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Ashkenazi Jewish and Other White APC I1307K Carriers Are at Higher Risk for Multiple Cancers.

ABSTRACT: Purpose: APC I1307K has a higher prevalence among Ashkenazi Jews (AJ), and a two-fold increased risk for colorectal cancer (CRC) compared to non-Jewish populations. We assessed CRC and extracolonic malignancies among I1307K carriers from AJ and non-AJ whites (NAW). Methods: We compared the rate of I1307K in cancer patients who underwent germline genetic testing via a multi-gene panel with healthy subjects retrieved from the gnomAD database. Cases undergoing testing were not selected and testing was undertaken through a commercial laboratory. Results: Overall, 586/7624 (7.6%) AJ with cancer carried I1307K compared to 342/4918 (6.9%) in the AJ control group (p = NS). In the NAW, 318/141,673 (0.2%) cancer patients and 73/58,918 (0.1%) controls carried the variant [OR = 1.8, (95% CI 1.41−2.35), p < 0.001]. I1307K in NAW was associated with an increased risk of CRC [OR = 1.95, (95% CI 1.39−2.73), p < 0.01], melanoma [OR = 2.54, (95% CI 1.57−3.98)], breast [females, OR = 1.73, (95% CI 1.18−2.65), p < 0.01], and prostate cancer [males, OR = 2.42, (95% CI 1.45−3.94), p < 0.01]. Among AJ, the variant increased the risk for CRC [OR = 1.67, (95% CI 1.36−2.05), p < 0.001] and renal cancer [OR = 1.64, (95% CI 1.04−2.47)]. AJ men had a higher risk for any cancer [OR = 1.32, (95% CI 1.05−1.66), p < 0.05] and melanoma [OR = 2.04, (95% CI 1.24−3.22); p < 0.05]. Conclusions: This is the most extensive study to date conducted on I1307K carriers, although it is amenable to selection bias. NAW carrying I1307K had a higher risk of any cancer and several specific cancer types, whereas AJ carrying the variant had a risk for only a few select cancers. Our data add to the research base on I1307 carriers concerning future risk management.

SUBMITTER: Forkosh E

PROVIDER: S-EPMC9740723 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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Ashkenazi Jewish and Other White <i>APC</i> I1307K Carriers Are at Higher Risk for Multiple Cancers.

Forkosh Esther E Bergel Michael M Hatchell Kathryn E KE Nielsen Sarah M SM Heald Brandie B Benson Ariel A AA Friedman Eitan E Esplin Edward D ED Katz Lior H LH

Cancers 20221129 23

Purpose: APC I1307K has a higher prevalence among Ashkenazi Jews (AJ), and a two-fold increased risk for colorectal cancer (CRC) compared to non-Jewish populations. We assessed CRC and extracolonic malignancies among I1307K carriers from AJ and non-AJ whites (NAW). Methods: We compared the rate of I1307K in cancer patients who underwent germline genetic testing via a multi-gene panel with healthy subjects retrieved from the gnomAD database. Cases undergoing testing were not selected and testing ...[more]

PMID: 36497357

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Project description:BackgroundEvidence has accumulated that multiple genetic and environmental factors play important roles in determining susceptibility to type 2 diabetes (T2D). Although variants from candidate genes have become prime targets for genetic analysis, few studies have considered their interplay. Our goal was to evaluate interactions among SNPs within genes frequently identified as associated with T2D.Methods/principal findingsLogistic regression was used to study interactions among 4 SNPs, one each from HNF4A[rs1884613], TCF7L2[rs12255372], WFS1[rs10010131], and KCNJ11[rs5219] in a case-control Ashkenazi sample of 974 diabetic subjects and 896 controls. Nonparametric multifactor dimensionality reduction (MDR) and generalized MDR (GMDR) were used to confirm findings from the logistic regression analysis. HNF4A and WFS1 SNPs were associated with T2D in logistic regression analyses [P<0.0001, P<0.0002, respectively]. Interaction between these SNPs were also strong using parametric or nonparametric methods: the unadjusted odds of being affected with T2D was 3 times greater in subjects with the HNF4A and WFS1 risk alleles than those without either (95% CI = [1.7-5.3]; P<or=0.0001). Although the univariate association between the TCF7L2 SNP and T2D was relatively modest [P = 0.02], when paired with the HNF4A SNP, the OR for subjects with risk alleles in both SNPs was 2.4 [95% CI = 1.7-3.4; P<or=0.0001]. The KCNJ11 variant reached significance only when paired with either the HNF4A or WFSI SNPs: unadjusted ORs were 2.0 [95% CI = 1.4-2.8; P<or=0.0001] and 2.3 [95% CI = 1.2-4.4; P<or=0.0001], respectively. MDR and GMDR results were consistent with the parametric findings.ConclusionsThese results provide evidence of strong independent associations between T2D and SNPs in HNF4A and WFS1 and their interaction in our Ashkenazi sample. We also observed an interaction in the nonparametric analysis between the HNF4A and KCNJ11 SNPs (P<or=0.001), demonstrating that an independently non-significant variant may interact with another variant resulting in an increased disease risk.

Project description:ImportanceInformation on age-specific risk for Parkinson disease (PD) in patients with Gaucher disease (GD) and glucocerebrosidase (GBA) heterozygotes is important for understanding the pathophysiology of the genetic association and for counseling these populations.ObjectiveTo estimate the age-specific risk for PD in Ashkenazi Jewish patients with type 1 GD and in GBA heterozygotes.Design, setting, and participantsThe study included patients with GD from 2 tertiary centers, Shaare Zedek Medical Center, Jerusalem, Israel (n = 332) and Mount Sinai School of Medicine, New York, New York (n = 95). GBA noncarrier non-PD spouse control participants were recruited at the Center for Parkinson's Disease at Columbia University, New York (n = 77). All participants were Ashekanzi Jewish and most patients (98.1%) with GD carried at least 1 N370S mutation.Main outcomes and measuresThe main outcome measure was a diagnosis of PD. Diagnosis was established in patients with GD on examination. We used a validated family history interview that identifies PD with a sensitivity of 95.5% and specificity of 96.2% to identify PD in family members. Kaplan-Meier survival curves were used to estimate age-specific PD risk among patients with GD (n = 427), among their parents who are obligate GBA mutation carriers (heterozygotes, n = 694), and among noncarriers (parents of non-PD, non-GD control participants, n = 154). The age-specific risk was compared among groups using the log-rank test.ResultsAmong those who developed PD, patients with GD had a younger age at onset than GBA heterozygotes (mean, 54.2 vs 65.2 years, respectively; P = .003). Estimated age-specific risk for PD at 60 and 80 years of age was 4.7% and 9.1% among patients with GD, 1.5% and 7.7% among heterozygotes, and 0.7% and 2.1% among noncarriers, respectively. The risk for PD was higher in patients with GD than noncarriers (P = .008, log-rank test) and in heterozygotes than noncarriers (P = .03, log-rank test), but it did not reach statistical significance between patients with GD and GBA heterozygotes (P = .07, log-rank test).Conclusions and relevancePatients with GD and GBA heterozygotes have an increased age-specific risk for PD compared with control individuals, with a similar magnitude of PD risk by 80 years of age; however, the number of mutant alleles may play an important role in age at PD onset.

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Ashkenazi Jewish and Other White APC I1307K Carriers Are at Higher Risk for Multiple Cancers.

Publications

Ashkenazi Jewish and Other White <i>APC</i> I1307K Carriers Are at Higher Risk for Multiple Cancers.

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