Quadri Marialuisa, Vetro Annalisa, Gismondi Viviana, Marabelli Monica, Bertario Lucio, Sala Paola, Varesco Liliana, Zuffardi Orsetta, Ranzani Guglielmina N
Department of Biology and Biotechnology, University of Pavia, Via Ferrata 1, 27100, Pavia, Italy.
Fam Cancer. 2015 Mar;14(1):41-9. doi: 10.1007/s10689-014-9750-3.
Familial adenomatous polyposis (FAP) is a dominantly inherited syndrome leading to the development of multiple intestinal polyps and colorectal cancer. FAP is associated with germline defects of APC tumor suppressor gene; although truncating mutations account for the majority of cases, large APC deletions represent a common disease-causing defect. While a number of intragenic deletions have been well-characterized, sequencing data of breakpoints involved in large APC rearrangements are extremely scanty. We characterized six deletions identified by multiplex ligation-dependent probe amplification (three intragenic and three larger deletions encompassing the APC locus): in each case, we precisely mapped the breakpoints by array-comparative genomic hybridization and/or long-range PCR followed by sequencing. All rearrangements were novel and no rearrangements proved to be recurrent or clustered. The three intragenic deletions involved exons 4, 9 and 14, respectively; larger deletions (30,444, 265,471 and 921,295 bp in length) involved APC as well as adjacent genes. Nine out of 12 breakpoints fell within repetitive elements (5 Alu, 2 LINE, 1 Tigger and 1 MIR), while the remaining 3 fell within unique sequences. In five out of six patients, non-allelic homologous recombination or non-homologous end joining appear as the most likely mechanisms behind APC rearrangements. Although a certain variability of clinical features was detectable both between and within families with deletions, all deletion carriers were classifiable as FAP patients showing colonic and extracolonic manifestations that belong to the spectrum of the syndrome. Therefore, different sized deletions, variable breakpoint localizations and haploinsufficiency for other genes besides APC, resulted in the same FAP clinical phenotype.
家族性腺瘤性息肉病（FAP）是一种常染色体显性遗传综合征，可导致多发性肠息肉和结直肠癌的发生。FAP与APC肿瘤抑制基因的种系缺陷相关；虽然截短突变占大多数病例，但APC大片段缺失是一种常见的致病缺陷。虽然一些基因内缺失已得到充分表征，但涉及APC大片段重排的断点测序数据却极为稀少。我们对通过多重连接依赖探针扩增鉴定出的6个缺失进行了表征（3个基因内缺失和3个包含APC基因座的更大缺失）：在每种情况下，我们通过阵列比较基因组杂交和/或长距离PCR随后测序精确绘制了断点。所有重排都是新发现的，没有重排被证明是反复出现或聚集的。3个基因内缺失分别涉及外显子4、9和14；更大的缺失（长度分别为30,444、265,471和921,295 bp）涉及APC以及相邻基因。12个断点中有9个位于重复元件内（5个Alu、2个LINE、1个Tigger和1个MIR），其余3个位于独特序列内。在6例患者中的5例中，非等位基因同源重组或非同源末端连接似乎是APC重排背后最可能的机制。虽然在有缺失的家族之间和家族内部都可检测到一定的临床特征变异性，但所有缺失携带者都可归类为FAP患者，表现出属于该综合征范围的结肠和结肠外表现。因此，不同大小的缺失、可变的断点定位以及除APC之外其他基因的单倍体不足，导致了相同的FAP临床表型。
