Risk of Different Cancers Among First-degree Relatives of Pancreatic Cancer Patients: Influence of Probands' Susceptibility Gene Mutation Status

Background Increased risk of malignancies other than pancreatic cancer (PC) has been reported among first-degree relatives (FDRs) of PC patients; however, the roles of susceptibility gene mutations are unclear. We assessed risk for 15 cancers among FDRs of unselected PC probands. Methods Data on 17162 FDRs, with more than 336000 person-years at risk, identified through 2305 sequential PC probands enrolled at Mayo Clinic (2000-2016) were analyzed. Family history data were provided by the probands. Standardized incidence ratios (SIRs) and 95% confidence intervals (CIs) were calculated, comparing malignancies observed among the FDRs with that expected using Surveillance, Epidemiology, and End Results (SEER) data. Genetic testing was performed among a subset of probands (n=2094), enabling stratified analyses among FDRs based on whether the related proband tested positive or negative for inherited mutation in 22 sequenced cancer susceptibility genes. All statistical tests were two-sided. Results Compared with SEER, PC risk was twofold higher among FDRs of PC probands (SIR = 2.04, 95% CI=1.78 to 2.31, P < .001). Primary liver cancer risk was elevated among female FDRs (SIR = 2.10, 95% CI=1.34 to 3.12, P < .001). PC risk was more elevated among FDRs of mutation-positive probands (SIR = 4.32, 95% CI=3.10 to 5.86) than FDRs of mutation-negative probands (SIR = 1.77, 95% CI=1.51 to 2.05, between-group P < .001). FDR PC risk was higher when the related proband was younger than age 60 years at diagnosis and mutation-positive (SIR = 5.24, 95% CI=2.93 to 8.64) than when the proband was younger than age 60 years but mutation-negative (SIR = 1.76, 95% CI=1.21 to 2.47, between-group P < .001). Breast (SIR = 1.29, 95% CI=1.01 to 1.63) and ovarian (SIR = 2.38, 95% CI=1.30 to 4.00) cancers were elevated among FDRs of mutation-positive probands. Conclusions Our study substantiates twofold risk of PC among FDRs of PC patients and suggests increased risk for primary liver cancer among female FDRs. FDRs of susceptibility mutation carriers had substantially increased risk for PC and increased risk for breast and ovarian cancers.