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  • 1
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 12_Supplement ( 2022-06-15), p. 5874-5874
    Kurzfassung: Diversity in Human Leukocyte Antigen (HLA) genes has been associated with risk of several diseases, including Non-Hodgkin’s lymphoma and ulcerative colitis. Reduced diversity at HLA loci may adversely affect the host’s ability to recognize foreign antigens and tumor neoantigens, and subsequently, increase disease burden. To better understand the role of inherited HLA diversity in colorectal cancer (CRC) risk, we utilized data from a population-based study of 10,347 participants (5,574 CRC cases and 4,773 healthy controls) from the Molecular Epidemiology of Colorectal Cancer Study (MECC). Germline DNA samples were genotyped using genome-wide arrays, and HLA Class I and II four-digit resolution alleles were imputed using SNP2HLA and a reference panel of 5,225 individuals from the Type 1 Diabetes Genetics Consortium. Heterozygosity and homozygosity at each HLA locus and the number of homozygous genotypes at class I loci (A, B, C) and class II loci (DQB1, DRB1, DPB1) were quantified. To examine the joint effect of Class I and Class II loci, we combined the total number of homozygotes for all loci and categorized into 3 groups: heterozygotes at all loci, 1 to 4 homozygotes, or 5 or more homozygotes. Logistic regression was used to estimate the risk of CRC associated with HLA locus homozygosity. Individuals with heterozygous genotypes for all loci served as the reference category, and analyses were adjusted for sex, age, genotyping platform, and global ancestry. Individuals with homozygous genotypes at all 3 Class I genes had an increased risk of CRC when compared to those with heterozygous genotypes at all Class I loci (OR: 1.34; 95% CI: 1.02-1.76, P = 0.033; Ptrend = 0.039). A similar association was observed for Class II loci, with an OR of 1.32 (95% CI: 1.05-1.65, P = 0.015; Ptrend = 0.157). For HLA Class I and II combined, individuals with five or more homozygous genotypes at HLA class I or II loci were at higher risk for developing CRC (OR: 1.84, 95% CI: 1.24-2.73, P = 0.0023; Ptrend = 0.015), when compared to those with all heterozygous genotypes. Our findings support a heterozygote advantage at HLA class I and II loci as a protective factor for CRC. This indicates an important role for HLA genetic variability in the etiology of CRC potentially operating through a mechanism of decreased diversity of tumor neoantigens that can be displayed to the adaptive immune system. Citation Format: Ya-Yu Tsai, Chenxu Qu, Joseph D. Bonner, Rebeca Sanz-Pamplona, Sidney Lindsey, Marilena Melas, Kevin J. McDonnell, Gregory E. Idos, Christopher P. Walker, Kevin K. Tsang, Diane M. Da Silva, Ferran Moratalla, Asaf Maoz, Hedy S. Rennert, W. Martin Kast, Joel K. Greenson, Victor Moreno, Gad Rennert, Stephen B. Gruber, Stephanie L. Schmit. Heterozygote advantage at HLA class I and II loci and colorectal cancer risk [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5874.
