A Rare Variant in ERF (rs144812092) Predisposes to Prostate and Bladder Cancers in an Extended Pedigree

Cannon‐Albright, Lisa A.; Teerlink, Craig C.; Stevens, Jeff; Huang, Franklin W.; Sipeky, Csilla; Schleutker, Johanna; Hernandez, Rolando; Facelli, Julio C.; Agarwal, Neeraj; Trump, Donald L.

doi:10.3390/cancers13102399

Cited by 4 publications

(5 citation statements)

References 32 publications

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“…High-risk pedigree studies remain a powerful mechanism for identification of predisposition genes and variants [ 31 , 32 , 33 , 34 ]. This has proven true for prostate cancer [ 35 , 36 ], although such high-risk prostate cancer pedigrees remain infrequently presented. Here, we have taken advantage of unique Utah resources, combined with an unusual and powerful study design that includes sampled affected cousin pairs, to generate, and begin to evaluate, a strong list of candidate predisposition variants for prostate cancer.…”

Section: Discussionmentioning

confidence: 99%

“…Extensive linked genealogic and disease registries existing in Utah have been used to identify and study thousands of Utah high-risk pedigrees [ 37 ]. We have previously used this same sequencing approach in affected cousins belonging to high-risk pedigrees to identify multiple candidate predisposition variants for several different phenotypes, including GOLM1 for melanoma [ 38 ], ERF for bladder cancer [ 36 ], FANCM for colorectal cancer [ 39 ], MEGF for osteoporosis [ 40 ], HOXC4 for Chiari Malformations [ 41 ], and multiple candidates for Alzheimer’s [ 42 ] and exceptional longevity [ 43 ], among others.…”

Section: Discussionmentioning

confidence: 99%

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High-Risk Pedigree Study Identifies LRBA (rs62346982) as a Likely Predisposition Variant for Prostate Cancer

Cannon‐Albright

Stevens

Facelli

et al. 2023

Cancers

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There is evidence for contribution of inherited factors to prostate cancer, and more specifically to lethal prostate cancer, but few responsible genes/variants have been identified. We examined genetic sequence data for 51 affected cousin pairs who each died from prostate cancer and who were members of high-risk prostate cancer pedigrees in order to identify rare variants shared by the cousins as candidate predisposition variants. Candidate variants were tested for association with prostate cancer risk in UK Biobank data. Candidate variants were also assayed in 1195 additional sampled Utah prostate cancer cases. We used 3D protein structure prediction methods to analyze structural changes and provide insights into mechanisms of pathogenicity. Almost 4000 rare (<0.005) variants were identified as shared in the 51 affected cousin pairs. One candidate variant was also significantly associated with prostate cancer risk among the 840 variants with data in UK Biobank, in the gene LRBA (p = 3.2 × 10−5; OR = 2.09). The rare risk variant in LRBA was observed to segregate in five pedigrees. The overall predicted structures of the mutant protein do not show any significant overall changes upon mutation, but the mutated structure loses a helical structure for the two residues after the mutation. This unique analysis of closely related individuals with lethal prostate cancer, who were members of high-risk prostate cancer pedigrees, has identified a strong set of candidate predisposition variants which should be pursued in independent studies. Validation data for a subset of the candidates identified are presented, with strong evidence for a rare variant in LRBA.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

High-Risk Pedigree Study Identifies LRBA (rs62346982) as a Likely Predisposition Variant for Prostate Cancer

Cannon‐Albright

Stevens

Facelli

et al. 2023

Cancers

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“…The Genetic Epidemiology biorepository at University of Utah has been the source of many high‐risk cancer pedigree studies and these studies have been critical to the identification of multiple cancer predisposition genes, including BRCA1 , BRCA2 and CDKN2A 50‐52 . More recently, similar studies of small sets of high‐risk pedigrees have presented multiple new cancer predisposition variants, including GOLM1 ‐melanoma 53 and ERF ‐prostate/bladder cancer, 54 among others. While many lung cancers are associated with tobacco use, Utah is recognized to have the lowest rates of tobacco use in the nation, which potentially served to reduce noise from this recognized lung cancer risk factor which can also cluster in relatives.…”

Section: Discussionmentioning

confidence: 99%

“…The Genetic Epidemiology biorepository at University of Utah has been the source of many high-risk cancer pedigree studies and these studies have been critical to the identification of multiple cancer predisposition genes, including BRCA1, BRCA2 and CDKN2A. [50][51][52] More recently, similar studies of small sets of high-risk pedigrees have presented multiple new cancer predisposition variants, including GOLM1melanoma 53 and ERF-prostate/bladder cancer, 54 limited number of candidate variants with case/control data available in UK Biobank for validation. While the cases sequenced were NSNSCLC cases, the pedigrees were identified as high-risk for lung cancer generally, and the UK Biobank identification was of lung cancer cases only; therefore, it is possible that these findings are not specific to NSNSCLC.…”

