RESUMO
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.
Assuntos
Antecipação Genética , Síndromes Neoplásicas Hereditárias/genética , Neoplasias Pancreáticas/genética , Adulto , Idoso , Métodos Epidemiológicos , Europa (Continente)/epidemiologia , Feminino , Predisposição Genética para Doença , Humanos , Longevidade , Masculino , Pessoa de Meia-Idade , Síndromes Neoplásicas Hereditárias/mortalidade , Neoplasias Pancreáticas/mortalidade , Linhagem , FumarRESUMO
BACKGROUND: The observation of a familial accumulation of ductal pancreatic adenocarcinoma (PC) and the increased risk for PC in certain hereditary tumor syndromes point to a genetic predisposition for PC. In order to evaluate the characteristics of familial PC, a German national case collection for familial pancreas cancer (FaPaCa) was established. PATIENTS AND METHODS: In FaPaCa, families of patients with PC are being collected, who have at least 1 first-degree relative with PC or with malignant melanoma. Histopathologic verification of tumor diagnoses, acquisition of clinical data, and full genetic counselling are prerequisites for the enrollment of PC families in FaPaCa. RESULTS: So far, 21 families fulfilled the criteria for partaking in FaPaCa. In 11 families, PC represented the sole tumor entity. Additional tumors included malignant melanoma in 5, breast cancer in 3, and prostatic, colon or lung cancer in 2 families. Compared to the preceding generation, a younger age at diagnosis of PC was observed in the offspring of PC patients (offspring median 53 years vs. parents median 75.5 years). CONCLUSION: The association of PC and breast cancer, and of PC and malignant melanoma suggests predisposing mutations in the BRCA2 or CDKN2A genes in about one third of the FaPaCa families. Mutational analyses in both candidate genes may help to identify individuals who are at an increased risk for developing PC. A shift towards a younger age at diagnosis in our PC families may indicate genetic anticipation and/or changes of patterns of exogenous risk factors.
Assuntos
Carcinoma Ductal Pancreático/genética , Neoplasias Pancreáticas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Antecipação Genética/genética , Carcinoma Ductal Pancreático/diagnóstico , Carcinoma Ductal Pancreático/patologia , Feminino , Aconselhamento Genético , Predisposição Genética para Doença/genética , Humanos , Masculino , Melanoma/diagnóstico , Melanoma/genética , Melanoma/patologia , Pessoa de Meia-Idade , Neoplasias Primárias Múltiplas/diagnóstico , Neoplasias Primárias Múltiplas/genética , Neoplasias Primárias Múltiplas/patologia , Síndromes Neoplásicas Hereditárias/diagnóstico , Síndromes Neoplásicas Hereditárias/genética , Síndromes Neoplásicas Hereditárias/patologia , Pâncreas/patologia , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/patologia , Linhagem , Risco , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologiaRESUMO
BACKGROUND/AIMS: The prevalence of familial pancreatic cancer (FPC) and the characteristics of FPC have not yet been well investigated in the German population. Therefore, a German case collection for FPC was established in July 1999 to collect and evaluate data on FPC families. METHODS: The prevalence of pancreatic cancer (PC) as well as other tumours and diseases was studied in families with at least 2 first-degree relatives with histologically confirmed PC, and in families of patients with PC and a first-degree relative with malignant melanoma. All participating family members were genetically counselled and evaluated by a standardised questionnaire. RESULTS: In an 18-month period, 73 independent kindreds with potential FPC contacted the national case collection. So far, 20 kindreds have fulfilled the criteria for FPC and have undergone complete workups. Most families revealed an autosomal dominant pattern of inheritance. Twelve families revealed an isolated accumulation of PC. Importantly, in 8 of 20 (35%) families, additional tumour types such as melanoma, breast and prostate cancer occurred. CONCLUSION: The observed phenotypic heterogeneity indicates an association with predisposing tumour suppressor genes p16 and BRCA2 in up to 30% of FPC families. Mutation analysis of these candidate genes might lead to the identification of the predisposing gene defect in a proportion of FPC families.
