ORCID Profile
0000-0002-2416-833X
Current Organisations
Hospital for Sick Children
,
Vector Institute
,
University of Toronto
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Publisher: American Association for Cancer Research (AACR)
Date: 05-2023
DOI: 10.1158/2767-9764.22726360.V1
Abstract: cisCSCE
Publisher: American Association for Cancer Research (AACR)
Date: 05-2023
DOI: 10.1158/2767-9764.CRC-22-0402
Abstract: Li-Fraumeni syndrome (LFS) is an autosomal dominant cancer-predisposition disorder. Approximately 70% of in iduals who fit the clinical definition of LFS harbor a pathogenic germline variant in the TP53 tumor suppressor gene. However, the remaining 30% of patients lack a TP53 variant and even among variant TP53 carriers, approximately 20% remain cancer-free. Understanding the variable cancer penetrance and phenotypic variability in LFS is critical to developing rational approaches to accurate, early tumor detection and risk-reduction strategies. We leveraged family-based whole-genome sequencing and DNA methylation to evaluate the germline genomes of a large, multi-institutional cohort of patients with LFS (n = 396) with variant (n = 374) or wildtype TP53 (n = 22). We identified alternative cancer-associated genetic aberrations in 8/14 wildtype TP53 carriers who developed cancer. Among variant TP53 carriers, 19/49 who developed cancer harbored a pathogenic variant in another cancer gene. Modifier variants in the WNT signaling pathway were associated with decreased cancer incidence. Furthermore, we leveraged the noncoding genome and methylome to identify inherited epimutations in genes including ASXL1, ETV6, and LEF1 that confer increased cancer risk. Using these epimutations, we built a machine learning model that can predict cancer risk in patients with LFS with an area under the receiver operator characteristic curve (AUROC) of 0.725 (0.633–0.810). Our study clarifies the genomic basis for the phenotypic variability in LFS and highlights the immense benefits of expanding genetic and epigenetic testing of patients with LFS beyond TP53. More broadly, it necessitates the dissociation of hereditary cancer syndromes as single gene disorders and emphasizes the importance of understanding these diseases in a holistic manner as opposed to through the lens of a single gene.
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/2767-9764.22535390.V1
Abstract: LFS Variants
Publisher: American Association for Cancer Research (AACR)
Date: 05-2023
DOI: 10.1158/2767-9764.22726390
Abstract: The LFS cohort. b A, /b Patient cohort and characteristics (age of first cancer onset, tumor type) by i TP53 /i status and whether profiling was performed using WGS, methylation or both. AA = adrenal adenoma ACC = adrenocortical carcinoma ALL = acute lymphoid leukemia CPC = choroid plexus carcinoma CSA = chondrosarcoma GCT = germ cell tumor LMS = leiomyosarcoma MFH = malignant fibrous histiocytoma MFS = myxofibrosarcoma NHL = non–Hodgkin lymphoma OS = osteosarcoma RMS = rhabdomyosarcoma. b B, /b Lollipop plot displaying the location and number of SNVs and indels on the canonical i TP53 /i transcript: NM_000546, which consists of a TAD, DBD, and tetramerization domain. i TP53 /i hotspot variants present in our cohort (175, 245, 248, 273, 282) are highlighted.