    Materialart: Online-Ressource
    ISSN: 1538-7445
    Sprache: Englisch
    Verlag: American Association for Cancer Research (AACR)
    Publikationsdatum: 2022
    ZDB Id: 2036785-5
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 2
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 5_Supplement ( 2023-03-01), p. PD14-03-PD14-03
    Kurzfassung: Background: Fanconi Anemia (FA) proteins facilitate homologous recombination (HR)-mediated repair of DNA interstrand cross-links. Germline monoallelic, pathogenic/likely pathogenic (P/LP) variants in the highly-penetrant (HP) breast cancer (BC) FA genes, BRCA1 (FANCS), BRCA2 (FANCD1) and PALB2 (FANCN)), compromise HR and predispose to hereditary BC. The effects of monoallelic, pathogenic variants in other non-HP BC FA genes upon HR and BC predisposition remain less understood. In this investigation we report the germline mutational landscape of FA gene P/LP variants and somatic molecular consequences of patients with BC diagnoses from City of Hope’s (COH) INSPIRE (Implementing Next-generation Sequencing for Precision Intervention and Risk Evaluation) study. Methods: COH-INSPIRE is a universal access study open to all patients at COH with a personal and/or family history of cancer. Patients undergo custom panel-based germline genetic testing to detect P/LP single nucleotide variants (SNVs), short insertions/deletions (indels) and exon-level deletions/duplications in 155 cancer-predisposition genes including the HP BC FA genes and 15 non-HP BC FA genes [FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCJ (BRIP1), FANCL, FANCM, FANCO (RAD51C), FANCP (SLX4), FANCQ (ERCC4) and FANCU (XRCC2)]. Patients’ tumor specimens undergo somatic tumor ( & gt;400X)-normal ( & gt;180X) whole exome and transcriptome sequencing ( & gt;50 million reads). Somatic sequencing identifies P/LP SNVs, indels, copy number events, and fusions. Secondary analyses assessed somatic homologous recombination deficiency (HRD) by examining tumor mutational signatures, as well as an ensemble HRD score derived by combining individual genomic loss of heterozygosity, telomeric allelic imbalance and large-scale molecular transition scores. Reference comparison of germline and somatic features to current FDA therapeutic guidelines and NIH clinical trials registrations determined eligibility for precision therapeutic intervention and clinical trial enrollment. Results: Of 7,584 patients enrolled in COH-INSPIRE, 1,651 (21.8%) patients had a BC diagnosis. Germline panel testing of BC patients identified 204 (12.4%) with germline P/LP variant in a FA gene. Greater than one third of FA gene-altered BC patients (37.7%) carried a P/LP variant in a non-HP BC FA gene. We observed that BC patients with a non-HP BC FA gene variant may demonstrate HR compromise as evidenced by presence of a Signature 3 mutational profile or an elevated combined HRD score ( & gt; 33 and/or & gt; 42). (Table 1) Further, we identified ostensible segregation of triple negative BC in a family harboring a germline pathogenic variant in FANCG. With regard to precision clinical actionability (i.e. qualification for targeted therapeutic intervention [PARP inhibitor (PARPi)] and/or clinical trial) for patients with advanced stage BC: All patients with germline P/LP HP BC FA gene variant and 20.7% (N=16) of patients with a P/LP FA non-HPBC FA gene variant met criteria for treatment with on/off-label PARPi. 100% of patients with advanced BC with germline P/LP HP BC or non-HPBC FA gene variant qualified for a clinical trial. Conclusions: Patients with BC often carry a germline monoallelic, P/LP FA gene variant; in more than one third, the FA gene alteration occurs in a non-HP BC FA gene. BC patients harboring a monoallelic germline non-HP BC P/LP FA gene may exhibit somatic mutational signatures and HRD scoring consistent with compromise of HR. Somatic tumor evaluation of BC patients with germline P/LP non-HP BC FA gene variants expands opportunities for precision therapeutic intervention and clinical trial enrollment. Continued appraisal will clarify emerging questions of germline non-HP P/LP FA gene-associated autosomal dominant BC risk and management as well as facilitate optimization of precision BC care. Table 1 Summary Molecular Features of BC patients with P/LP Variants in FA gene from COH-INSPIRE Citation Format: Laura Kruper, Kevin McDonnell, Joseph Bonner, Kevin K. Tsang, Veronica Jones, Joanne Mortimer, Sidney S. Lindsey, Ilana Solomon, Heather Hampel, Wai Park, Gregory E. Idos, Stacy Gray, Stephen Gruber. PD14-03 Reappraising the Fanconi Anemia DNA repair pathway in breast cancer risk and precision intervention: Insights and opportunities from the City of Hope INSPIRE study [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD14-03.
