The Prevalence of Founder Mutations among Individuals from Families with Familial Pancreatic Cancer Syndrome

Abstract

PurposeFamilial pancreatic cancer describes families with at least two first-degree relatives with pancreatic cancer that do not fulfil the criteria of other inherited tumor syndromes with increased risks of pancreatic cancer. Although much has been learned regarding the aggregation of pancreatic cancer in some families, the genetic basis for this familial aggregation is poorly understood. This study evaluated the prevalence of 10 Polish founder mutations in four genes among individuals from families with diagnosed familial pancreatic cancer syndrome and assessed their possible association with the familial pancreatic cancer (FPC) risk in Poland.Materials and MethodsIn this study, 400 FPC individuals and 4,000 control subjects were genotyped for founder mutations in BRCA1 (5382insC, 4153delA, C61G), CHEK2 (1100delC, IVS2+1G>A, del5395, I157T), NBS1 (657del5), and PALB2 (509_510delGA, 172_175delTTGT) genes.ResultsA statistically significant association was observed between the 172_175delTTGT mutation of the PALB2 gene and an increased risk of FPC syndrome (odds ratio [OR], 10.05; p=0.048). In addition, an increased risk of cancer was observed in the FPC family members with a BRCA1 mutation (OR, 6.72; p=0.006). Novel associations were found between the FPC family members with cancer and CHEK2 mutations (OR, 2.26; p=0.008) with a noticeable contribution of the missense variant, I157T of CHEK2 (OR, 2.17; p=0.026).ConclusionThe founder mutations in the genes, BRCA1, PALB2, and CHEK2, cause a small percentage of familial pancreatic cancer syndrome in the Polish population. Following confirmation in larger studies, these mutations can be added to the panel of genes to be tested in families with a diagnosis of FPC syndrome.

Germline BRCA2 K3326X and CHEK2 I157T mutations increase risk for sporadic pancreatic ductal adenocarcinoma

“…Similarly, the lowpenetrance CHEK2 rs17879961 was reported to be associated with higher risk (OR = 2.17) of pancreatic familial cancer among cancer-affected individuals from the Familial Pancreatic Cancer (FPC) syndrome families in a well-powered study (105 cases and 4,000 controls). 16 Reports from nonfamilial cancer investigations on the other hand, among different Caucasian populations have consistently suggested an increased risk conferred by BRCA2 rs11571833 in relation to different cancers. [20][21][22][23][24][25] Paradoxically however, a protective effect of CHEK2 rs17879961 has been observed in association with urinary tract, lung and upper aerodigestive tract cancers; 20,25,26 while the opposite increased effect was seen in differentiated thyroid, colon, prostate and breast cancer risk.…”

“…12 The missense mutation c.470T>C in exon 3 (I157T/p.Ile157Thr; hereafter referred to as rs17879961) results from a substitution of isoleucine for threonine in the protein and lies in a functionally important domain which results in highly reduced or abolished binding of some or all CHEK2 protein substrates (p53, BRCA1, Cdc25c and Cdc25A). [13][14][15] An association between the missense CHEK2 I157T mutation and familial PDAC has previously been suggested, 16 however its effect on sporadic PDAC risk remains largely unknown. Both BRCA2 and CHEK2 are critical for DNA repair and maintenance of genomic stability and it is plausible that these mutations compromise the DNA repair capacity of some individuals, thus predisposing them to PDAC.…”

Spectrum of APC and MUTYH germ‐line mutations in Russian patients with colorectal malignancies

“…High occurrence of CHEK2 p.I157T substitution in genetically unexplained colon polyposis patients (Table S3) is of potential interest, given that the frequency of this variant in Slavic populations does not exceed 5% . CHEK2 p.I157T allele was repeatedly shown to be moderately overrepresented in various categories of oncological patients, including subjects with breast, prostate, colorectal and pancreatic carcinomas. Interestingly, CHEK2 analysis of patients with MSI‐negative and familial CRC demonstrated an association only for p.I157T allele, while common truncating mutations in CHEK2 gene did not increase the CRC risk .…”

Assembling and Validating Bioinformatic Pipelines for Next-Generation Sequencing Clinical Assays

“…However, there are several founder mutations close to 1% allele frequency that are still pathogenic within a population, such as CHEK2 (checkpoint kinase 2) c.1100delC (Europeans) or certain BRCA1/2 (Breast Cancer Type 1 Susceptibility Protein) mutations in Ashkenazi Jewish people. 67 Population sequencing of healthy individuals has been performed to address this very issue. The Exome Aggregation Consortium (ExAC; more than 60 000 healthy individuals) and genome Aggregation Database (gnomAD; with more than 126 000 individuals) performed whole-exome or whole-genome sequencing of healthy individuals to better estimate allele frequency of normal human variation.…”