Publisher: American Association for Cancer Research (AACR)
Date: 05-2023
DOI: 10.1158/2767-9764.C.6547847.V2
Abstract: Li-Fraumeni syndrome (LFS) is an autosomal dominant cancer-predisposition disorder. Approximately 70% of in iduals who fit the clinical definition of LFS harbor a pathogenic germline variant in the i TP53 /i tumor suppressor gene. However, the remaining 30% of patients lack a i TP53 /i variant and even among variant i TP53 /i carriers i , /i approximately 20% remain cancer-free. Understanding the variable cancer penetrance and phenotypic variability in LFS is critical to developing rational approaches to accurate, early tumor detection and risk-reduction strategies. We leveraged family-based whole-genome sequencing and DNA methylation to evaluate the germline genomes of a large, multi-institutional cohort of patients with LFS ( i n /i = 396) with variant ( i n /i = 374) or wildtype i TP53 /i ( i n /i = 22). We identified alternative cancer-associated genetic aberrations in 8/14 wildtype i TP53 /i carriers who developed cancer. Among variant i TP53 /i carriers, 19/49 who developed cancer harbored a pathogenic variant in another cancer gene. Modifier variants in the WNT signaling pathway were associated with decreased cancer incidence. Furthermore, we leveraged the noncoding genome and methylome to identify inherited epimutations in genes including i ASXL1 /i , i ETV6 /i , and i LEF1 /i that confer increased cancer risk. Using these epimutations, we built a machine learning model that can predict cancer risk in patients with LFS with an area under the receiver operator characteristic curve (AUROC) of 0.725 (0.633–0.810). Significance: Our study clarifies the genomic basis for the phenotypic variability in LFS and highlights the immense benefits of expanding genetic and epigenetic testing of patients with LFS beyond i TP53 /i . More broadly, it necessitates the dissociation of hereditary cancer syndromes as single gene disorders and emphasizes the importance of understanding these diseases in a holistic manner as opposed to through the lens of a single gene. /
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/2767-9764.22535390
Abstract: LFS Variants
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/2767-9764.C.6547847.V1
Abstract: Abstract Li-Fraumeni syndrome (LFS) is an autosomal dominant cancer-predisposition disorder. Approximately 70% of in iduals who fit the clinical definition of LFS harbour a pathogenic germline variant in the TP53 tumour suppressor gene. However, the remaining 30% of patients lack a TP53 variant and even among variant TP53 carriers, approximately 20% remain cancer-free. Understanding the variable cancer penetrance and phenotypic variability in LFS is critical to developing rational approaches to accurate, early tumour detection and risk-reduction strategies. We leveraged family-based whole-genome sequencing and DNA methylation to evaluate the germline genomes of a large, multi-institutional cohort of LFS patients (n=396) with variant (n=374) or wildtype TP53 (n=22). We identified alternative cancer-associated genetic aberrations in 8/14 wildtype TP53 carriers who developed cancer. Among variant TP53 carriers, 19/49 who developed cancer harboured a pathogenic variant in another cancer gene. Modifier variants in the WNT signaling pathway were associated with decreased cancer incidence. Furthermore, we leveraged the non-coding genome and methylome to identify inherited epimutations in genes including ASXL1, ETV6 and LEF1 that confer increased cancer risk. Using these epimutations, we built a machine learning model that can predict cancer risk in LFS patients with an AUROC of 0.725 [0.633-0.810]. /
Publisher: American Association for Cancer Research (AACR)
Date: 05-2023
DOI: 10.1158/2767-9764.22726387.V1
Abstract: Germline genetic variants in LFS. b A, /b Classification scheme for genetic variants identified from WGS. The pyramid (top) shows how genes were prioritized into four tiers from highest known cancer predisposition potential to lowest. All variants were then classified using a i Cancer Variant Classification Schema /i (Materials and Methods) into five classes (bottom) based on pathogenicity and whether the gene fell into Tier 1–4. AD: autosomal dominant AR: autosomal recessive CPG: cancer predisposition gene. b B, /b Frequency of P/LP variants in known cancer genes (class 1–3) in LFS, KiCS and 1kGP. Fisher exact test i P /i values for comparisons between the LFS cohorts and KiCS/1kGP shown. b C, /b Kaplan–Meier survival curve comparing patients with P/LP variants in the WNT signaling pathway (yellow), patients with at least one class 1–3 variant (red) and patients with neither WNT signaling or class 1–3 variants (blue). b D, /b Landscape of genetic alterations in cancer genes (class 1–3) in LFS. Annotated with family, cancer type and i TP53 /i variant status. Genetic variants are indicated as a deletion (blue), SNV or indel (red) or duplication (purple). b E, /b The proportion of in iduals in the wildtype and variant i TP53 /i cohorts with classes 1–5 variants (Materials and Methods). b F, /b The number of P/LP variants in cancer genes (class 1–3) in in iduals that developed cancer compared with unaffected in iduals, stratified by i TP53 /i status. b G, /b The number of P/LP variants (class 1–3) in wildtype versus variant i TP53 /i carriers, stratified by cancer status. On the basis of the premise that variants in the WNT signaling pathway are associated with decreased cancer incidence in LFS, these variants were removed from the comparisons made in F and G.
