In an analysis intended to identify underlying factors conferring a younger onset of PC, we found that several cancers known to be associated with familial cancer syndromes that include PC might be important. Patients reporting a family history (first- or second-degree relative) of breast cancer, ovarian cancer, colorectal cancer, or melanoma have a younger age of onset of PC, after taking into account reported smoking intensity and gender. Surprisingly, having a family history of PC was not associated with a younger age at diagnosis, although probands with more than 1 affected family member trended toward a younger age of onset. Family history of all other cancers combined and other smoking-related cancers (bladder, head/neck, and lung cancer) also showed no difference in the age of onset of PC in our probands.
Possibilities for this association include shared genetic risk factors such as the familial cancer syndromes described earlier, shared environmental factors, reporting bias, and chance. The cancer family syndromes that have been identified are thought to be relatively rare. However, when present, they could shift the age of onset enough to give the results found. Interestingly, studies involving breast cancer patients note an earlier age of onset not only in patients with known BRCA1/2
mutations but also in those with relatives affected with breast cancer in the absence of detected mutations.17
A shared genetic association, however, would likely increase overall risk for the respective cancers in families with PC, and no increase in risk for breast (SIR, .73), ovarian (SIR, .90), colorectal (SIR, .83) cancers, and melanoma (SIR, .65) was seen in our prior studies in relatives of PC patients.18
However, a trend was noted in families of PC patients diagnosed younger than the age of 60 years toward an increased risk for ovarian cancer (SIR, 2.20; 95% CI, .72–5.12), melanoma (SIR, 1.73; 95% CI, .70–3.57), and colorectal cancer (SIR, 1.37; 95% CI, .80–2.19). Although not statistically significant, these data could be expected if a subset of patients who carry shared genetic risk for pancreatic and these other cancers went on to develop pancreatic cancer at a young age. Hemminki and Li1
in a population registry in Sweden showed increased risk for lung cancer (SIR, 3.14; 95% CI, 1.86–4.97) in offspring of PC patients diagnosed younger than the age of 60 years. Bladder cancer (1.57), melanoma (1.92), endometrial (1.97), colon (1.46), rectal (1.45), and PC all showed trends toward increased risk, but they did not reach significance. Smoking status was not included in that analysis. Further studies assessing the impact of genetic mutation carriers in young-onset PC will be necessary to determine the full contribution of these genetic syndromes to young-onset PC. In the absence of definitive genetic testing, these family history associations provide some insight into potential underlying genetic predispositions. We included first- and second-degree relatives to maximize the number of relatives who have achieved ages of risk for the relevant cancers, whereas limiting the analysis to first-degree relatives would have enabled us only to have parents included in the analysis, because children of most patients would not have reached the peak ages of risk for most cancers, and siblings might or might not be a potential source of bias, on the basis of the age of the proband.
Shared environmental factors are another possible explanation, and our adjustment for smoking intensity helped to address this common risk factor. The lack of association of tobacco-related cancers and age of onset along with the dose-dependent effect of tobacco on age of onset in our study support our approach to correct the analysis for smoking. Although unknown risk factors could theoretically affect our results, no other environmental factor is known at this time to affect age of onset, and hence no further corrections were applied in our study. Reporting bias of family history of cancers could also affect the results, but prior validation of our family history reporting showed high sensitivity (86.4%) and specificity (100%) for reporting of cancer in first-degree relatives of PC patients.18
Finally, there is a possibility that our results are due to chance. However, our sample is probably the most comprehensive and unbiased sample of self-reported family history of cancer by PC patients to date. Our ultra-rapid ascertainment ensures that we obtained data from the majority of all PC patients approached at our institution. The patterns of associations observed are also inconsistent with chance associations.
The earlier age of onset in patients with a family history of these cancers has implications for genetic counseling. Persons with family histories of breast cancer, ovarian cancer, melanoma, or colorectal cancer appear to be at risk for PC at a younger age. As screening and prevention studies and strategies emerge for PC, identifying populations at risk, especially those at a younger age, will be vital for targeting these interventions.
Interestingly, we did not observe that a family history of PC alone affects age of onset, a finding that was not expected, given prior reports of a younger age of onset among FPC kindreds.7,15,19
No prior studies had controlled for smoking status, which could potentially be the sole cause for these reports of younger ages of onset in FPC.