Anticipation in familial pancreatic cancer

Division of Surgery and Oncology, University of Liverpool L69 3GA, UK.
Gut (Impact Factor: 14.66). 03/2006; 55(2):252-8. DOI: 10.1136/gut.2005.065045
Source: PubMed


Previous studies of anticipation in familial pancreatic cancer have been small and subject to ascertainment bias. Our aim was to determine evidence for anticipation in a large number of European families.
A total of 1223 individuals at risk from 106 families (264 affected individuals) were investigated. Generation G3 was defined as the latest generation that included any individual aged over 39 years; preceding generations were then defined as G2 and G1.
With 80 affected child-parent pairs, the children died a median (interquartile range) of 10 (7, 14) years earlier. The median (interquartile range) age of death from pancreatic cancer was 70 (59, 77), 64 (57, 69), and 49 (44, 56) years for G1, G2, and G3, respectively. These indications of anticipation could be the result of bias. Truncation of Kaplan-Meier analysis to a 60 year period to correct for follow up time bias and a matched test statistic indicated significant anticipation (p=0.002 and p<0.001). To minimise bias further, an iterative analysis to predict cancer numbers was developed. No single risk category could be applied that accurately predicted cancer cases in every generation. Using three risk categories (low with no pancreatic cancer in earlier generations, high with a single earlier generation, and very high where two preceding generations were affected), incidence was estimated without significant error. Anticipation was independent of smoking.
This study provides the first strong evidence for anticipation in familial pancreatic cancer and must be considered in genetic counselling and the commencement of secondary screening for pancreatic cancer.

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Available from: John P Neoptolemos, Jan 07, 2015
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    • "The presence of an inherited genetic component and possibility of a hereditary pancreatic cancer syndrome was first suggested by several case reports describing familial aggregation of pancreatic cancers (MacDermott and Kramer, 1973; Reimer et al., 1977; Ehrenthal et al., 1987). Lynch et al performed the first systematic study of 18 families with pancreatic cancer in 1990 and subsequent case-control and cohort studies have shown that individuals with a family history of PDAC are at an increased risk of developing pancreatic cancer themselves (Lynch et al., 1990, 1996; Klein et al., 2001). Furthermore, the odds of having a family history of PDAC are 1.9-to 13-fold higher in pancreatic cancer patients compared to healthy controls (Ghadirian et al., 1991; Jacobs et al., 2010; Klein, 2012). "
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    • "Applying the screening principles of colorectal cancer by beginning screening for pancreatic cancer 10 years earlier than the youngest affected member in the family is a reasonable starting point. Taking into account, however, the long time between initiation of a PDAC tumor cell and the presence of a PDAC tumor beginning to have metastatic capability (11.7 ± 3.1 years [62]), and taking into account evidence that consecutive generations with FPC die of PC a median of 10 years sooner each subsequent generation [63], and finally taking into account that smokers with FPC develop cancer a decade before nonsmokers, it is reasonable to use judgment in screening selected individuals much earlier. A reasonable screening algorithm is presented in Figure 1. "
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    • "The fact that the risk of pancreatic cancer associated with sibling history was higher might indicate a recessive mode of inheritance. The greater risk in siblings than in offspring could also suggest that anticipation is operative in familial pancreatic cancer (Lerch, 2006; McFaul et al, 2006). Previous studies reported an increased risk of pancreatic cancer in the offspring of patients with cancers of the pancreas, rectum and lungs (Hemminki and Li, 2003a). "
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