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/2767-9764.22535393
Abstract: KiCS Variants
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/2767-9764.22535396.V1
Abstract: G Variants
Publisher: American Association for Cancer Research (AACR)
Date: 05-2023
DOI: 10.1158/2767-9764.22726351
Abstract: Genomics informed risk stratification guidelines for patients with LFS with a germline i TP53 /i variant
Publisher: American Association for Cancer Research (AACR)
Date: 05-2023
DOI: 10.1158/2767-9764.22726354.V1
Abstract: Variants in cancer predisposition genes (class 1–2) in the wildtype and variant i TP53 /i cohorts, annotated with cancer type, sex, LFS criteria, inheritance status, segregation, variant location, variant function, and zygosity
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/2767-9764.22535384.V1
Abstract: Supplementary Figures
Publisher: American Association for Cancer Research (AACR)
Date: 05-2023
DOI: 10.1158/2767-9764.22726375
Abstract: LFS Cohort
Publisher: American Association for Cancer Research (AACR)
Date: 05-2023
DOI: 10.1158/2767-9764.22726375.V1
Abstract: LFS Cohort
Publisher: American Association for Cancer Research (AACR)
Date: 05-2023
DOI: 10.1158/2767-9764.22726354
Abstract: Variants in cancer predisposition genes (class 1–2) in the wildtype and variant i TP53 /i cohorts, annotated with cancer type, sex, LFS criteria, inheritance status, segregation, variant location, variant function, and zygosity
Publisher: American Association for Cancer Research (AACR)
Date: 05-2023
DOI: 10.1158/2767-9764.22726372
Abstract: Tier 1-3 Gene Lists
Publisher: American Association for Cancer Research (AACR)
Date: 05-2023
DOI: 10.1158/2767-9764.22726372.V1
Abstract: Tier 1-3 Gene Lists
Publisher: American Association for Cancer Research (AACR)
Date: 05-2023
DOI: 10.1158/2767-9764.22726366
Abstract: KiCS Variants
Publisher: American Association for Cancer Research (AACR)
Date: 05-2023
DOI: 10.1158/2767-9764.22726369
Abstract: G Variants
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/2767-9764.22535384
Abstract: Supplementary Figures
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/2767-9764.22535387
Abstract: cisCSCE
Publisher: American Association for Cancer Research (AACR)
Date: 05-2023
DOI: 10.1158/2767-9764.22726366.V1
Abstract: KiCS Variants
Publisher: American Association for Cancer Research (AACR)
Date: 05-2023
DOI: 10.1158/2767-9764.22726381.V1
Abstract: Secondary constitutional epimutations in LFS. b A, /b Concordance between enrichment scores of 931 EWAS probes found significantly associated with cancer status in the discovery cohort and the validation cohort, for both the internal (left) and external (right) validation cohort. Blue = associated with cancer status and a i cis /i -CSCE Red = associated with cancer status but not a i cis /i -CSCE. b B, /b Manhattan plot of adjusted i P /i values from meQTL association tests between the 931 EWAS probes and their most correlated rsSNP. Red line: FDR = 0.1 Blue line: FDR = 0.01 Green points: probes in cancer genes with FDR 0.1. b C, /b Top i cis /i -CSCE in i ETV6, TET3, MIR143, ASXL1, PARVB /i , and i LRG1. /i b D, /b Feature enrichment heatmap of the 259 significant i cis /i -CSCE loci showing adjusted i P /i value (p) and effect size (d). b E, /b ROC curve of the epimutation cancer risk model on the test set. b F, /b UMAP projection of methylation at 259 i cis /i -CSCE for all patients, colored by cancer status. b G, /b UMAP projection of methylation at 259 i cis /i -CSCE for all patients, colored by clusters associated with risk. b H, /b Kaplan–Meier survival curve demonstrating significant differences in survival probability between the three epimutation clusters.