Section: S X 60smentioning

confidence: 99%

A rare FGF5 candidate variant (rs112475347) for predisposition to nonsquamous, nonsmall‐cell lung cancer

Cannon‐Albright

Teerlink

Stevens

et al. 2023

Intl Journal of Cancer

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A unique approach with rare resources was used to identify candidate variants predisposing to familial nonsquamous nonsmall‐cell lung cancers (NSNSCLC). We analyzed sequence data from NSNSCLC‐affected cousin pairs belonging to high‐risk lung cancer pedigrees identified in a genealogy of Utah linked to statewide cancer records to identify rare, shared candidate predisposition variants. Variants were tested for association with lung cancer risk in UK Biobank. Evidence for linkage with lung cancer was also reviewed in families from the Genetic Epidemiology of Lung Cancer Consortium. Protein prediction modeling compared the mutation with reference. We sequenced NSNSCLC‐affected cousin pairs from eight high‐risk lung cancer pedigrees and identified 66 rare candidate variants shared in the cousin pairs. One variant in the FGF5 gene also showed significant association with lung cancer in UKBiobank. This variant was observed in 3/163 additional sampled Utah lung cancer cases, 2 of whom were related in another independent pedigree. Modeling of the predicted protein predicted a second binding site for SO4 that may indicate binding differences. This unique study identified multiple candidate predisposition variants for NSNSCLC, including a rare variant in FGF5 that was significantly associated with lung cancer risk and that segregated with lung cancer in the two pedigrees in which it was observed. FGF5 is an oncogenic factor in several human cancers, and the mutation found here (W81C) changes the binding ability of heparan sulfate to FGF5, which might lead to its deregulation. These results support FGF5 as a potential NSNSCLC predisposition gene and present additional candidate predisposition variants.

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“…Pedigree studies based on the UPDB have previously provided the identification of BRCA1 and BRCA2 [5][6][7], and more recently have identified additional rare cancer predisposition variants (GOLM1 [38]; CELF4 [39]; FANCM [40]; ERF [41]; LRBA [42]; FGF5 [43]) in similar sets of sampled high-risk pedigrees. The identification of the known pathogenic PMS2 and CHEK2 variants as well as the initial BRCA1 Q1313X-variant-segregating pedigree found in the present study provide additional validation of this predisposition gene identification approach in high-risk pedigrees.…”

Section: Discussionmentioning

confidence: 99%

A Rare Variant in MDH2 (rs111879470) Is Associated with Predisposition to Recurrent Breast Cancer in an Extended High-Risk Pedigree

Cannon-Albright,

Stevens,

Teerlink

et al. 2023

Cancers

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A significant fraction of breast cancer recurs, with lethal outcome, but specific genetic variants responsible have yet to be identified. Five cousin pairs with recurrent breast cancer from pedigrees with a statistical excess of recurrent breast cancer were sequenced to identify rare, shared candidate predisposition variants. The candidates were tested for association with breast cancer risk with UKBiobank data. Additional breast cancer cases were assayed for a subset of candidate variants to test for co-segregation. Three-dimensional protein structure prediction methods were used to investigate how the mutation under consideration is predicted to change structural and electrostatic properties in the mutated protein. One hundred and eighty-one rare candidate predisposition variants were shared in at least one cousin pair from a high-risk pedigree. A rare variant in MDH2 was found to segregate with breast-cancer-affected relatives in one extended pedigree. MDH2 is an estrogen-stimulated gene encoding the protein malate dehydrogenase, which catalyzes the reversible oxidation of malate to oxaloacetate. The molecular simulation results strongly suggest that the mutation changes the NAD+ binding pocket electrostatics of MDH2. This small sequencing study, using a powerful approach based on recurrent breast cancer cases from high-risk pedigrees, identified a set of strong candidate variants for inherited predisposition for breast cancer recurrence, including MDH2, which should be pursued in other resources.

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A Rare Variant in ERF (rs144812092) Predisposes to Prostate and Bladder Cancers in an Extended Pedigree

Cited by 4 publications

References 32 publications

High-Risk Pedigree Study Identifies LRBA (rs62346982) as a Likely Predisposition Variant for Prostate Cancer

High-Risk Pedigree Study Identifies LRBA (rs62346982) as a Likely Predisposition Variant for Prostate Cancer

A rare FGF5 candidate variant (rs112475347) for predisposition to nonsquamous, nonsmall‐cell lung cancer

A Rare Variant in MDH2 (rs111879470) Is Associated with Predisposition to Recurrent Breast Cancer in an Extended High-Risk Pedigree

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