Fanconi anaemia (FA) is a rare autosomal recessive disease that is characterised by bone marrow failure, pancytopenia, and an increased susceptibility to cancers. Recently, D’Andrea and coworkers identified biallelic BRCA2 gene mutations as a cause of FA.¹ Because of the role of BRCA2 gene mutations in pancreatic cancer development, their findings suggested other members of the FA pathway may be targeted for genetic inactivation in pancreatic cancer. Indeed, somatic and inherited mutations of FANCC and somatic mutations in FANCG were subsequently identified in patients with apparently sporadic pancreatic cancer.² These data led to analysis of the FANCC and FANCG genes in the germline of families with multiple pancreatic cancers, but no mutations were identified.³ In most populations, FANCA is the most commonly mutated gene in patients with FA.^4–14 In this study we determined if FANCA gene mutations predispose to the development of familial pancreatic cancer.

METHODS

Subjects

Lymphocyte DNA was analysed from patients with familial pancreatic cancer enrolled in the National Familial Pancreatic Tumor Registry.¹⁵ Patients with pancreatic cancer were selected if they had at least two or more first degree relatives with pancreatic cancer (mean (SD) age of 66.7 (12.3) years, males 50.3%). Variants were analysed in 110 additional patients with familial pancreatic cancer. To determine the carrier frequency of c.2574C>G (p.Ser868Arg), we analysed three control populations: healthy spouses of patients with familial pancreatic cancer (115 samples from spouses with a mean (SD) age of 66.9 (11.3) years, males 43.1%), patients who had undergone cholecystectomy (65 samples matched in age with sporadic cases) for non-malignant disease at Johns Hopkins Hospital, and individuals undergoing routine screening colonoscopy (668 samples) at the Mayo Clinic. The mean age of the colonoscopy controls was similar to our pancreatic cancer population (mean (SD) age of 59.3 (12.3) years, males 52.9%). …