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/2767-9764.22535402
Abstract: LFS Cohort
Publisher: American Association for Cancer Research (AACR)
Date: 05-2023
DOI: 10.1158/2767-9764.22726384.V1
Abstract: Pedigrees and class 1–3 variants for two wildtype i TP53 /i families that fit the classic LFS criteria. b A, /b Pedigree of wildtype i TP53 /i family ( i WT4 /i ) that fits the classic LFS criteria with four family members sequenced, two that developed cancer and two that are cancer-free. b B, /b Pedigree of wildtype i TP53 /i family ( i WT6 /i ) that fits the classic LFS criteria with six family members sequenced: five that developed cancer and one that is cancer-free.
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/2767-9764.22535402.V1
Abstract: LFS Cohort
Publisher: American Association for Cancer Research (AACR)
Date: 05-2023
DOI: 10.1158/2767-9764.22726357.V1
Abstract: Supplementary Figures
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/2767-9764.22535393.V1
Abstract: KiCS Variants
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/2767-9764.22535387.V1
Abstract: cisCSCE
Publisher: American Association for Cancer Research (AACR)
Date: 05-2023
DOI: 10.1158/2767-9764.22726390.V1
Abstract: The LFS cohort. b A, /b Patient cohort and characteristics (age of first cancer onset, tumor type) by i TP53 /i status and whether profiling was performed using WGS, methylation or both. AA = adrenal adenoma ACC = adrenocortical carcinoma ALL = acute lymphoid leukemia CPC = choroid plexus carcinoma CSA = chondrosarcoma GCT = germ cell tumor LMS = leiomyosarcoma MFH = malignant fibrous histiocytoma MFS = myxofibrosarcoma NHL = non–Hodgkin lymphoma OS = osteosarcoma RMS = rhabdomyosarcoma. b B, /b Lollipop plot displaying the location and number of SNVs and indels on the canonical i TP53 /i transcript: NM_000546, which consists of a TAD, DBD, and tetramerization domain. i TP53 /i hotspot variants present in our cohort (175, 245, 248, 273, 282) are highlighted.
Publisher: American Association for Cancer Research (AACR)
Date: 05-2023
DOI: 10.1158/2767-9764.22726384
Abstract: Pedigrees and class 1–3 variants for two wildtype i TP53 /i families that fit the classic LFS criteria. b A, /b Pedigree of wildtype i TP53 /i family ( i WT4 /i ) that fits the classic LFS criteria with four family members sequenced, two that developed cancer and two that are cancer-free. b B, /b Pedigree of wildtype i TP53 /i family ( i WT6 /i ) that fits the classic LFS criteria with six family members sequenced: five that developed cancer and one that is cancer-free.
Publisher: American Association for Cancer Research (AACR)
Date: 05-2023
DOI: 10.1158/2767-9764.22726363
Abstract: LFS Variants
Publisher: American Association for Cancer Research (AACR)
Date: 05-2023
DOI: 10.1158/2767-9764.22726378.V1
Abstract: Differential regulation of WNT signaling and i LEF1 /i in LFS. b A, /b Probes in the WNT signaling pathway ( i WNT4, SMAD3, SFRP4, SERPINF /i ) significantly associated with cancer status. b B, /b Probe in the body of i LEF1 /i (cg03041109) associated with cancer status (FDR = 0.07). b C, /b Methylation of probe in body of i LEF1 /i (cg03041109) across members within each LFS family. Probands almost unanimously have higher i LEF1 /i methylation than their unaffected family members. b D, /b Plasma cfDNA methylation of the body o i f LEF1 /i (chr4:109056901-109057200), between patients with LFS and HBCs. b E, /b Tumor methylation of the body of i LEF1 /i (cg03041109) in CPTs, with and without a germline variant in i TP53 /i .