    Materialart: Online-Ressource
    ISSN: 1538-7445
    Sprache: Englisch
    Verlag: American Association for Cancer Research (AACR)
    Publikationsdatum: 2023
    ZDB Id: 2036785-5
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 3
    In: Nature Communications, Springer Science and Business Media LLC, Vol. 15, No. 1 ( 2024-04-26)
    Kurzfassung: Genome-wide association studies (GWAS) have identified more than 200 common genetic variants independently associated with colorectal cancer (CRC) risk, but the causal variants and target genes are mostly unknown. We sought to fine-map all known CRC risk loci using GWAS data from 100,204 cases and 154,587 controls of East Asian and European ancestry. Our stepwise conditional analyses revealed 238 independent association signals of CRC risk, each with a set of credible causal variants (CCVs), of which 28 signals had a single CCV. Our cis-eQTL/mQTL and colocalization analyses using colorectal tissue-specific transcriptome and methylome data separately from 1299 and 321 individuals, along with functional genomic investigation, uncovered 136 putative CRC susceptibility genes, including 56 genes not previously reported. Analyses of single-cell RNA-seq data from colorectal tissues revealed 17 putative CRC susceptibility genes with distinct expression patterns in specific cell types. Analyses of whole exome sequencing data provided additional support for several target genes identified in this study as CRC susceptibility genes. Enrichment analyses of the 136 genes uncover pathways not previously linked to CRC risk. Our study substantially expanded association signals for CRC and provided additional insight into the biological mechanisms underlying CRC development.
    Materialart: Online-Ressource
    ISSN: 2041-1723
    Sprache: Englisch
    Verlag: Springer Science and Business Media LLC
    Publikationsdatum: 2024
    ZDB Id: 2553671-0
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 4
    In: Frontiers in Immunology, Frontiers Media SA, Vol. 14 ( 2023-10-24)
    Kurzfassung: Reduced diversity at Human Leukocyte Antigen (HLA) loci may adversely affect the host’s ability to recognize tumor neoantigens and subsequently increase disease burden. We hypothesized that increased heterozygosity at HLA loci is associated with a reduced risk of developing colorectal cancer (CRC). Methods We imputed HLA class I and II four-digit alleles using genotype data from a population-based study of 5,406 cases and 4,635 controls from the Molecular Epidemiology of Colorectal Cancer Study (MECC). Heterozygosity at each HLA locus and the number of heterozygous genotypes at HLA class -I ( A , B , and C ) and HLA class -II loci ( DQB1 , DRB1 , and DPB1 ) were quantified. Logistic regression analysis was used to estimate the risk of CRC associated with HLA heterozygosity. Individuals with homozygous genotypes for all loci served as the reference category, and the analyses were adjusted for sex, age, genotyping platform, and ancestry. Further, we investigated associations between HLA diversity and tumor-associated T cell repertoire features, as measured by tumor infiltrating lymphocytes (TILs; N=2,839) and immunosequencing (N=2,357). Results Individuals with all heterozygous genotypes at all three class I genes had a reduced odds of CRC (OR: 0.74; 95% CI: 0.56-0.97, p = 0.031). A similar association was observed for class II loci, with an OR of 0.75 (95% CI: 0.60-0.95, p = 0.016). For class-I and class-II combined, individuals with all heterozygous genotypes had significantly lower odds of developing CRC (OR: 0.66, 95% CI: 0.49-0.87, p = 0.004) than those with 0 or one heterozygous genotype. HLA class I and/or II diversity was associated with higher T cell receptor (TCR) abundance and lower TCR clonality, but results were not statistically significant. Conclusion Our findings support a heterozygote advantage for the HLA class-I and -II loci, indicating an important role for HLA genetic variability in the etiology of CRC.
