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Abstract：
BACKGROUND: Ampullary adenocarcinoma (AMPAC) is a rare malignancy, treated as pancreatic or intestinal cancer based on its histologic subtype. Little is known about the genomic features of Chinese patients with AMPAC.
METHODS: We enrolled 145 Chinese AMPAC patients in our local cohort and performed a compressive somatic and germline genetic testing using a 156 gene panel. Expression of PD-L1 (clone 28 - 8) was also assessed in tumor specimens from 64 patients.
RESULTS: The frequency of genetic alterations (GAs) in Chinese patients with AMPAC was found to be distinctive, with TP53, KRAS, SMAD4, APC, CTNNB1, ARID1A, and CDKN2A emerged as the most frequently mutated genes. Comparing with Western patients, significant differences were observed in the prevalence of PIK3CA and ARID2. Furthermore, the incidence of MSI-H was lower in the Chinese cohort, with only two patients identified as MSI-H. Conversely, 11 patients (8.27%) had pathogenic/likely pathogenic germline alterations, all of which were in the DNA damage response (DDR) pathway. In our cohort, 34.48% (22/64) of patients exhibited positive PD-L1 expression in tumor cells, and this expression was associated with GAs in CTNNB1 and BLM. Importantly, over three-fourths of Chinese AMPAC patients in our study had at least one actionable GA, with more than one-fifth of them having actionable GAs classified as Level 3. These actionable GAs were primarily involved in the DDR and PI3K pathways. Notably, GAs in the DDR pathway were detected in both Chinese and Western patients, and regardless of their functional impact, these alterations demonstrated enhanced overall survival rates and higher tumor mutational burden (TMB) levels.
CONCLUSIONS: These findings underscore the distinct genomic landscape of Chinese AMPAC patients and highlight the potential for targeted therapies based on the identified GAs.
METHODS: We enrolled 145 Chinese AMPAC patients in our local cohort and performed a compressive somatic and germline genetic testing using a 156 gene panel. Expression of PD-L1 (clone 28 - 8) was also assessed in tumor specimens from 64 patients.
RESULTS: The frequency of genetic alterations (GAs) in Chinese patients with AMPAC was found to be distinctive, with TP53, KRAS, SMAD4, APC, CTNNB1, ARID1A, and CDKN2A emerged as the most frequently mutated genes. Comparing with Western patients, significant differences were observed in the prevalence of PIK3CA and ARID2. Furthermore, the incidence of MSI-H was lower in the Chinese cohort, with only two patients identified as MSI-H. Conversely, 11 patients (8.27%) had pathogenic/likely pathogenic germline alterations, all of which were in the DNA damage response (DDR) pathway. In our cohort, 34.48% (22/64) of patients exhibited positive PD-L1 expression in tumor cells, and this expression was associated with GAs in CTNNB1 and BLM. Importantly, over three-fourths of Chinese AMPAC patients in our study had at least one actionable GA, with more than one-fifth of them having actionable GAs classified as Level 3. These actionable GAs were primarily involved in the DDR and PI3K pathways. Notably, GAs in the DDR pathway were detected in both Chinese and Western patients, and regardless of their functional impact, these alterations demonstrated enhanced overall survival rates and higher tumor mutational burden (TMB) levels.
CONCLUSIONS: These findings underscore the distinct genomic landscape of Chinese AMPAC patients and highlight the potential for targeted therapies based on the identified GAs.
摘要：
背景：壶腹腺癌（AMPAC）是一种罕见的恶性肿瘤，根据其组织学亚型被视为胰腺癌或肠癌。关于中国AMPAC患者的基因组特征知之甚少。
方法：我们在当地队列中招募了145名中国AMPAC患者，并使用156个基因组进行了压缩体细胞和种系遗传检测。还在来自64名患者的肿瘤样本中评估了PD-L1(克隆28-8)的表达。
结果：发现中国AMPAC患者的遗传改变（GAs）频率是独特的，TP53，KRAS，SMAD4,APC,CTNNB1,ARID1A,CDKN2A是最常见的突变基因。与西方患者相比，观察到PIK3CA和ARID2的患病率存在显著差异.此外，MSI-H在中国队列中的发病率较低，只有两名患者被确定为MSI-H。相反，11例患者（8.27%）有致病性/可能致病性种系改变，所有这些都是在DNA损伤反应（DDR）途径。在我们的队列中，34.48%(22/64)的患者在肿瘤细胞中PD-L1阳性表达,这种表达与CTNNB1和BLM中的GAs相关。重要的是,在我们的研究中，超过四分之三的中国AMPAC患者至少有一个可操作的GA，超过五分之一的人有可操作的GAs被归类为3级。这些可操作的GA主要参与DDR和PI3K途径。值得注意的是,在中国和西方患者中都检测到DDR通路中的GAs，不管它们的功能影响如何，这些改变表明总生存率提高,肿瘤突变负荷(TMB)水平提高.
结论：这些发现强调了中国AMPAC患者独特的基因组景观，并强调了基于已确定的GA的靶向治疗的潜力。
方法：我们在当地队列中招募了145名中国AMPAC患者，并使用156个基因组进行了压缩体细胞和种系遗传检测。还在来自64名患者的肿瘤样本中评估了PD-L1(克隆28-8)的表达。
结果：发现中国AMPAC患者的遗传改变（GAs）频率是独特的，TP53，KRAS，SMAD4,APC,CTNNB1,ARID1A,CDKN2A是最常见的突变基因。与西方患者相比，观察到PIK3CA和ARID2的患病率存在显著差异.此外，MSI-H在中国队列中的发病率较低，只有两名患者被确定为MSI-H。相反，11例患者（8.27%）有致病性/可能致病性种系改变，所有这些都是在DNA损伤反应（DDR）途径。在我们的队列中，34.48%(22/64)的患者在肿瘤细胞中PD-L1阳性表达,这种表达与CTNNB1和BLM中的GAs相关。重要的是,在我们的研究中，超过四分之三的中国AMPAC患者至少有一个可操作的GA，超过五分之一的人有可操作的GAs被归类为3级。这些可操作的GA主要参与DDR和PI3K途径。值得注意的是,在中国和西方患者中都检测到DDR通路中的GAs，不管它们的功能影响如何，这些改变表明总生存率提高,肿瘤突变负荷(TMB)水平提高.
结论：这些发现强调了中国AMPAC患者独特的基因组景观，并强调了基于已确定的GA的靶向治疗的潜力。
