对家族性胰腺癌家族的候选基因进行全面分析，揭示了高频率的潜在致病性种系变异。
A comprehensive analysis of candidate genes in familial pancreatic cancer families reveals a high frequency of potentially pathogenic germline variants.
机构信息
Molecular Epidemiology and Predictive Tumor Markers Group, Medical Oncology Research Laboratory, Ramón y Cajal Health Research Institute (IRYCIS), Carretera Colmenar Km 9100, 28034 Madrid, Spain; Biomedical Research Network in Cancer (CIBERONC), C/Monforte de Lemos 3-5, Pabellón 11, 28029 Madrid, Spain.
Molecular Epidemiology and Predictive Tumor Markers Group, Medical Oncology Research Laboratory, Ramón y Cajal Health Research Institute (IRYCIS), Carretera Colmenar Km 9100, 28034 Madrid, Spain; Biomedical Research Network in Cancer (CIBERONC), C/Monforte de Lemos 3-5, Pabellón 11, 28029 Madrid, Spain.
出版信息
EBioMedicine. 2020 Mar;53:102675. doi: 10.1016/j.ebiom.2020.102675. Epub 2020 Feb 27.
BACKGROUND
The 5-year survival rate of patients with pancreatic ductal adenocarcinoma (PDAC) is around 5% due to the fact that the majority of patients present with advanced disease that is treatment resistant. Familial pancreatic cancer (FPC) is a rare disorder that is defined as a family with at least two affected first degree relatives, with an estimated incidence of 4%-10%. The genetic basis is unknown in the majority of families although around 10%-13% of families carry germline mutations in known genes associated with hereditary cancer and pancreatitis syndromes.
METHODS
Panel sequencing was performed of 35 genes associated with hereditary cancer in 43 PDAC cases from families with an apparent hereditary pancreatic cancer syndrome.
FINDINGS
Pathogenic variants were identified in 19% (5/26) of PDAC cases from pure FPC families in the genes MLH1, CDKN2A, POLQ and FANCM. Low frequency potentially pathogenic VUS were also identified in 35% (9/26) of PDAC cases from FPC families in the genes FANCC, MLH1, PMS2, CFTR, APC and MUTYH. Furthermore, an important proportion of PDAC cases harboured more than one pathogenic, likely pathogenic or potentially pathogenic VUS, highlighting the multigene phenotype of FPC.
INTERPRETATION
The genetic basis of familial or hereditary pancreatic cancer can be explained in 21% of families by previously described hereditary cancer genes. Low frequency variants in other DNA repair genes are also present in 35% of families which may contribute to the risk of pancreatic cancer development.
FUNDING
This study was funded by the Instituto de Salud Carlos III (Plan Estatal de I + D + i 2013-2016): ISCIII (PI09/02221, PI12/01635, PI15/02101 and PI18/1034) and co-financed by the European Development Regional Fund ''A way to achieve Europe'' (ERDF), the Biomedical Research Network in Cancer: CIBERONC (CB16/12/00446), Red Temática de investigación cooperativa en cáncer: RTICC (RD12/0036/0073) and La Asociación Española contra el Cáncer: AECC (Grupos Coordinados Estables 2016).
背景
由于大多数患者患有治疗抵抗的晚期疾病，胰腺导管腺癌（PDAC）患者的 5 年生存率约为 5%。家族性胰腺癌（FPC）是一种罕见的疾病，其定义为至少有两个受影响的一级亲属的家族，估计发病率为 4%-10%。尽管大约 10%-13%的家族携带与遗传性癌症和胰腺炎综合征相关的已知基因中的种系突变，但大多数家族的遗传基础尚不清楚。
方法
对来自具有明显遗传性胰腺癌综合征的家族的 43 例 PDAC 病例中的 35 个与遗传性癌症相关的基因进行了面板测序。
结果
在纯 FPC 家族的 26 例 PDAC 病例中，有 19%（5/26）的病例发现 MLH1、CDKN2A、POLQ 和 FANCM 基因中有致病性变异。在 FPC 家族的 26 例 PDAC 病例中，有 35%（9/26）的病例还发现了低频潜在致病性 VUS ，这些 VUS 存在于 FANCC、MLH1、PMS2、CFTR、APC 和 MUTYH 基因中。此外，相当一部分 PDAC 病例携带一个以上的致病性、可能致病性或潜在致病性 VUS，突出了 FPC 的多基因表型。
解释
通过先前描述的遗传性癌症基因，可以解释 21%的家族的家族性或遗传性胰腺癌的遗传基础。其他 DNA 修复基因中的低频变异也存在于 35%的家族中，这可能导致胰腺癌的发展风险增加。
资金
本研究由西班牙卡洛斯三世健康研究所（2013-2016 年国家研究、发展和创新计划）资助：ISCIII（PI09/02221、PI12/01635、PI15/02101 和 PI18/1034），并由欧洲发展区域基金“通往欧洲之路”共同资助（ERDF），肿瘤生物医学研究网络：CIBERONC（CB16/12/00446），合作式癌症研究主题网络：RTICC（RD12/0036/0073）和西班牙癌症协会：AECC（2016 年稳定协调组）。
Zotero 插件