    Materialart: Online-Ressource
    ISSN: 1664-3224
    Sprache: Unbekannt
    Verlag: Frontiers Media SA
    Publikationsdatum: 2023
    ZDB Id: 2606827-8
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 5
    In: BMC Genomics, Springer Science and Business Media LLC, Vol. 25, No. 1 ( 2024-04-25)
    Kurzfassung: To evaluate the contribution of germline genetics to regulating the briskness and diversity of T cell responses in CRC, we conducted a genome-wide association study to examine the associations between germline genetic variation and quantitative measures of T cell landscapes in 2,876 colorectal tumors from participants in the Molecular Epidemiology of Colorectal Cancer Study (MECC). Methods Germline DNA samples were genotyped and imputed using genome-wide arrays. Tumor DNA samples were extracted from paraffin blocks, and T cell receptor clonality and abundance were quantified by immunoSEQ (Adaptive Biotechnologies, Seattle, WA). Tumor infiltrating lymphocytes per high powered field (TILs/hpf) were scored by a gastrointestinal pathologist. Regression models were used to evaluate the associations between each variant and the three T-cell features, adjusting for sex, age, genotyping platform, and global ancestry. Three independent datasets were used for replication. Results We identified a SNP (rs4918567) near RBM20 associated with clonality at a genome-wide significant threshold of 5 × 10 − 8 , with a consistent direction of association in both discovery and replication datasets. Expression quantitative trait (eQTL) analyses and in silico functional annotation for these loci provided insights into potential functional roles, including a statistically significant eQTL between the T allele at rs4918567 and higher expression of ADRA2A ( P  = 0.012) in healthy colon mucosa. Conclusions Our study suggests that germline genetic variation is associated with the quantity and diversity of adaptive immune responses in CRC. Further studies are warranted to replicate these findings in additional samples and to investigate functional genomic mechanisms.
    Materialart: Online-Ressource
    ISSN: 1471-2164
    Sprache: Englisch
    Verlag: Springer Science and Business Media LLC
    Publikationsdatum: 2024
    ZDB Id: 2041499-7
    SSG: 12
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 6
    In: Genetics in Medicine, Elsevier BV, Vol. 25, No. 7 ( 2023-07), p. 100837-
    Materialart: Online-Ressource
    ISSN: 1098-3600
    Sprache: Englisch
    Verlag: Elsevier BV
    Publikationsdatum: 2023
    ZDB Id: 1455352-1
    SSG: 12
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 7
    In: Cancer Genetics, Elsevier BV, Vol. 209, No. 3 ( 2016-03), p. 75-81
    Materialart: Online-Ressource
    ISSN: 2210-7762
    Sprache: Englisch
    Verlag: Elsevier BV
    Publikationsdatum: 2016
    ZDB Id: 2599227-2
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 8
    In: Nature Communications, Springer Science and Business Media LLC, Vol. 6, No. 1 ( 2015-07-07)
    Materialart: Online-Ressource
    ISSN: 2041-1723
    Sprache: Englisch
    Verlag: Springer Science and Business Media LLC
    Publikationsdatum: 2015
    ZDB Id: 2553671-0
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 9
    In: Gynecologic Oncology, Elsevier BV, Vol. 159, No. 3 ( 2020-12), p. 869-876
    Materialart: Online-Ressource
    ISSN: 0090-8258
    Sprache: Englisch
    Verlag: Elsevier BV
    Publikationsdatum: 2020
    ZDB Id: 801461-9
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 10
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 5_Supplement ( 2023-03-01), p. P6-02-07-P6-02-07
