Dataset Information

Identification of Recessively Inherited Genetic Variants Potentially Linked to Pancreatic Cancer Risk.

ABSTRACT: Although 21 pancreatic cancer susceptibility loci have been identified in individuals of European ancestry through genome-wide association studies (GWASs), much of the heritability of pancreatic cancer risk remains unidentified. A recessive genetic model could be a powerful tool for identifying additional risk variants. To discover recessively inherited pancreatic cancer risk loci, we performed a re-analysis of the largest pancreatic cancer GWAS, the Pancreatic Cancer Cohort Consortium (PanScan) and the Pancreatic Cancer Case-Control Consortium (PanC4), including 8,769 cases and 7,055 controls of European ancestry. Six single nucleotide polymorphisms (SNPs) showed associations with pancreatic cancer risk according to a recessive model of inheritance. We replicated these variants in 3,212 cases and 3,470 controls collected from the PANcreatic Disease ReseArch (PANDoRA) consortium. The results of the meta-analyses confirmed that rs4626538 (7q32.2), rs7008921 (8p23.2) and rs147904962 (17q21.31) showed specific recessive effects (p<10^-5) compared with the additive effects (p>10^-3), although none of the six SNPs reached the conventional threshold for genome-wide significance (p < 5×10^-8). Additional bioinformatic analysis explored the functional annotations of the SNPs and indicated a possible relationship between rs36018702 and expression of the BCL2L11 and BUB1 genes, which are known to be involved in pancreatic biology. Our findings, while not conclusive, indicate the importance of considering non-additive genetic models when performing GWAS analysis. The SNPs associated with pancreatic cancer in this study could be used for further meta-analysis for recessive association of SNPs and pancreatic cancer risk and might be a useful addiction to improve the performance of polygenic risk scores.

SUBMITTER: Lu Y

PROVIDER: S-EPMC8678088 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Identification of Recessively Inherited Genetic Variants Potentially Linked to Pancreatic Cancer Risk.

Lu Ye Y Gentiluomo Manuel M Macauda Angelica A Gioffreda Domenica D Gazouli Maria M Petrone Maria C MC Kelemen Dezső D Ginocchi Laura L Morelli Luca L Papiris Konstantinos K Greenhalf William W Izbicki Jakob R JR Kiudelis Vytautas V Mohelníková-Duchoňová Beatrice B Bueno-de-Mesquita Bas B Vodicka Pavel P Brenner Hermann H Diener Markus K MK Pezzilli Raffaele R Ivanauskas Audrius A Salvia Roberto R Szentesi Andrea A Aoki Mateus Nóbrega MN Németh Balázs C BC Sperti Cosimo C Jamroziak Krzysztof K Chammas Roger R Oliverius Martin M Archibugi Livia L Ermini Stefano S Novák János J Kupcinskas Juozas J Strouhal Ondřej O Souček Pavel P Cavestro Giulia M GM Milanetto Anna C AC Vanella Giuseppe G Neoptolemos John P JP Theodoropoulos George E GE van Laarhoven Hanneke W M HWM Mambrini Andrea A Moz Stefania S Kala Zdenek Z Loveček Martin M Basso Daniela D Uzunoglu Faik G FG Hackert Thilo T Testoni Sabrina G G SGG Hlaváč Viktor V Andriulli Angelo A Lucchesi Maurizio M Tavano Francesca F Carrara Silvia S Hegyi Péter P Arcidiacono Paolo G PG Busch Olivier R OR Lawlor Rita T RT Puzzono Marta M Boggi Ugo U Guo Feng F Małecka-Panas Ewa E Capurso Gabriele G Landi Stefano S Talar-Wojnarowska Renata R Strobel Oliver O Gao Xin X Vashist Yogesh Y Campa Daniele D Canzian Federico F

Frontiers in oncology 20211203

Although 21 pancreatic cancer susceptibility loci have been identified in individuals of European ancestry through genome-wide association studies (GWASs), much of the heritability of pancreatic cancer risk remains unidentified. A recessive genetic model could be a powerful tool for identifying additional risk variants. To discover recessively inherited pancreatic cancer risk loci, we performed a re-analysis of the largest pancreatic cancer GWAS, the Pancreatic Cancer Cohort Consortium (PanScan) ...[more]

PMID: 34926279

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Project description:Aims/hypothesisIn a recent study using a standard additive genetic model, we identified a TBC1D4 loss-of-function variant with a large recessive impact on risk of type 2 diabetes in Greenlanders. The aim of the current study was to identify additional genetic variation underlying type 2 diabetes using a recessive genetic model, thereby increasing the power to detect variants with recessive effects.MethodsWe investigated three cohorts of Greenlanders (B99, n = 1401; IHIT, n = 3115; and BBH, n = 547), which were genotyped using Illumina MetaboChip. Of the 4674 genotyped individuals passing quality control, 4648 had phenotype data available, and type 2 diabetes association analyses were performed for 317 individuals with type 2 diabetes and 2631 participants with normal glucose tolerance. Statistical association analyses were performed using a linear mixed model.ResultsUsing a recessive genetic model, we identified two novel loci associated with type 2 diabetes in Greenlanders, namely rs870992 in ITGA1 on chromosome 5 (OR 2.79, p = 1.8 × 10-8), and rs16993330 upstream of LARGE1 on chromosome 22 (OR 3.52, p = 1.3 × 10-7). The LARGE1 variant did not reach the conventional threshold for genome-wide significance (p < 5 × 10-8) but did withstand a study-wide Bonferroni-corrected significance threshold. Both variants were common in Greenlanders, with minor allele frequencies of 23% and 16%, respectively, and were estimated to have large recessive effects on risk of type 2 diabetes in Greenlanders, compared with additively inherited variants previously observed in European populations.Conclusions/interpretationWe demonstrate the value of using a recessive genetic model in a historically small and isolated population to identify genetic risk variants. Our findings give new insights into the genetic architecture of type 2 diabetes, and further support the existence of high-effect genetic risk factors of potential clinical relevance, particularly in isolated populations.Data availabilityThe Greenlandic MetaboChip-genotype data are available at European Genome-Phenome Archive (EGA; https://ega-archive.org/ ) under the accession EGAS00001002641.