Publisher: American Association for Cancer Research (AACR)
Date: 05-2023
DOI: 10.1158/2767-9764.22726387
Abstract: Germline genetic variants in LFS. b A, /b Classification scheme for genetic variants identified from WGS. The pyramid (top) shows how genes were prioritized into four tiers from highest known cancer predisposition potential to lowest. All variants were then classified using a i Cancer Variant Classification Schema /i (Materials and Methods) into five classes (bottom) based on pathogenicity and whether the gene fell into Tier 1–4. AD: autosomal dominant AR: autosomal recessive CPG: cancer predisposition gene. b B, /b Frequency of P/LP variants in known cancer genes (class 1–3) in LFS, KiCS and 1kGP. Fisher exact test i P /i values for comparisons between the LFS cohorts and KiCS/1kGP shown. b C, /b Kaplan–Meier survival curve comparing patients with P/LP variants in the WNT signaling pathway (yellow), patients with at least one class 1–3 variant (red) and patients with neither WNT signaling or class 1–3 variants (blue). b D, /b Landscape of genetic alterations in cancer genes (class 1–3) in LFS. Annotated with family, cancer type and i TP53 /i variant status. Genetic variants are indicated as a deletion (blue), SNV or indel (red) or duplication (purple). b E, /b The proportion of in iduals in the wildtype and variant i TP53 /i cohorts with classes 1–5 variants (Materials and Methods). b F, /b The number of P/LP variants in cancer genes (class 1–3) in in iduals that developed cancer compared with unaffected in iduals, stratified by i TP53 /i status. b G, /b The number of P/LP variants (class 1–3) in wildtype versus variant i TP53 /i carriers, stratified by cancer status. On the basis of the premise that variants in the WNT signaling pathway are associated with decreased cancer incidence in LFS, these variants were removed from the comparisons made in F and G.
Publisher: American Association for Cancer Research (AACR)
Date: 05-2023
DOI: 10.1158/2767-9764.22726381
Abstract: Secondary constitutional epimutations in LFS. b A, /b Concordance between enrichment scores of 931 EWAS probes found significantly associated with cancer status in the discovery cohort and the validation cohort, for both the internal (left) and external (right) validation cohort. Blue = associated with cancer status and a i cis /i -CSCE Red = associated with cancer status but not a i cis /i -CSCE. b B, /b Manhattan plot of adjusted i P /i values from meQTL association tests between the 931 EWAS probes and their most correlated rsSNP. Red line: FDR = 0.1 Blue line: FDR = 0.01 Green points: probes in cancer genes with FDR 0.1. b C, /b Top i cis /i -CSCE in i ETV6, TET3, MIR143, ASXL1, PARVB /i , and i LRG1. /i b D, /b Feature enrichment heatmap of the 259 significant i cis /i -CSCE loci showing adjusted i P /i value (p) and effect size (d). b E, /b ROC curve of the epimutation cancer risk model on the test set. b F, /b UMAP projection of methylation at 259 i cis /i -CSCE for all patients, colored by cancer status. b G, /b UMAP projection of methylation at 259 i cis /i -CSCE for all patients, colored by clusters associated with risk. b H, /b Kaplan–Meier survival curve demonstrating significant differences in survival probability between the three epimutation clusters.
