Our results indicated that individuals with a family history of pancreatic cancer are at an increased risk of cancer-related mortality. We have previously demonstrated a two-fold increased risk of pancreatic cancer in first-degree relatives of patients with sporadic pancreatic cancer, and a nine-fold increased risk of pancreatic cancer in first-degree relatives of patients with familial pancreatic cancer (17
Here we show that, in addition to an increased risk of pancreatic cancer, individuals with a family history of pancreatic cancer have an increased risk of dying from breast, ovarian, colon, prostate, liver and bile duct cancers. For breast, ovarian and colon cancers, the risk increases as the individual’s family history of pancreatic cancer increases suggesting a shared genetic predisposition.
The association of breast and ovarian cancers with pancreatic cancer is not surprising. Pancreatic cancer, breast and ovarian cancer share susceptibility genes, such as BRCA2
. Germline BRCA2
gene mutations account for 6–19% of familial pancreatic cancers, and these mutations increase the risk of breast, pancreatic and ovarian cancers (5
). Similarly, we have recently demonstrated that germline PALB2
gene mutations are the 2nd
most common cause of the familial clustering of pancreatic cancer (3
). Approximately 3% of familial pancreatic cancer patients carry germline truncating variants in the PALB2
), and germline PALB2
gene mutations increase the risk of both pancreatic and breast cancer(27
). Thus there appears to be a well-defined genetic basis for at least some of the co-aggregation of breast and pancreatic cancer in families.
The observed co-aggregation of pancreatic cancer and colon cancer may be due to an increased risk of pancreatic cancers among individuals with hereditary nonpolyposis colorectal cancer syndrome (HNPCC), however, the risk of pancreatic cancer in HNPCC kindreds remains poorly defined(28
). There have been anectdoctal reports of pancreatic cancers in HNPCC kindreds, and studies of medullary carcinomas of the pancreas have demonstrated that medullary pancreatic cancers that are microsatellite unstable (MSI+
) can be associated with a family history of cancer (29
). However, the majority of families in the current study reporting both pancreatic cancer and colon cancer, do not meet the Amsterdam or Bethesda guidelines for HNPCC, therefore it is unlikely that mutations in these genes explain a significant fraction of the observed co-aggregation of colon and pancreatic cancer.
The findings of an increased risk of breast and colon cancer among the relatives of young-onset pancreatic cancer patients is supported by a recent study which showed pancreatic cancer patients with a family history (first- or second-degree relative) of breast, ovarian or colon cancer were on average younger than pancreatic cancer patients without a family history of these cancers(30
Germline mutations in the CDKN2A
gene are associated with familial melanoma and pancreatic cancer(12
mutations are relatively rare, and so it is not surprising that while we did observe an increased risk of melanoma in our families this increase was not statistically significant.
In addition to cancers of the breast, ovary and colon we also found increased mortality from bile-duct cancer in relatives of patients with pancreatic cancer. The excess of bile duct cancer in both the relatives of familial and sporadic pancreatic cancer patients could due to a shared environmental and/or a common genetic component. However, given the intrapancreatic location of the distal common bile duct and the resultant difficulty in distinguishing distal bile duct and pancreatic adenocarcinomas, misclassification could also explain some of this association. It should be noted, however, that the increased risk of bile duct cancer persisted when analysis as limited to intrahepatic bile duct carcinomas (wSMR 3.38,95% CI 1.34 –7.07). Ascertainment bias could also play a role, in that families may have perceived that pancreatic and bile duct cancers are related and are thereby more likely to participate in our research study if they have a family history of pancreatic and bile duct cancer. To minimize this bias, individuals with bile duct cancer who were initially reported to have pancreatic cancer were treated as probands and excluded from the analysis.
Despite the excess in cancer mortality observed in our families, and our ability to obtain extensive death records through the NDI, all cause mortality was 18% lower in our study population compared with the general US population. One potential explanation for this decreased risk is that NFPTR participants have a healthier lifestyle and/or higher socioeconomic status (SES) than the SEER population. High SES has been associated with lower mortality compared with the lower income groups after controlling for age, sex, race, urbanicity and education(31
). High SES has also been associated with lower cancer mortality risk(32
). If this is the case, the relative risk estimates we obtained may, in fact, underestimate the true risk to relatives of pancreatic cancer patients in the general population.
The large registry based nature of our study population allowed us to assess and directly compare the risk of other cancers in relatives of both familial and sporadic pancreatic cancer patients. We were able to minimize bias by verifying date and cause of death using the NDI Plus service. Our analyses were limited to mortality because of our ability to obtain high quality cause of death data from the NDI. Previous studies have demonstrated severe under-reporting of cancer incidence in relatives, which causes a downward bias in risk estimates. However, the use of mortality instead of incidence data does have some limitations. SMRs only provide an estimate of relative incidence. For example, if there was higher-incidence but longer survival from a particular cancer type, the use of mortality data may not detect this increase in incidence due to the associated lower mortality.
In summary, our study suggests that relatives of patients with pancreatic cancer have a higher risk of dying from cancers at other sites. In particular, relatives of patients with familial pancreatic cancer have an increased risk of dying from breast, colon and ovarian cancer. These data can help to inform genetic counseling and screening recommendations for high-risk families.