如果没有治疗,家族性腺瘤性息肉病(FAP)患者在一生中不可避免地会发展为结直肠癌(CRC)。然而,手术创伤是硬纤维瘤(DT)的高风险,FAP患者死亡的主要原因之一。到目前为止,结肠切除术的时机主要基于临床医生的经验和患者的偏好;大多数患者在20岁左右接受手术。在这项研究中,我们分析了来自不同家庭的35例FAP患者的种系突变分布,其中16人被诊断为DTs。我们还研究了分子改变与临床病理特征之间的关联。使用一组520个基因对肿瘤组织和来自最初诊断为CRC的18个FAP先证者的配对正常粘膜或白细胞进行基于捕获的靶向测序。在所有35名FAP患者中,其中30个(85.7%)具有从密码子161到1578散布的种系APC突变。16位DT患者的突变从密码子457分散到1578。所有三名在1444密码子的3'处具有突变的患者均被诊断为DT。在1062或1062-1578的5\'处具有突变的高风险DT(III或IV期)的百分比分别为14.3%和77.8%,分别,并且所有3例具有1399个密码子突变的患者均具有高风险。此外,通过使用公共数据库,我们在莱顿开放变异数据库中将140例接受DT的FAP患者与所有1880例FAP患者进行了比较,发现在密码子159和495中DT的奇数比率为0.34,而在密码子1310和2011中DT的奇数比率为2.36.与零星的CRC相比,FAPCRC的体细胞谱与早发性CRC相似,具有较高的TP53(94.1%)和较低的体细胞APC突变(65.7%),但KRAS突变率最高(58.5%)。18个FAPCRC中的一个被确定为微卫星不稳定性高(MSI-H),肿瘤突变负荷(TMB)为115.65mut/Mb。鉴于在低级和高级腺瘤中未检测到TP53突变,ctDNATP53测序可用于FAP结肠切除术前的密切监测。总之,除了APC的5'末端的突变(5'至495),所有FAP患者都需要考虑结肠切除术后DT的风险.威胁生命的DTs的机会在3'1062密码子突变的患者中更高,而在3'1399密码子突变的患者中达到峰值。TP53ctDNA的计划监控被认为是优化操作时间的新颖工具。
Without treatment, familial adenomatous polyposis (FAP) patients will inevitably develop colorectal cancer (CRC) during lifetime. Yet, surgical trauma is a high risk of
desmoid tumor (DT), one of the main causes of death in FAP patients. So far, the timing for colectomy is primarily based on the clinician\'s experience and the patient\'s preference; most patients undergo surgery at mid-20\'s. In this
study, we analyzed the germline mutation distribution in 35 FAP patients from different families, 16 of them diagnosed with DTs. We also investigated the association between the molecular alterations and the clinicopathological features. Capture-based targeted sequencing using a panel of 520 genes was performed on tumor tissue and paired normal mucosa or white blood cells from 18 FAP probands who were initially diagnosed with CRC. Of all 35 FAP patients, 30 (85.7%) of them harbored germline APC mutations scattered from codon 161 to 1578. The mutations in the 16 DT patients scattered from codon 457 to 1578. All three patients with the mutation at the 3\' of 1444 codon were diagnosed with DT. The percentage of high-risk DT (stage III or IV) harboring mutations at the 5\' of 1062 or 1062-1578 was 14.3% and 77.8%, respectively, and all three patients with 3\' of 1399 codon mutation had high risk. In addition, by using public database, we compared 140 FAP patients with DT to all 1880 FAP patients on the Leiden Open Variation Database and found that the odd ratio of DT in codon 159 to 495 was 0.34, while in codon 1310 to 2011 was 2.36. Compared to sporadic CRCs, the somatic spectrum of FAP CRCs was similar to the early onset CRCs, with higher TP53 (94.1%) and lower somatic APC mutations (65.7%), but the KRAS mutation rate was the highest (58.5%). One of the 18 FAP CRCs was identified as microsatellite instability-high (MSI-H), with tumor mutation burden (TMB) of 115.65 mut/Mb. Given that no TP53 mutations were detected in the low- and high-grade adenomas, ctDNA TP53 sequencing might be used for the close monitoring before FAP colectomy. In conclusion, except mutations at the 5\' end of APC (5\' to 495), all FAP patients need to consider the risk of DT after colectomy. The chance of life-threating DTs was higher in patients with 3\' 1062 codon mutation and peaked in patients with 3\' 1399 codon mutation. Scheduled monitoring of TP53 ctDNA is proposed to be a novel tool for optimizing the operation time.