EPCO-04. GENOMIC AND EPIGENOMIC HALLMARKS OF SCHWANNOMATOSIS SCHWANNOMAS

Abstract Schwannomatosis (SWNTS) is a genetic cancer predisposition syndrome that manifests as multiple and often, painful neuronal tumors called schwannomas (SWNs). Very little is known about the epigenomic and genomic alterations in SWNTS related SWNs (SWNTS-SWNs) other than germline mutations in SMARCB1 and LZTR1 plus somatic mutations in NF2 and loss of heterozygosity in chromosome 22q. Herein, we have comprehensively established the specific molecular signatures of SWNTS-SWNs. We found that tumor anatomic location was associated with pain and distinct DNA methylation and transcriptional signatures. DNA sequencing revealed several novel non-22q deletions, specifically in LZTR1-mutant cases. Whole-genome sequencing identified novel recurrent structural rearrangements. Further, chromosomal aberrations in SWNTS-SWNs were accompanied by increased transcription of mismatch repair genes. Our transcriptome analysis detected the SH3PXD2A-HTRA1 gene fusion in SWNTS-SWNs, more commonly in LZTR1-mutant tumors. In addition, we identified the specific genetic, epigenetic, and transcriptional hallmarks of painful SWNs that may be harnessed to develop new treatments for this debilitating syndrome.

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Epigenomic, genomic, and transcriptomic landscape of schwannomatosis

Acta Neuropathologica ◽

10.1007/s00401-020-02230-x ◽

2020 ◽

Vol 141 (1) ◽

pp. 101-116

Author(s):

Sheila Mansouri ◽

Suganth Suppiah ◽

Yasin Mamatjan ◽

Irene Paganini ◽

Jeffrey C. Liu ◽

...

Keyword(s):

Gene Fusion ◽

Somatic Mutations ◽

Genomic Analysis ◽

Germline Mutations ◽

Tumor Location ◽

Molecular Signature ◽

Structural Rearrangements ◽

Genomic Features ◽

Cancer Predisposition Syndrome ◽

Neuronal Tumors

AbstractSchwannomatosis (SWNTS) is a genetic cancer predisposition syndrome that manifests as multiple and often painful neuronal tumors called schwannomas (SWNs). While germline mutations in SMARCB1 or LZTR1, plus somatic mutations in NF2 and loss of heterozygosity in chromosome 22q have been identified in a subset of patients, little is known about the epigenomic and genomic alterations that drive SWNTS-related SWNs (SWNTS-SWNs) in a majority of the cases. We performed multiplatform genomic analysis and established the molecular signature of SWNTS-SWNs. We show that SWNTS-SWNs harbor distinct genomic features relative to the histologically identical non-syndromic sporadic SWNs (NS-SWNS). We demonstrate the existence of four distinct DNA methylation subgroups of SWNTS-SWNs that are associated with specific transcriptional programs and tumor location. We show several novel recurrent non-22q deletions and structural rearrangements. We detected the SH3PXD2A-HTRA1 gene fusion in SWNTS-SWNs, with predominance in LZTR1-mutant tumors. In addition, we identified specific genetic, epigenetic, and actionable transcriptional programs associated with painful SWNTS-SWNs including PIGF, VEGF, MEK, and MTOR pathways, which may be harnessed for management of this syndrome.

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The role of germline mutations in the BRCA1/2 and mismatch repair genes in men ascertained for early-onset and/or familial prostate cancer

Familial Cancer ◽

10.1007/s10689-015-9832-x ◽

2015 ◽

Vol 15 (1) ◽

pp. 111-121 ◽

Cited By ~ 15

Author(s):

Sofia Maia ◽

Marta Cardoso ◽

Paula Paulo ◽

Manuela Pinheiro ◽

Pedro Pinto ◽

...

Keyword(s):

Prostate Cancer ◽

Mismatch Repair ◽

Early Onset ◽

Germline Mutations ◽

Mismatch Repair Genes ◽

Repair Genes

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Somatic mutations in mismatch repair genes in sporadic gastric carcinomas are not a cause but a consequence of the mutator phenotype

Cancer Genetics and Cytogenetics ◽

10.1016/j.cancergencyto.2007.09.022 ◽

2008 ◽

Vol 180 (2) ◽

pp. 110-114 ◽

Cited By ~ 19

Author(s):

Mafalda Pinto ◽

Ying Wu ◽

Rob G.J. Mensink ◽

Luís Cirnes ◽

Raquel Seruca ◽

...

Keyword(s):

Mismatch Repair ◽

Somatic Mutations ◽

Mismatch Repair Genes ◽

Mutator Phenotype ◽

Gastric Carcinomas ◽

Repair Genes

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Genetic counseling processes and outcomes among prostate cancer patients (ProGen).

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.7_suppl.tps343 ◽

2019 ◽

Vol 37 (7_suppl) ◽

pp. TPS343-TPS343 ◽

Cited By ~ 1

Author(s):

Donna Rachel Vatnick ◽

Sandjida Aktar ◽

Jill E. Stopfer ◽

Lindsay Kipnis ◽

Samantha K. Culver ◽

...

Keyword(s):

Prostate Cancer ◽

Dna Repair ◽

Genetic Counseling ◽

Genetic Testing ◽

Cancer Risk ◽

Mismatch Repair ◽

Metastatic Prostate Cancer ◽

Germline Mutations ◽

Mismatch Repair Genes ◽

Repair Genes

TPS343 Background: Prostate cancer (PC) is among the leading causes of cancer mortality in males. Recent studies found 8-12% of advanced PC cases may be hereditary. Germline mutations have been reported in BRCA1/2, other DNA repair genes including ATM, CHEK2, PALB2 and DNA mismatch repair genes. Genetic testing can inform treatment decisions including drug targeting, such as PARP inhibitors for men with BRCA mutations, and checkpoint inhibitors for those with pathogenic mutations in mismatch repair genes2. Discovering a pathogenic mutation associated with increased cancer risk also prompts dissemination of this information to family, where subsequent testing can lead to risk stratification and impactful opportunities for cancer screening and prevention. It is critical that men with high risk and potentially lethal prostate cancer routinely be offered genetic testing as a component of their cancer care. Genetic counseling services are limited, and more efficient services are needed. Methods: We are investigating video education prior to genetic testing compared with in-person pretest counseling with a licensed genetic counselor (GC). ProGen is an ongoing randomized trial evaluating two distinct models of cancer genetics service delivery in 450 PC cases over a two-year period. The study is conducted in collaboration with Ambry Genetics utilizing a 67-gene cancer panel. The primary aim is analysis of the proportion and type of germline mutations identified. Secondary aims include testing uptake by arm, evaluation of distress, knowledge, satisfaction with testing services, family communication, and impact on cancer care. Results are communicated by telephone with a GC. Inclusion criteria are: potentially lethal PC (metastatic, localized with Gleason score ≥8, rising/persistent PSA after local therapy), early diagnosis (≤ 55 years), prior malignancy, and/or family history potentially indicating a hereditary cancer risk. Enrollment is 74% completed at a single institution. (NCT03328091). 1 Pritchard CC, et al. Inherited DNA‐repair gene mutations in men with metastatic prostate cancer. NEJM. 2016;375:443 2 Mateo J, et al. DNA-Repair Defects and Olaparib in Metastatic Prostate Cancer. NEJM . 2015;373(18):1697-1708 Clinical trial information: NCT03328091.

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