15. Loss of MSH2 and MSH6 is frequently observed in prostate neoplasms with mismatch repair deficiency

Gokce Toruner

Gokce Toruner, MD, PhD is a laboratory geneticist specialized in clinical cytogenetics and clinical molecular genetics. He is currently an associate professor in the Department of Hematopathology at the MD Anderson Cancer Center. Dr. Toruner received his medical degree from Hacettepe University, Turkey and earned his Ph.D. from Bilkent University, Turkey. Following his research post-doctoral training at the Rutgers-New Jersey Medical School, he completed a clinical laboratory fellowship in clinical molecular genomics and cytogenomics in the same institution. His clinical expertise is on cancer cytogenomics, NGS based solid tumor testing, and liquid biopsy. His current academic activities focus on structural and copy number aberration in neoplasia and incidental constitutional genetic findings detected during somatic genetic testing


Ian Kinga, Jason Salibab, Arpad Danosb, Ariana Gonzalezc, Bethany Baumannd, Christine Walkoe, Erin McMullinf, Gokce Torunerg, Jeanine Ruggerih, Sayed Ali Hosseinii, Kara Buij, Amber Pryzbylskik, Sameek Roychowdhuryl, Shashikant Kulkarnim, Obi L. Griffithb, Malachi Griffithb, Shamini Selvarajahn

aUniversity Health Network and University of Toronto, Toronto, ON, CA; bWashington University School of Medicine, St. Louis, MO, USA; cHeritas, Rosario, Santa Fe, Argentina; dPlanet Pharma/Genentech, Chicago, IL, USA; eMoffitt Cancer Center, Tampa, FL, USA; fBard College at Simon’s Rock, Great Barrington, MA, USA; gThe University of Texas MD Anderson Cancer Center, Houston, TX, USA; hUniversity of Michigan, Ann Arbor, MI, USA; iInvitae, South San Francisco, CA, USA; jCaris Life Sciences, Dallas, TX, USA; kMayo Clinic, Rochester, MN, USA; lOhio State University, Columbus, OH, USA; mBaylor College of Medicine, Houston, TX, USA; nUniversity Health Network, Toronto, ON, CA

Genomic aberrations disrupting fibroblast growth factor receptors (FGFR) signalling have been implicated in several human cancers and are an emerging focus of targeted therapies. While routine large-scale sequencing has resulted in the identification of numerous variants in the FGFR genes, these variants have never been uniformly and comprehensively classified for their clinical significance has been challenging due to their rarity. Thus, we formed the ClinGen FGFR Somatic Cancer Variant Curation Expert Panel (SC-VCEP) to standardize interpretation of FGFR gene variants, principally in FGFR3, but also FGFR1, FGFR2 and FGFR4 through adaptation of AMP/ASCO/CAP[PMID:27993330] and ClinGen/CGC/VICC [PMID: 35101336] guidelines.

Our SC-VCEP is composed of 17 multi-disciplinary members with expertise in FGFR mutation-driven neoplasms, and has received Step 1 approval from ClinGen. Our initial focus has been the assessment of FGFR3 variants in bladder cancers. Using publicly available variant curation databases, a set of 67 single nucleotide variants (SNVs) in FGFR3 was compiled and assessed using the recently published Oncogenicity Standards for Somatic Variants [PMID: 35101336]. From this process, we identified classification challenges including interpreting the intricacies and key metrics of functional assays, and identifying appropriate ensemble bioinformatics approaches for predicting the pathogenicity of FGFR variants. Our SC-VCEP is working to establish and validate specifications to address these gaps, which will ultimately support the generation of publicly available high-quality, clinically significant somatic cancer variant assertions in the CIViC knowledgebase and ClinVar.