Anticipation in familial pancreatic cancer

Abstract

Background: 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. Patients and methods: 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. Results: 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. Conclusion: 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.

Familial association of pancreatic cancer with other malignancies in Swedish families

“…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).…”

Possible anticipation in familial epidermolytic palmoplantar keratoderma with the p.R163W mutation of Keratin 9

“…Anticipation has been well recognized in a number of disorders including Huntington's disease (Ranen et al, 1995), familial chronic myeloproliferative disorders (Rumi et al, 2007), Lynch syndrome (Nilbert et al, 2009), familial hematologic malignancies (Tegg et al, 2011), and familial pancreatic cancer (McFaul et al, 2006). The underlying mechanisms for anticipation likely differ between different types of disorders.…”

Endoscopic ultrasonography for surveillance of individuals at high risk for pancreatic cancer

“…This risk has been estimated to be 2.3 to 4.5-fold greater in individuals with one FDR with pancreatic cancer, 6.4-fold greater in individuals with two FDRs with the disease and 32 to 57-fold greater in individuals with three or more FDRs affected [29][30][31][32] . Similarly to other familial tumors, the median age of presentation in patients with FPC is up to 20 years earlier than in patients with sporadic cancer (49 years vs 61 years) [33][34][35] with an ''anticipation phenomenon'' in the affected kindred and a trend to become more severe and appear at an earlier age as the disorder is passed from one generation to the next [35,36] . Currently, the genetic etiology of most cases of FPC remains undetermined but complex segregation analysis of these patients has led to the discovery of various candidate pancreatic cancer susceptibility genes such as BRCA2 (6%-17% of cases) [37,38] , partner and localizer of BRCA2 (PALB2) (1%-4% of cases) [39,40] and palladin, even if mutations of the latter have been identified in normal controls as well [41][42][43] .…”