Hereditary pancreatitis and the risk of pancreatic cancer
Hereditary pancreatitis and the risk of pancreatic cancer
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DOI：
10.1093/jnci/89.6.442
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发表时间：
1997-03-19
期刊：
影响因子：
--
通讯作者：
Elias, E
中科院分区：
文献类型：
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作者：
Lowenfels, AB;Maisonneuve, P;Elias, E
背景：遗传性胰腺炎是一种常染色体显性遗传疾病，表现多样，估计发病率为80%。这种疾病的基因最近被定位在染色体7 q35上，这种缺陷被认为是由阳离子胰蛋白酶原基因突变引起的。腹痛的急性发作开始在生命的早期，疾病往往进展为慢性胰腺炎。虽然胰腺癌的风险被认为在更常见的慢性胰腺炎类型中增加，但胰腺癌在遗传性胰腺炎类型中的频率尚不确定。目的：本研究的目的是评估遗传性胰腺炎患者胰腺癌和其他肿瘤的发生率。研究方法：为了确定遗传性胰腺炎的自然史，我们邀请了美国胰腺协会和国际胰腺病协会的所有成员参加对这种罕见形式的胰腺炎的纵向研究。患者合格性的初始标准如下：症状发作时的早期年龄（小于或等于30岁）、阳性家族史和无其他原因。从1995年4月至1996年2月，来自10个国家的37名医生提供了246名（125名男性和121名女性）患者的病历，这些患者被认为最有可能诊断为遗传性胰腺炎。该组包括218例诊断为高度可能的患者和28例遗传性胰腺炎诊断不太确定的患者：25例患者相对较晚发病，有阳性家族史，3例患者在30岁之前发病，但家族史不确定。我们回顾了所有的死亡原因，并将观察到的遗传性胰腺炎患者的癌症发生率与预期发生率进行了比较。通过标准化发病率（SIR）估计胰腺炎和胰腺癌之间的关联强度，SIR是队列中观察到的胰腺癌病例与背景人群中预期胰腺癌的比率，根据年龄、性别和国家进行校正。结果：出现胰腺炎症状时的平均年龄（+/-标准差[SD]）为13.9 +/- 12.2岁。与预期的0.150例相比，在8531人-年的随访中，8例胰腺腺癌发生（诊断胰腺癌时的平均年龄+/- SD：56.9 +/- 11.2岁），SIR为53（95%置信区间[CI] = 23-105）。其他肿瘤的频率未增加：SIR = 0.7（95% CI = 0.3-1.6）。队列中报告的20例死亡中有8例死于胰腺癌。队列中的30名成员已经接受了遗传性胰腺炎基因缺陷的检测：所有30名成员都携带胰蛋白酶原基因的突变拷贝。在238名无胰腺癌的患者中，有168名和8名胰腺癌患者中有6名已知遗传性胰腺炎的传播模式。在238名没有胰腺癌的患者中，有99名和6名胰腺癌患者通过家族的父系遗传了这种疾病。遗传性胰腺炎患者到70岁时胰腺癌的累积风险估计接近40%，对于父系遗传模式的患者，胰腺癌的累积风险约为75%。结论：遗传性胰腺炎患者在胰腺炎发病后几十年内发生胰腺癌的风险很高。父系遗传模式增加了患胰腺癌的可能性。
Background: Hereditary pancreatitis is an autosomal-dominant disease, with a variable expression and an estimated penetrance of 80%. The gene for this disease has recently been mapped to chromosome 7q35, and the defect is believed to be caused by a mutation in the cationic trypsinogen gene. Acute attacks of abdominal pain begin early in life and the disease often progresses to chronic pancreatitis. Although the risk of pancreatic cancer is thought to be increased in more common types of chronic pancreatitis, the frequency of pancreatic cancer in the inherited type of pancreatitis is uncertain. Purpose: The aim of this study was to assess the frequency of pancreatic cancer and other tumors in patients with hereditary form of pancreatitis. Methods: To determine the natural history of hereditary pancreatitis, we invited all members of the American Pancreatic Association and the International Association of Pancreatology to participate in a longitudinal study of this rare form of pancreatitis. The initial criteria for patient eligibility were as follows: early age (less than or equal to 30 years) at onset of symptoms, positive family history, and absence of other causes. From April 1995 through February 1996, 37 physicians from 10 countries contributed medical records of 246 (125 males and 121 females) patients thought to have hereditary pancreatitis as the most likely diagnosis. This group included 218 patients where the diagnosis appeared to be highly probable and 28 additional patients where the diagnosis of hereditary pancreatitis was less certain: 25 patients who had relatively late onset of disease and a positive family history and three patients with onset of disease before age 30 years but with an uncertain family history. We reviewed all causes of death and compared the observed to the expected frequency of cancer in this historical cohort of patients with hereditary pancreatitis. The strength of the association between pancreatitis and pancreatic cancer was estimated by the standardized incidence ratio (SIR), which is the ratio of observed pancreatic cancer cases in the cohort to the expected pancreatic cancers in the background population, adjusted for age, sex, and country. Results: The mean age (+/- standard deviation [SD]) at onset of symptoms of pancreatitis was 13.9 +/- 12.2 years. Compared with an expected number of 0.150, eight pancreatic adenocarcinomas developed (mean age +/- SD at diagnosis of pancreatic cancer: 56.9 +/- 11.2 years) during 8531 person-years of follow-up, yielding an SIR of 53 (95% confidence interval [CI] = 23-105). The frequency of other tumors was not increased: SIR = 0.7 (95% CI = 0.3-1.6). Eight of 20 reported deaths in the cohort were from pancreatic cancer. Thirty members of the cohort have already been tested for the defective hereditary pancreatitis gene: all 30 carry a mutated copy of the trypsinogen gene. The transmission pattern of hereditary pancreatitis was known for 168 of 238 patients without pancreatic cancer and six of eight with pancreatic cancer. Ninety-nine of the 238 patients without pancreatic cancer and six of the patients with pancreatic cancer inherited the disease through the paternal side of the family. The estimated cumulative risk of pancreatic cancer to age 70 years in patients with hereditary pancreatitis approaches 40%.For patients with a paternal inheritance pattern, the cumulative risk of pancreatic cancer is approximately 75%. Conclusions: Patients with hereditary pancreatitis have a high risk of pancreatic cancer several decades after the initial onset of pancreatitis. A paternal inheritance pattern increases the probability of developing pancreatic cancer.