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Abstract：
BACKGROUND: Pancreatic ductal adenocarcinoma (PDA) is a lethal cancer with complex genomes and dense fibrotic stroma. This study was designed to identify clinically relevant somatic aberrations in pancreatic cancer genomes of patients with primary and metastatic disease enrolled and treated in two clinical trials.
METHODS: Tumour nuclei were flow sorted prior to whole genome copy number variant (CNV) analysis. Targeted or whole exome sequencing was performed on most samples. We profiled biopsies from 68 patients enrolled in two Stand Up to Cancer (SU2C)-sponsored clinical trials. These included 38 resected chemoradiation naïve tumours (SU2C 20206-003) and metastases from 30 patients who progressed on prior therapies (SU2C 20206-001). Patient outcomes including progression-free survival (PFS) and overall survival (OS) were observed.
RESULTS: We defined: (a) CDKN2A homozygous deletions that included the adjacent MTAP gene, only its\' 3\' region, or excluded MTAP; (b) SMAD4 homozygous deletions that included ME2; (c) a pancreas-specific MYC super-enhancer region; (d) DNA repair-deficient genomes; and (e) copy number aberrations present in PDA patients with long-term (⩾ 40 months) and short-term (⩽ 12 months) survival after surgical resection.
CONCLUSIONS: We provide a clinically relevant framework for genomic drivers of PDA and for advancing novel treatments.
METHODS: Tumour nuclei were flow sorted prior to whole genome copy number variant (CNV) analysis. Targeted or whole exome sequencing was performed on most samples. We profiled biopsies from 68 patients enrolled in two Stand Up to Cancer (SU2C)-sponsored clinical trials. These included 38 resected chemoradiation naïve tumours (SU2C 20206-003) and metastases from 30 patients who progressed on prior therapies (SU2C 20206-001). Patient outcomes including progression-free survival (PFS) and overall survival (OS) were observed.
RESULTS: We defined: (a) CDKN2A homozygous deletions that included the adjacent MTAP gene, only its\' 3\' region, or excluded MTAP; (b) SMAD4 homozygous deletions that included ME2; (c) a pancreas-specific MYC super-enhancer region; (d) DNA repair-deficient genomes; and (e) copy number aberrations present in PDA patients with long-term (⩾ 40 months) and short-term (⩽ 12 months) survival after surgical resection.
CONCLUSIONS: We provide a clinically relevant framework for genomic drivers of PDA and for advancing novel treatments.
摘要：
背景：胰腺导管腺癌（PDA）是一种具有复杂基因组和致密纤维化基质的致死性癌症。这项研究旨在确定在两项临床试验中纳入和治疗的原发性和转移性疾病患者的胰腺癌基因组中临床相关的躯体畸变。
方法:在全基因组拷贝数变体(CNV)分析之前,对肿瘤细胞核进行流式分选。对大多数样品进行靶向或全外显子组测序。我们对来自两项癌症挺身而出（SU2C）赞助的临床试验中的68名患者的活检进行了分析。其中包括38例切除的化疗初治肿瘤（SU2C20206-003）和30例先前治疗进展的患者（SU2C20206-001）的转移。观察患者预后，包括无进展生存期（PFS）和总生存期（OS）。
结果：我们定义：（a）包含相邻MTAP基因的CDKN2A纯合缺失，只有它的\'3\'区域，或排除MTAP;(b)包括ME2的SMAD4纯合缺失;(c)胰腺特异性MYC超增强子区;(d)DNA修复缺陷型基因组;(e)手术切除后长期(40个月)和短期(12个月)生存的PDA患者存在拷贝数畸变。
结论：我们为PDA的基因组驱动因素和新的治疗方法提供了临床相关的框架。
方法:在全基因组拷贝数变体(CNV)分析之前,对肿瘤细胞核进行流式分选。对大多数样品进行靶向或全外显子组测序。我们对来自两项癌症挺身而出（SU2C）赞助的临床试验中的68名患者的活检进行了分析。其中包括38例切除的化疗初治肿瘤（SU2C20206-003）和30例先前治疗进展的患者（SU2C20206-001）的转移。观察患者预后，包括无进展生存期（PFS）和总生存期（OS）。
结果：我们定义：（a）包含相邻MTAP基因的CDKN2A纯合缺失，只有它的\'3\'区域，或排除MTAP;(b)包括ME2的SMAD4纯合缺失;(c)胰腺特异性MYC超增强子区;(d)DNA修复缺陷型基因组;(e)手术切除后长期(40个月)和短期(12个月)生存的PDA患者存在拷贝数畸变。
结论：我们为PDA的基因组驱动因素和新的治疗方法提供了临床相关的框架。