Project description:BackgroundInherited germline TP53 pathogenic and likely pathogenic variants (gTP53) cause autosomal dominant multicancer predisposition including Li-Fraumeni syndrome (LFS). However, there is no known association of prostate cancer with gTP53.ObjectiveTo determine whether gTP53 predisposes to prostate cancer.Design, setting, and participantsThis multi-institutional retrospective study characterizes prostate cancer incidence in a cohort of LFS males and gTP53 prevalence in a prostate cancer cohort.Outcome measurements and statistical analysisWe evaluated the spectrum of gTP53 variants and clinical features associated with prostate cancer.Results and limitationsWe identified 31 prostate cancer cases among 163 adult LFS males, including 26 of 54 aged ≥50 yr. Among 117 LFS males without prostate cancer at the time of genetic testing, six were diagnosed with prostate cancer over a median (interquartile range [IQR]) of 3.0 (1.3-7.2) yr of follow-up, a 25-fold increased risk (95% confidence interval [CI] 9.2-55; p < 0.0001). We identified gTP53 in 38 of 6850 males (0.6%) in the prostate cancer cohort, a relative risk 9.1-fold higher than that of population controls (95% CI 6.2-14; p < 0.0001; gnomAD). We observed hotspots at the sites of attenuated variants not associated with classic LFS. Two-thirds of available gTP53 prostate tumors had somatic inactivation of the second TP53 allele. Among gTP53 prostate cancer cases in this study, the median age at diagnosis was 56 (IQR: 51-62) yr, 44% had Gleason ≥8 tumors, and 29% had advanced disease at diagnosis.ConclusionsComplementary analyses of prostate cancer incidence in LFS males and gTP53 prevalence in prostate cancer cohorts suggest that gTP53 predisposes to aggressive prostate cancer. Prostate cancer should be considered as part of LFS screening protocols and TP53 considered in germline prostate cancer susceptibility testing.Patient summaryInherited pathogenic variants in the TP53 gene are likely to predispose men to aggressive prostate cancer.

Project description:Aims/hypothesisCurrent clinical guidelines for childhood-onset monogenic diabetes outside infancy are mainly focused on identifying and testing for dominantly inherited, predominantly MODY genes. There are no systematic studies of the recessively inherited causes of monogenic diabetes that are likely to be more common in populations with high rates of consanguinity. We aimed to determine the contribution of recessive causes of monogenic diabetes in paediatric diabetes clinics and to identify clinical criteria by which to select individuals for recessive monogenic diabetes testing.MethodsWe conducted a cross-sectional study of 1093 children from seven paediatric diabetes clinics across Turkey (a population with high rates of consanguinity). We undertook genetic testing of 50 known dominant and recessive causes of monogenic diabetes for 236 children at low risk of type 1 diabetes. As a comparison, we used monogenic diabetes cases from UK paediatric diabetes clinics (a population with low rates of consanguinity).ResultsThirty-four children in the Turkish cohort had monogenic diabetes, equating to a minimal prevalence of 3.1%, similar to that in the UK cohort (p = 0.40). Forty-one per cent (14/34) had autosomal recessive causes in contrast to 1.6% (2/122) in the UK monogenic diabetes cohort (p < 0.0001). All conventional criteria for identifying monogenic diabetes (parental diabetes, not requiring insulin treatment, HbA1c ≤ 58 mmol/mol [≤7.5%] and a composite clinical probability of MODY >10%) assisted the identification of the dominant (all p ≤ 0.0003) but not recessive cases (all p ≥ 0.2) in Turkey. The presence of certain non-autoimmune extra-pancreatic features greatly assisted the identification of recessive (p < 0.0001, OR 66.9) but not dominant cases.Conclusions/interpretationRecessively inherited mutations are a common cause of monogenic diabetes in populations with high rates of consanguinity. Present MODY-focused genetic testing strategies do not identify affected individuals. To detect all cases of monogenic paediatric diabetes, it is crucial that recessive genes are included in genetic panels and that children are selected for testing if they have certain non-autoimmune extra-pancreatic features in addition to current criteria.

Dataset Information

Identification of Recessively Inherited Genetic Variants Potentially Linked to Pancreatic Cancer Risk.

Publications

Identification of Recessively Inherited Genetic Variants Potentially Linked to Pancreatic Cancer Risk.

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