Prevalence of pancreaticobiliary cancers in Irish families with pathogenic BRCA1 and BRCA2 variants
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Prevalence of pancreaticobiliary cancers in Irish families with pathogenic BRCA1 and BRCA2 variants Robert Power1,3 · Cristin Leavy2,3 · Carmel Nolan2,3 · Niamh White2,3 · Roisin Clarke2,3 · Karen A. Cadoo1,2,3 · David James Gallagher1,2,3 · Maeve Aine Lowery1,3 Received: 24 October 2019 / Accepted: 27 August 2020 © Springer Nature B.V. 2020
Abstract Pathogenic variants (PVs) in the BRCA1 and BRCA2 genes are associated with an increased lifetime risk of pancreatic ductal adenocarcinoma (PDAC), and more recently have been associated with increased risk of biliary tract cancers (BTC). This study assessed the prevalence, age and gender distribution of PDAC/BTC cases in families known to carry a BRCA1/2 PV compared to those of the Irish population. A review of all families referred to a national genetics clinic from 09/11/1997 to 01/06/2018 was performed. The BOADICEA algorithm was used to estimate the probability that an untested relative of a known BRCA1/2 PV carrier with PDAC was a carrier. We reviewed 3252 family pedigrees, 1193 contained a proband who underwent testing for BRCA1/2 based on Manchester score ≥ 15. Among 128 BRCA2 PV-positive families, 27 (21%) contained a 1st/2nd/3rd-degree relative with PDAC, while of 116 BRCA1 PV-positive families, 11 (9%) contained a 1st/2nd/3rddegree relative with PDAC. Within these 38 families, 25 patients with PDAC had ≥ 50% likelihood of being a BRCA1/2 PV carrier. This cohort had a median age at diagnosis of 55 years (range 33–75), with a mean (55 years) lower than 8364 patients with PDAC identified through the National Cancer Registry of Ireland (71 years, p G c.2474delC c.547 + 1G > T BRCA2 c.7977-1G > C c.4163_4164delinsA c.755_758_delACAG2 c.6486_6489delACAA c.6275_6276delTT c.5073dupA c.2957dupA c.4276dupA c.8927delC c.956A > G c.8585dupT c.7601C > T c.2637T > G c.3717delA c.7680dupT c.4398_4402delACATT c.5684C > A, c.6092C > A c.1456C > T c.8205-1G > C c.4866delT c.8924C > G
N BTC 3 1 1 1 1 1 1 1 1 2 2 2 2 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1
N
c.427G > T 1 c.4065_4068delTCAA 1
c.9253dupA c.5804_5807delTTAA c.5576_5579delTTAA c.3717delA c.1889delC
5 1 1 1 1
The genetic alterations are presented using Human Genome Variation Society (HGVS) (https://www.hgvs.org/rec.html) nomenclature. Incomplete records prevented the characterisation of 2 BRCA2 pathogenic variants (PVs) and 1 BRCA1 PV in PDAC families, and 1 BRCA2 PV in a family with BTC
not detected in any BTC or PDAC families. Three probands with a BRCA2 VUS had a FH of PDAC, including one VUS (c.9976 A > T) that has been associated with familial PDAC. No families with PDAC had a BRCA1 VUS, and no probands with a FH of BTC had a VUS in BRCA1/2.
Clinical characteristics of likely BRCA1/2 carriers We sought to identify clinical characteristics of PDAC patients that were likely to carry the familial BRCA1/2 PV and compare this group to unselected patients from a national registry. Out of the 38 families with PDAC and a BRCA1/2 PV identified, the mean age of diagnosis was lower than that
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