Genetic Susceptibility and Risk of Pancreatic Cancer

Introduction

This year in the United States, an estimated 45,220 people will be diagnosed with pancreatic cancer and 38,460 will die from the disease . Although pancreatic cancer is the 10th most commonly diagnosed cancer in the United States, it is the 4th most common cause of cancer death in both sexes . The best chance for survival is early detection when the tumor can be removed surgically. Most pancreatic cancers are asymptomatic at early stages, however, and by the time they are diagnosed, the majority of patients present with distant metastases. Only about 15–20% of pancreatic adenocarcinoma (PDAC) cases are diagnosed early enough for surgery . Survival is correlated to stage: patients who present with distant metastases at diagnosis have dismal 5-year survival rates of only 2%, whereas patients diagnosed at an early stage exceed 20%, indicating the potential benefit of early detection . These rates are still bleak, however, and call out for new and better strategies for prevention, early diagnosis, and treatment of pancreatic cancer to reduce the burden of this disease.

Known risk factors for pancreatic cancer include smoking, diabetes, obesity, chronic pancreatitis, heavy alcohol consumption, age, and a family history of the disease . A small proportion of the familial aggregation of pancreatic cancer can be explained by hereditary cancer syndromes and inherited forms of pancreatitis, caused by rare high-risk inherited mutations . The genetic basis for the majority of familial aggregation of pancreatic cancer has yet to be explained. The search for common and rare germline variants that influence risk of pancreatic cancer through genomewide association studies (GWAS) and high-throughput sequencing based studies is under way, and this search holds the promise of increasing our knowledge of variants and genes that play a role in inherited susceptibility of this devastating disease.

Familial Risk of Pancreatic Cancer

Epidemiological studies have shown that individuals with a family history of pancreatic cancer are at an increased risk of developing pancreatic cancer. One of the largest studies reported to date was conducted within the Pancreatic Cancer Cohort consortium (PanScan) and included 11 studies (10 cohort and 1 case–control studies) with 1183 cases and 1205 controls. A family history of pancreatic cancer in a first-degree relative was associated with an increased risk of pancreatic cancer with an odds ratio (OR) of 1.76 (95% confidence interval, CI 1.19–2.61). Individuals with two or more first-degree relatives diagnosed with pancreatic cancer, although not common, were at even greater risk (OR = 4.26, 95% CI 0.48–37.79) . Results from other large studies have described similar increases. A cancer registry–based analysis conducted within the Swedish Family-Cancer Database reported a 1.73-fold increase in the incidence of pancreatic cancer (standardized incidence ratio, SIR = 1.73, 95% CI 1.13–2.54) among offspring of patients diagnosed with PDAC .

A study linking the Utah Cancer Registry to the Utah Population Database, showed a significant familial clustering for pancreatic cancer, both in first-degree (RR = 1.84; 95% CI 1.47–2.29; P < 0.0001) and second-degree (RR = 1.59; 95% CI 1.31–2.91; P < 0.0001) relatives of individuals with pancreatic cancer . A population-based study in Iceland, linking cancer registry information, including all pancreatic cancer patients diagnosed in the country from 1955 to 2002 ( n = 930) with a population-wide genealogy database, reported somewhat higher risk to first-degree relatives (RR = 2.33, 90% CI 1.83–2.96) .

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