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Abstract：
BACKGROUND: Esophageal carcinoma (EC) and gastric cardiac adenocarcinoma (GCA) have high incidence rates in the Chaoshan region of South China. Multifocal esophageal and cardiac cancer (MECC) is commonly observed in this region in clinical practice. However, the genomic characteristics of MECC remains unclear.
METHODS: In this study, a total of 2123 clinical samples of EC and GCA were analyzed to determine the frequency of multifocal tumors, as well as their occurrence sites and pathological types. Cox proportional hazards regression was used to model the relationship between age, sex, and tumor state concerning survival in our analysis of the cohort of 541 patients with available follow-up data. We performed whole-genome sequencing on 20 tumor foci and 10 normal samples from 10 MECC patients to infer clonal structure on 6 MECC patients to explore genome characteristics.
RESULTS: The MECC rate of EC and GCA was 5.65% (121 of 2123). Age and sex were potential factors that may influence the risk of MECC (p < 0.001). Furthermore, MECC patients showed worse survival compared with single tumor patients. We found that 12 foci from 6 patients were multicentric origin model (MC), which exhibited significant heterogeneity of variations in paired foci and had an increased number of germline mutations in immune genes compared to metastatic model. In MC cases, different lesions in the same patient were driven by distinct mutation and copy number variation (CNV) events. Although TP53 and other driver mutation genes have a high frequency in the samples, their mutation sites show significant heterogeneity in paired tumor specimens. On the other hand, CNV genes exhibited higher concordance in paired samples, especially in the amplification of oncogenes and the deletion of tumor suppressor genes.
CONCLUSIONS: The extent of inter-tumor heterogeneity suggests both monoclonal and polyclonal origins of MECC, which could provide insight into the genome diversity of MECC and guide clinical implementation.
METHODS: In this study, a total of 2123 clinical samples of EC and GCA were analyzed to determine the frequency of multifocal tumors, as well as their occurrence sites and pathological types. Cox proportional hazards regression was used to model the relationship between age, sex, and tumor state concerning survival in our analysis of the cohort of 541 patients with available follow-up data. We performed whole-genome sequencing on 20 tumor foci and 10 normal samples from 10 MECC patients to infer clonal structure on 6 MECC patients to explore genome characteristics.
RESULTS: The MECC rate of EC and GCA was 5.65% (121 of 2123). Age and sex were potential factors that may influence the risk of MECC (p < 0.001). Furthermore, MECC patients showed worse survival compared with single tumor patients. We found that 12 foci from 6 patients were multicentric origin model (MC), which exhibited significant heterogeneity of variations in paired foci and had an increased number of germline mutations in immune genes compared to metastatic model. In MC cases, different lesions in the same patient were driven by distinct mutation and copy number variation (CNV) events. Although TP53 and other driver mutation genes have a high frequency in the samples, their mutation sites show significant heterogeneity in paired tumor specimens. On the other hand, CNV genes exhibited higher concordance in paired samples, especially in the amplification of oncogenes and the deletion of tumor suppressor genes.
CONCLUSIONS: The extent of inter-tumor heterogeneity suggests both monoclonal and polyclonal origins of MECC, which could provide insight into the genome diversity of MECC and guide clinical implementation.
摘要：
背景：食管癌和贲门腺癌在中国南方潮汕地区发病率较高。多灶性食管癌和贲门癌（MECC）在临床实践中通常在该地区观察到。然而,MECC的基因组特征仍不清楚.
方法：在本研究中，总共分析了2123例EC和GCA的临床样本，以确定多灶性肿瘤的频率，以及它们的发生部位和病理类型。Cox比例风险回归用于建立年龄之间的关系模型，性别,在我们对541例患者队列的分析中，肿瘤状态与生存有关，有可用的随访数据。我们对10例MECC患者的20个肿瘤病灶和10个正常样本进行了全基因组测序，以推断6例MECC患者的克隆结构，以探索基因组特征。
结果：EC和GCA的MECC率为5.65％（2123中的121）。年龄和性别是可能影响MECC风险的潜在因素(p<0.001)。此外，与单肿瘤患者相比，MECC患者的生存率较差。我们发现6例患者的12个病灶是多中心起源模型(MC)，与转移模型相比，其在成对病灶中表现出明显的异质性，并且免疫基因中的种系突变数量增加。在MC案例中，同一患者的不同病变由不同的突变和拷贝数变异(CNV)事件驱动.尽管TP53和其他驱动突变基因在样本中的频率很高，它们的突变位点在配对肿瘤标本中显示出显著的异质性.另一方面,CNV基因在配对样本中表现出更高的一致性，特别是在癌基因的扩增和抑癌基因的缺失方面。
结论：肿瘤间异质性的程度表明MECC的单克隆和多克隆起源，这可以深入了解MECC的基因组多样性并指导临床实施。
方法：在本研究中，总共分析了2123例EC和GCA的临床样本，以确定多灶性肿瘤的频率，以及它们的发生部位和病理类型。Cox比例风险回归用于建立年龄之间的关系模型，性别,在我们对541例患者队列的分析中，肿瘤状态与生存有关，有可用的随访数据。我们对10例MECC患者的20个肿瘤病灶和10个正常样本进行了全基因组测序，以推断6例MECC患者的克隆结构，以探索基因组特征。
结果：EC和GCA的MECC率为5.65％（2123中的121）。年龄和性别是可能影响MECC风险的潜在因素(p<0.001)。此外，与单肿瘤患者相比，MECC患者的生存率较差。我们发现6例患者的12个病灶是多中心起源模型(MC)，与转移模型相比，其在成对病灶中表现出明显的异质性，并且免疫基因中的种系突变数量增加。在MC案例中，同一患者的不同病变由不同的突变和拷贝数变异(CNV)事件驱动.尽管TP53和其他驱动突变基因在样本中的频率很高，它们的突变位点在配对肿瘤标本中显示出显著的异质性.另一方面,CNV基因在配对样本中表现出更高的一致性，特别是在癌基因的扩增和抑癌基因的缺失方面。
结论：肿瘤间异质性的程度表明MECC的单克隆和多克隆起源，这可以深入了解MECC的基因组多样性并指导临床实施。
