Genotype-phenotype correlation in 99 familial adenomatous polyposis patients: A prospective prevention protocol
Genotype-phenotype correlation in 99 familial adenomatous polyposis patients: A prospective prevention protocol
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DOI：
10.1002/cam4.2098
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发表时间：
2019-05-01
期刊：
影响因子：
4
通讯作者：
Rossi, Benedito M.
中科院分区：
文献类型：
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作者：
de Oliveira, Junea C.;Viana, Danilo V.;Rossi, Benedito M.
背景家族性腺瘤性息肉病(FAP)是一种由抑癌基因腺瘤性息肉病(APC)的胚系致病变异引起的综合征。APC致病变异位点的鉴定和基因-表型的相关性对于确定、监测和治疗受影响家庭的成员非常重要。这项研究的目的是关联携带APC致病种系变异和FAP的巴西个体的基因型和表型。方法对2013年7月至2014年12月间35个家系99人的息肉表型进行前瞻性研究。评估了7种结肠外表现，其临床表现与APC基因相关。结果研究对象的年龄从12岁到67岁不等(中位数29岁)。共鉴定出26个APC致病变异体。55例存在无意义的致病变异体(55.6%)。移码改变39例(39.4%)。异常剪接1例(1%)。重排3例(3%)。1例(1%)发现无意义变异与重排有关。经基因-表型相关分析，94例(94.9%)为经典型FAP。5例(5.1%)出现大量息肉。确诊肿瘤36例，其中结直肠癌29例(80.6%)，脑癌1例(2.7%)，甲状腺乳头状癌4例(11.2%)，胃癌2例(5.5%)。结肠外表现包括硬纤维瘤9例，骨瘤10例，先天性视网膜色素上皮肥大9例。结论巴西FAP患者的基因型-表型相关性揭示了以前在其他队列中没有报道的特殊发现，表明不同人群中关于可变致病变异和临床表现的知识与对患有这种疾病的患者进行适当的个体化临床管理具有相关性。
Background Familial adenomatous polyposis (FAP) is a syndrome caused by germline pathogenic variants in the tumor suppressor gene adenomatous polyposis coli (APC). Identification of APC pathogenic variants sites and the genotype-phenotype correlation are important for characterizing, monitoring, and treating members of affected families. The aim of this study was to correlate genotype-phenotype of Brazilian individuals carrying APC pathogenic germline variants and that have FAP. Methods The polyposis phenotype of 99 individuals from 35 families between July 2013 and December 2014 were prospectively evaluated based on the InSIGHT polyposis staging classification. Seven extra-colonic manifestations were assessed and the clinical manifestations correlated with the APC genotype. Results The age of the study participants ranged from 12 to 67 years (median of 29 years). Twenty-six APC pathogenic variants were identified. Fifty-five cases harbored nonsense pathogenic variants (55.6%). Frameshift alterations were noted in 39 cases (39.4%). Aberrant splicing was noted in 1 case (1%). Rearrangements were observed in 3 cases (3%). An association between nonsense variants and rearrangement was noted in 1 case (1%). The genotype-phenotype correlation analysis led the identification of classic FAP in 94 cases (94.9%). Profuse polyposis was identified in 5 cases (5.1%). Thirty-six cases were diagnosed with cancer of which 29 cases (80.6%) were colorectal cancer, 1 case (2.7%) was brain cancer, 4 cases (11.2%) were papillary thyroid cancer, and 2 cases (5.5%) were stomach cancer. The extra-colonic manifestations included 9 individuals with desmoids tumors, 10 with osteomas, and 9 with congenital hypertrophy of the retinal pigment epithelium. Conclusions The genotype-phenotype correlation in Brazilian individuals with FAP revealed specific findings not previously reported for other cohorts, demonstrating the relevance of knowledge regarding the variable pathogenic variants and clinical presentation in different populations for adequate individual clinical management of patients harboring this medical condition.