Arcand Suzanna L, Akbari Mohammed R, Mes-Masson Anne-Marie, Provencher Diane, Foulkes William D, Narod Steven A, Tonin Patricia N
Cancer Research Program, The Research Institute of the McGill University Health Centre, 1001 Decarie Boulevard, E02.6217, Montreal, Quebec, H4A 3J1, Canada.
Women's College Research Institute, Women's College Hospital, and University of Toronto, Toronto, Ontario, Canada.
BMC Med Genet. 2015 Apr 12;16:24. doi: 10.1186/s12881-015-0169-y.
Specific germline mutations in the hereditary breast-ovarian cancer susceptibility (HBC/HBOC) genes, BRCA1, BRCA2 and PALB2, have been shown to recur in French Canadians of Quebec, Canada, and this has been attributed to common ancestors. Germline TP53 mutation carriers are known to segregate in Li-Fraumeni syndrome families, which feature young age of onset breast cancer. We have reported rare TP53 mutation carriers in French Canadian HBC families, though none recurred possibly due to the limited number of cancer families investigated. Here we describe TP53 germline mutations found in French Canadian cancer families provided from hereditary cancer clinics; investigate 37 new BRCA1 and BRCA2 mutation-negative HBC/HBOC families for the TP53 mutations; and assess the frequency of TP53 mutations in a 1235 French Canadian breast cancer cases not selected for family history of cancer.
TP53 mutation-positive pedigrees from French Canadian cancer families were provided from local hereditary cancer clinics. Bidirectional Sanger sequencing of all protein encoding exons of TP53 was performed using peripheral blood lymphocyte DNA from breast/ovarian cancer probands from 37 HBC/HBOC families of French Canadian descent. Targeted bidirectional Sanger sequencing assay of regions containing the identified TP53 mutations was performed on 1235 French Canadian breast cancer cases not selected for family history cancer.
Five new TP53 mutations were identified in six pedigrees from hereditary cancer clinics. No deleterious mutations were identified in cancer probands from 37 HBC/HBOC families. A targeted mutation screen of the 1235 breast cancer cases identified a c.844C>T [p.Arg282Trp] mutation carrier. This mutation was also found among the six mutation-positive cancer families provided by the local hereditary cancer clinics. The targeted screen also uncovered a new TP53 mutation, c.685T>C [p.Cys229Arg] that was found in two breast cancer cases. All TP53 mutation carriers were among the 656 women with breast cancer diagnosed less than 50 years of age.
In all six new TP53 mutations were identified in French Canadians, where two each occurred in independently ascertained cases/families. Although all newly identified breast cancer mutation carriers reported a family history of cancer, none were consistent with features of Li-Fraumeni syndrome families.
遗传性乳腺癌-卵巢癌易感性（HBC/HBOC）基因BRCA1、BRCA2和PALB2中的特定种系突变，在加拿大魁北克的法裔加拿大人中已被证明会反复出现，这归因于共同祖先。已知种系TP53突变携带者在李-弗劳梅尼综合征家族中呈分离状态，这些家族的特点是乳腺癌发病年龄较小。我们曾报道在法裔加拿大HBC家族中有罕见的TP53突变携带者，不过由于所调查的癌症家族数量有限，没有出现重复的情况。在此，我们描述了从遗传性癌症诊所获得的法裔加拿大癌症家族中发现的TP53种系突变；对37个新的BRCA1和BRCA2突变阴性的HBC/HBOC家族进行TP53突变检测；并评估1235例未因癌症家族史而被选择的法裔加拿大乳腺癌病例中TP53突变的频率。
从当地遗传性癌症诊所获得法裔加拿大癌症家族中TP53突变阳性的家系。使用来自37个法裔加拿大血统的HBC/HBOC家族的乳腺癌/卵巢癌先证者的外周血淋巴细胞DNA，对TP53的所有蛋白质编码外显子进行双向桑格测序。对1235例未因癌症家族史而被选择的法裔加拿大乳腺癌病例，进行包含已鉴定的TP53突变区域的靶向双向桑格测序分析。
在遗传性癌症诊所的6个家系中鉴定出5个新的TP53突变。在37个HBC/HBOC家族的癌症先证者中未鉴定出有害突变。对1235例乳腺癌病例的靶向突变筛查发现一名c.844C>T [p.Arg282Trp]突变携带者。在当地遗传性癌症诊所提供的6个突变阳性癌症家族中也发现了该突变。靶向筛查还发现了一个新的TP53突变，c.685T>C [p.Cys229Arg]，在2例乳腺癌病例中发现。所有TP53突变携带者均在656名年龄小于50岁被诊断为乳腺癌的女性中。
在法裔加拿大人中总共鉴定出6个新TP53突变，其中两个分别出现在独立确定的病例/家族中。尽管所有新鉴定出的乳腺癌突变携带者都报告有癌症家族史，但均不符合李-弗劳梅尼综合征家族的特征。
