家族性非髓样甲状腺癌(FNMTC)是一种内分泌恶性肿瘤,表现出常染色体显性遗传模式,种系分子机制未知。遗传性非息肉病性结直肠癌综合征(HNPCC)是另一种遗传性常染色体显性遗传癌症综合征,如果证明是由错配修复基因(MMR)-MLHL中的种系突变引起的,MSH2、MSH6、PMS2和EPCAM被称为Lynch综合征(LS)。LS导致多种癌症的遗传易感性,尤其是结直肠癌和子宫内膜癌。LS中的肿瘤的特征在于微卫星不稳定性(MSI)和/或免疫组织化学(IHC)中MMR蛋白表达的丧失。MSI是甲状腺癌(TC)的罕见事件,尽管已知在高达2.5%的散发性滤泡性TC病例中发生。关于种系MMR变体FNMTC的作用的数据有限。这项研究的目的是分析HNPCC和FNMTC之间潜在的临床和分子关联。我们进行了一项队列研究,分析人口统计学,临床,和43个家族的病理数据,包括383名参与者(104名受影响,279未受影响),FNMTC的年龄为43.5[7-99]岁,并对选定的168名参与者(54名受FNMTC影响,114名未受影响)的外周血DNA样本进行了高通量全外显子组测序(WES).每个家庭受甲状腺癌成员影响的总人数在2至9名患者之间。FNMTC在女性中更为普遍(68.3%),其特征是中位肿瘤大小为1.0[0.2-5.0]cm,多灶性增长44%,甲状腺外的总延伸为11.3%。40.3%的患者在就诊时发现中央颈部淋巴结转移,12.9%表现为颈外侧淋巴结转移,没有远处转移。家族史筛查显示一个高加索家庭符合FNMTC和HNPCC的临床标准,5名成员受FNMTC影响,至少8名未受HNPCC相关肿瘤影响。此外,两名家庭成员受到黑色素瘤的影响.基因组分析工具试剂盒(GATK)流水线用于变体分析。在168名测序参与者中,MSH2基因中的杂合错义变体(rs373226409;c.2120G>A;p.Cys707Tyr)仅在FNMTC-HNPCB-家族中检测到。在这个家庭里,在一名受FNMTC影响的成员中进行测序,HPNCC相关肿瘤和黑色素瘤,一名成员仅受HNPCC相关肿瘤影响,和只有FNMTC的一名成员,以及七个未受影响的家庭成员。该变体存在于所有三个受影响的成年人中,以及受影响成员的两个未受影响的孩子,未满18岁,并且在未受影响的成年人中缺席。预测该变体在17/20计算机模型中具有破坏性/致病性。然而,在受FNMTC家族成员影响的两个甲状腺肿瘤组织上进行的免疫染色显示MSH2的完整核表达,并且在测试的两个肿瘤中都处于微卫星稳定状态。尽管MSH2p.Cys707Tyr变体在高加索人中很少见,其次要等位基因频率(MAF)为0.00006;在南亚人群中更常见,为0.003MAF。因此,在该家族中观察到的MSH2变异不太可能是甲状腺癌的病因因素,FNMTC和HNPCC之间的共同遗传关联尚未确定.这是我们已知的关于FNMTC和HNPCC共现的第一份报告。FNMTC和HNPCC相关肿瘤的同时发生是罕见的事件,尽管在我们的大型FNMTC队列中出现在单个家族中,无法确定两种合并症之间的共同遗传背景。
Familial non-medullary thyroid cancer (FNMTC) is a form of endocrine malignancy exhibiting an autosomal dominant mode of inheritance with largely unknown germline molecular mechanism. Hereditary nonpolyposis colorectal cancer syndrome (HNPCC) is another hereditary autosomal dominant cancer syndrome which, if proven to be caused by germline mutations in mismatch repair genes (MMR)-MLHL, MSH2, MSH6, PMS2, and EPCAM-is called Lynch syndrome (LS). LS results in hereditary predisposition to a number of cancers, especially colorectal and endometrial cancers. Tumors in LS are characterized by microsatellite instability (MSI) and/or loss of MMR protein expression in immunohistochemistry (IHC). MSI is a rare event in thyroid cancer (TC), although it is known to occur in up to 2.5% of sporadic follicular TC cases. There are limited data on the role of germline MMR variants FNMTC. The goal of this study was to analyze the potential clinical and molecular association between HNPCC and FNMTC. We performed a cohort study analyzing the demographic, clinical, and pathologic data of 43 kindreds encompassing 383 participants (104 affected, 279 unaffected), aged 43.5 [7-99] years with FNMTC, and performed high-throughput whole-exome sequencing (WES) of peripheral blood DNA samples of selected 168 participants (54 affected by FNMTC and 114 unaffected). Total affected by thyroid cancer members per family ranged between 2 and 9 patients. FNMTC was more prevalent in women (68.3%) and characterized by a median tumor size of 1.0 [0.2-5.0] cm, multifocal growth in 44%, and gross extrathyroidal extension in 11.3%. Central neck lymph node metastases were found in 40.3% of patients at presentation, 12.9% presented with lateral neck lymph node metastases, and none had distant metastases. Family history screening revealed one Caucasian family meeting the clinical criteria for FNMTC and HNPCC, with five members affected by FNMTC and at least eight individuals reportedly unaffected by HNPCC-associated tumors. In addition, two family members were affected by melanoma. Genome Analysis Tool Kit (GATK) pipeline was used in variant analysis. Among 168 sequenced participants, a heterozygous missense variant in the MSH2 gene (rs373226409; c.2120G>A; p.Cys707Tyr) was detected exclusively in FNMTC- HNPCC- kindred. In this family, the sequencing was performed in one member affected by FNMTC, HPNCC-associated tumors and melanoma, one member affected solely by HNPCC-associated tumor, and one member with FNMTC only, as well as seven unaffected family members. The variant was present in all three affected adults, and in two unaffected children of the affected member, under the age of 18 years, and was absent in non-affected adults. This variant is predicted to be damaging/pathogenic in 17/20 in-silico models. However, immunostaining performed on the thyroid tumor tissue of two affected by FNMTC family members revealed intact nuclear expression of MSH2, and microsatellite stable status in both tumors that were tested. Although the MSH2 p.Cys707Tyr variant is rare with a minor allele frequency (MAF) of 0.00006 in Caucasians; it is more common in the South Asian population at 0.003 MAF. Therefore, the MSH2 variant observed in this family is unlikely to be an etiologic factor of thyroid cancer and a common genetic association between FNMTC and HNPCC has not yet been identified. This is the first report known to us on the co-occurrence of FNMTC and HNPCC. The co-occurrence of FNMTC and HNPCC-associated tumors is a rare event and although presented in a single family in our large FNMTC cohort, a common genetic background between the two comorbidities could not be established.