in this cohort. Interestingly， among these mutations， RECQL c.796C>T was identified in two unrelated families. 3 out of 6 mutations (50%) affect the splice donor consensus sequence. And one mutation (c.974_977delAAGA) is a small deletion. The mean age of diagnosis is 49.3 year old. Interestingly， more than one type of cancers， including hepatocellular carcinoma， colorectal cancer， lung cancer and prostate cancer， were reported in each family. Notably， there seemed to have an association with cardiovascular disease in 3 of the families.

Conclusions: RECQL germline mutations have been found in 0.5% of familial breast cancer patients who do not have detectable germline mutation of BRCA1， BRCA2， TP53 and PTEN in the Chinese population. Further studies are warranted to delineate the clinical application of including RECQL in the genetic testing panel， and its association with different cancers or cardiovascular disease.