Publisher: American Association for Cancer Research (AACR)
Date: 05-2023
DOI: 10.1158/2767-9764.22726360
Abstract: cisCSCE
Publisher: American Association for Cancer Research (AACR)
Date: 05-2023
DOI: 10.1158/2767-9764.22726351.V1
Abstract: Genomics informed risk stratification guidelines for patients with LFS with a germline i TP53 /i variant
Publisher: American Association for Cancer Research (AACR)
Date: 05-2023
DOI: 10.1158/2767-9764.22726369.V1
Abstract: G Variants
Publisher: American Association for Cancer Research (AACR)
Date: 05-2023
DOI: 10.1158/2767-9764.C.6547847
Abstract: Li-Fraumeni syndrome (LFS) is an autosomal dominant cancer-predisposition disorder. Approximately 70% of in iduals who fit the clinical definition of LFS harbor a pathogenic germline variant in the i TP53 /i tumor suppressor gene. However, the remaining 30% of patients lack a i TP53 /i variant and even among variant i TP53 /i carriers i , /i approximately 20% remain cancer-free. Understanding the variable cancer penetrance and phenotypic variability in LFS is critical to developing rational approaches to accurate, early tumor detection and risk-reduction strategies. We leveraged family-based whole-genome sequencing and DNA methylation to evaluate the germline genomes of a large, multi-institutional cohort of patients with LFS ( i n /i = 396) with variant ( i n /i = 374) or wildtype i TP53 /i ( i n /i = 22). We identified alternative cancer-associated genetic aberrations in 8/14 wildtype i TP53 /i carriers who developed cancer. Among variant i TP53 /i carriers, 19/49 who developed cancer harbored a pathogenic variant in another cancer gene. Modifier variants in the WNT signaling pathway were associated with decreased cancer incidence. Furthermore, we leveraged the noncoding genome and methylome to identify inherited epimutations in genes including i ASXL1 /i , i ETV6 /i , and i LEF1 /i that confer increased cancer risk. Using these epimutations, we built a machine learning model that can predict cancer risk in patients with LFS with an area under the receiver operator characteristic curve (AUROC) of 0.725 (0.633–0.810). Significance: Our study clarifies the genomic basis for the phenotypic variability in LFS and highlights the immense benefits of expanding genetic and epigenetic testing of patients with LFS beyond i TP53 /i . More broadly, it necessitates the dissociation of hereditary cancer syndromes as single gene disorders and emphasizes the importance of understanding these diseases in a holistic manner as opposed to through the lens of a single gene. /
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/2767-9764.22535399.V1
Abstract: Tier 1-3 Gene Lists
Publisher: American Association for Cancer Research (AACR)
Date: 05-2023
DOI: 10.1158/2767-9764.22726378
Abstract: Differential regulation of WNT signaling and i LEF1 /i in LFS. b A, /b Probes in the WNT signaling pathway ( i WNT4, SMAD3, SFRP4, SERPINF /i ) significantly associated with cancer status. b B, /b Probe in the body of i LEF1 /i (cg03041109) associated with cancer status (FDR = 0.07). b C, /b Methylation of probe in body of i LEF1 /i (cg03041109) across members within each LFS family. Probands almost unanimously have higher i LEF1 /i methylation than their unaffected family members. b D, /b Plasma cfDNA methylation of the body o i f LEF1 /i (chr4:109056901-109057200), between patients with LFS and HBCs. b E, /b Tumor methylation of the body of i LEF1 /i (cg03041109) in CPTs, with and without a germline variant in i TP53 /i .
Publisher: American Association for Cancer Research (AACR)
Date: 05-2023
DOI: 10.1158/2767-9764.22726357
Abstract: Supplementary Figures
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/2767-9764.22535396
Abstract: G Variants
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/2767-9764.22535399
Abstract: Tier 1-3 Gene Lists
Publisher: American Association for Cancer Research (AACR)
Date: 05-2023
DOI: 10.1158/2767-9764.22726363.V1
Abstract: LFS Variants
No related grants have been discovered for Anna Goldenberg.