    Kurzfassung: Purpose: Multiplex gene panel testing (MGPT) is used to identify individuals with an inherited susceptibility to cancer. However, little is known about the uptake of screening and surveillance among patients after MGPT and genetic counseling. The purpose of this study was to measure the uptake of guideline-concordant breast cancer screening after genetic testing and counseling. Patients and Methods: 2,000 patients who met NCCN testing guidelines or had ≥2.5% probability of a pathogenic/likely pathogenic variant (PV) were recruited at three cancer genetics clinics (University of Southern California (USC) Norris Comprehensive Cancer Center, Los Angeles County + USC Medical Center, Stanford Cancer Institute) from July 2014 through November 2016. All patients had 25- or 28-gene MGPT and results were disclosed by a genetic counselor, who provided screening recommendations to patients based on their risk. Post-test surveys were administered at three months, six months, one year, two years, and three years. Results: 1,614/2,000 (80.7%) patients were female and 1,147/1,614 (71.7%) completed at least one survey regarding MRI screening for breast cancer over the three years of longitudinal follow-up. Of these, 94/1,147 (8.2%) patients tested positive for at least one PV in a breast cancer risk gene; 58/94 (61.7%) tested positive for PVs in a high-risk breast cancer gene (BRCA1/2 (n=53), CDH1, PALB2, TP53 (n=5)), and 34/94 (36.2%) of patients tested positive for a PV in a gene characterized as moderate-risk at the time of disclosure (CHEK2, ATM, NBN). MRIs were recommended to 43/58 (74.1%) patients with a high-risk breast cancer gene PV, 20/34 (58.8%) patients with a moderate-risk gene PV, and 171/1,053 (16.2%) patients without a breast cancer risk gene PV. Multivariate logistic regression models revealed that patients with a high-risk gene PV were more likely to undergo MRI screening within 3 months of receiving genetic test results (OR=6.54 95% CI [3.09 - 14.43], p & lt; 0.001), within one year (OR=1.34 95% CI [1.18 - 1.52], p & lt; 0.001), two years (OR=1.43 95% CI [1.24 – 1.65], p & lt; 0.001), and three years (OR=1.44 95% CI [1.25 – 1.66], p & lt; 0.001) when compared to patients without a PV. Patients with a moderate-risk PV were also more likely to have undergone MRI within 3 months of receiving genetic test results (OR=2.89 95% CI [1.05 - 7.81], p=0.036), within one year (OR=1.33 95% CI [1.10 - 1.62] , p=0.004), two years (OR=1.31 95% CI [1.09 - 1.59], p=0.004), and three years (OR=1.44 95% CI [1.18 - 1.76] , p & lt; 0.001), compared to those without a PV (Table 1). Conclusions: After three years of longitudinal follow up of 2000 patients in this multicenter prospective cohort study, patients with a PV in a breast cancer susceptibility gene were more likely to undergo guideline concordant breast MRI compared to patients without a PV. Carriers of high-risk breast cancer gene PVs were over six times as likely to have undergone MRI compared to patients without PVs within the first three months after genetic results disclosure and counseling. These results demonstrate the effectiveness of MGPT and genetic counseling in guiding patients with PVs in breast cancer susceptibility genes to the appropriate adoption of guideline-concordant screening. Odds ratios of MRI screening in patients carrying PV in breast cancer risk genes. Odds in relation to patients who do not carry a PV High risk gene PV: BRCA1/2, CDH1, PALB2, TP53; Moderate Risk PV: CHEK2, ATM, NBN. Percent of patients having undergone an MRI at the specified time points High risk gene PV: BRCA1/2, CDH1, PALB2, TP53; Moderate Risk PV: CHEK2, ATM, NBN. Citation Format: Leah A. Naghi, Charite N. Ricker, Duveen Sturgeon, Julie Culver, Kerry Kingham, Rachel Hodan, Nicolette M. Chun, John Kidd, Joseph Bonner, Christine Hong, Meredith Mills, Sidney S. Lindsey, Kevin McDonnell, Uri Ladabaum, James M. Ford, Stephen Grube, Allison W. Kurian, Gregory E. Idos. Uptake of Breast Cancer MRI Screening in Patients After Multiplex Gene Panel Testing [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-02-07.
    Materialart: Online-Ressource
    ISSN: 1538-7445
    Sprache: Englisch
    Verlag: American Association for Cancer Research (AACR)
    Publikationsdatum: 2023
    ZDB Id: 2036785-5
    Standort Signatur Einschränkungen Verfügbarkeit
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