Data_Sheet_2_External Replication of Urinary Bladder Cancer Prognostic Polymorphisms in the UK Biobank.PDF

Introduction: Multiple studies have reported genetic associations with prognostic outcomes of urinary bladder cancer. However, the lack of replication of these associations prohibits establishing further evidence-based research directions. Moreover, there is a lack of independent bladder cancer patient samples that contain prognostic measures, making genetic replication analyses even more challenging.
Materials and Methods: We have identified 1,534 eligible patients and used data on Hospital Episode Statistics in the UK Biobank to model variables of otherwise non-collected events on bladder cancer recurrence and progression. Data on survival was extracted from the Death Registry. We have used SNPTEST software to replicate previously reported genetic associations with bladder cancer recurrence (N = 69), progression (N = 23), survival (N = 53), and age at the time of diagnosis (N = 20).
Results: Using our algorithm, we have identified 618 recurrence and 58 UBC progression events. In total, there were 209 deaths (106 UBC-specific). In replication analyses, eight SNPs have reached nominal statistical significance (p < 0.05). Rs2042329 (CWC27) for UBC recurrence; rs804256, rs4639, and rs804276 (in/close to NEIL2) for NMIBC recurrence; rs2293347 (EGFR) for UBC OS; rs3756712 (PDCD6) for NMIBC OS; rs2344673 (RGS5) for MIBC OS, and rs2297518 (NOS2) for UBC progression. However, none have remained significant after adjustments for multiple comparisons.
Discussion: External replication in genetic epidemiology is an essential step to identify credible findings. In our study, we identify potential genetic targets of higher interest for UBC prognosis. In addition, we propose an algorithm for identifying UBC recurrence and progression using routinely-collected data on patient interventions.

## 引言
多项研究已报道膀胱癌预后结局与遗传变异存在关联。然而，此类关联缺乏重复验证，阻碍了后续循证研究方向的确立。此外，目前缺乏携带预后相关检测数据的独立膀胱癌患者样本，进一步加大了遗传重复分析的难度。

## 材料与方法
本研究纳入1534名符合条件的患者，依托英国生物银行（UK Biobank）的住院事件统计数据，对膀胱癌复发与进展这类原本未被直接采集的事件相关变量进行建模。生存相关数据提取自死亡登记系统。本研究使用SNPTEST软件，对既往报道的与膀胱癌复发（N=69）、进展（N=23）、生存（N=53）及诊断时年龄（N=20）相关的遗传关联开展重复验证。

## 结果
借助本研究开发的算法，共识别出618例复发事件与58例膀胱癌（Urinary Bladder Cancer，下文简称UBC）进展事件。本队列累计发生209例死亡，其中106例为UBC特异性死亡。在重复分析中，8个单核苷酸多态性（Single Nucleotide Polymorphism，SNP）位点达到名义统计学显著性（p<0.05）：分别为与UBC复发相关的Rs2042329（位于CWC27基因区域）；与非肌层浸润性膀胱癌（Non-Muscle Invasive Bladder Cancer，NMIBC）复发相关的rs804256、rs4639及rs804276（位于NEIL2基因内或邻近区域）；与UBC总生存期（Overall Survival，OS）相关的rs2293347（位于EGFR基因区域）；与NMIBC OS相关的rs3756712（位于PDCD6基因区域）；与肌层浸润性膀胱癌（Muscle Invasive Bladder Cancer，MIBC）OS相关的rs2344673（位于RGS5基因区域）；以及与UBC进展相关的rs2297518（位于NOS2基因区域）。但经多重比较校正后，所有位点均未达到统计学显著性阈值。

## 讨论
遗传流行病学研究中，外部重复验证是确认可靠研究结果的必要步骤。本研究筛选出若干与UBC预后相关的潜在高价值遗传靶点。此外，本研究还提出了一种依托患者常规诊疗干预数据，识别UBC复发与进展事件的算法模型。