Oncogenetics Department, Barretos Cancer Hospital, Barretos, SP, Brazil.
Biostatistics Department, Barretos Cancer Hospital, Barretos, SP, Brazil.
Cancer Med. 2019 May;8(5):2114-2122. doi: 10.1002/cam4.2098. Epub 2019 Mar 21.
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.
背景：家族性腺瘤性息肉病（FAP）是一种由腺瘤性结肠息肉病基因（APC）的种系致病性变异引起的综合征。确定 APC 致病性变异位点和基因型-表型相关性对于描述、监测和治疗受影响家族的成员非常重要。本研究的目的是分析携带 APC 种系致病性变异且患有 FAP 的巴西个体的基因型-表型相关性。
方法：2013 年 7 月至 2014 年 12 月期间，前瞻性评估了 35 个家族的 99 名个体的息肉病表型，依据 InSIGHT 息肉病分期分类。评估了 7 种结外表现，并将临床表现与 APC 基因型相关联。
结果：研究参与者的年龄为 12 至 67 岁（中位数为 29 岁）。鉴定出 26 种 APC 致病性变异。55 例存在无义致病性变异（55.6%）。39 例存在移码改变（39.4%）。1 例存在异常剪接（1%）。3 例存在重排（3%）。1 例观察到无义变异和重排之间的关联（1%）。基因型-表型相关性分析确定 94 例（94.9%）为经典 FAP。5 例（5.1%）为多发息肉。36 例诊断为癌症，其中 29 例（80.6%）为结直肠癌，1 例（2.7%）为脑癌，4 例（11.2%）为甲状腺乳头癌，2 例（5.5%）为胃癌。结外表现包括 9 例硬纤维瘤，10 例骨瘤和 9 例先天性视网膜色素上皮肥厚。
结论：巴西 FAP 患者的基因型-表型相关性揭示了特定的发现，这些发现以前在其他队列中没有报道过，证明了在不同人群中了解不同致病性变异和临床表现的重要性，以便对携带这种疾病的患者进行适当的个体化临床管理。
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