Advancing Precision Oncology in Hereditary Paraganglioma-Pheochromocytoma Syndromes: Integrated Interpretation and Data Sharing of the Germline and Tumor Genomes

Overview

Journal Cancers (Basel)

Publisher MDPI

Specialty Oncology

Date 2024 Mar 13

PMID 38473309

Authors

Huma Q Rana

Diane R Koeller

McKenzie Walker

Busra Unal

Alison Schwartz Levine

Anu Chittenden

Raymond A Isidro

Connor P Hayes

Monica D Manam

Ryan M Buehler

Danielle K Manning

Justine A Barletta

Jason L Hornick

Judy E Garber

Arezou A Ghazani

Int2grate Oncology Consortium

Affiliations

Soon will be listed here.

Abstract

Standard methods of variant assessment in hereditary cancer susceptibility genes are limited by the lack of availability of key supporting evidence. In cancer, information derived from tumors can serve as a useful source in delineating the tumor behavior and the role of germline variants in tumor progression. We have previously demonstrated the value of integrating tumor and germline findings to comprehensively assess germline variants in hereditary cancer syndromes. Building on this work, herein, we present the development and application of the INTGRATE|HPPGL platform. INTGRATE (INTegrated INTerpretation of GeRmline And Tumor gEnomes) is a multi-institution oncology consortium that aims to advance the integrated application of constitutional and tumor data and share the integrated variant information in publicly accessible repositories. The INTGRATE|HPPGL platform enables automated parsing and integrated assessment of germline, tumor, and genetic findings in hereditary paraganglioma-pheochromocytoma syndromes (HPPGLs). Using INTGRATE|HPPGL, we analyzed 8600 variants in succinate dehydrogenase (SDHx) genes and their associated clinical evidence. The integrated evidence includes germline variants in SDHx genes; clinical genetics evidence: personal and family history of HPPGL-related tumors; tumor-derived evidence: somatic inactivation of SDHx alleles, and status in gastrointestinal stromal tumors (GISTs), multifocal or extra-adrenal tumors, and metastasis status; and immunohistochemistry staining status for and genes. After processing, 8600 variants were submitted programmatically from the INTGRATE|HPPGL platform to ClinVar via a custom-made INTGRATE|HPPGL variant submission schema and an application programming interface (API). This novel integrated variant assessment and data sharing in hereditary cancers aims to improve the clinical assessment of genomic variants and advance precision oncology.

References

Fishbein L, Del Rivero J, Else T, Howe J, Asa S, Cohen D . The North American Neuroendocrine Tumor Society Consensus Guidelines for Surveillance and Management of Metastatic and/or Unresectable Pheochromocytoma and Paraganglioma. Pancreas. 2021; 50(4):469-493. DOI: 10.1097/MPA.0000000000001792. View

Koeller D, Manning D, Schwartz A, Chittenden A, Hayes C, Abraamyan F . An optimized protocol for evaluating pathogenicity of germline variants in patients suspected with von Hippel-Lindau syndrome: Using somatic genome to inform the role of germline variants. MethodsX. 2022; 9:101761. PMC: 9237939. DOI: 10.1016/j.mex.2022.101761. View

Gill A, Benn D, Chou A, Clarkson A, Muljono A, Meyer-Rochow G . Immunohistochemistry for SDHB triages genetic testing of SDHB, SDHC, and SDHD in paraganglioma-pheochromocytoma syndromes. Hum Pathol. 2010; 41(6):805-14. DOI: 10.1016/j.humpath.2009.12.005. View

Taieb D, Wanna G, Ahmad M, Lussey-Lepoutre C, Perrier N, Nolting S . Clinical consensus guideline on the management of phaeochromocytoma and paraganglioma in patients harbouring germline SDHD pathogenic variants. Lancet Diabetes Endocrinol. 2023; 11(5):345-361. PMC: 10182476. DOI: 10.1016/S2213-8587(23)00038-4. View

Amar L, Pacak K, Steichen O, Akker S, Aylwin S, Baudin E . International consensus on initial screening and follow-up of asymptomatic SDHx mutation carriers. Nat Rev Endocrinol. 2021; 17(7):435-444. PMC: 8205850. DOI: 10.1038/s41574-021-00492-3. View

Andrews K, Ascher D, Pires D, Barnes D, Vialard L, Casey R . Tumour risks and genotype-phenotype correlations associated with germline variants in succinate dehydrogenase subunit genes , and . J Med Genet. 2018; 55(6):384-394. PMC: 5992372. DOI: 10.1136/jmedgenet-2017-105127. View

Wang Y, Gu M, Ji F . Succinate dehydrogenase-deficient gastrointestinal stromal tumors. World J Gastroenterol. 2015; 21(8):2303-14. PMC: 4342905. DOI: 10.3748/wjg.v21.i8.2303. View

Letouze E, Martinelli C, Loriot C, Burnichon N, Abermil N, Ottolenghi C . SDH mutations establish a hypermethylator phenotype in paraganglioma. Cancer Cell. 2013; 23(6):739-52. DOI: 10.1016/j.ccr.2013.04.018. View

Bernardo-Castineira C, Valdes N, Sierra M, Saenz-de-Santa-Maria I, Bayon G, Perez R . SDHC Promoter Methylation, a Novel Pathogenic Mechanism in Parasympathetic Paragangliomas. J Clin Endocrinol Metab. 2017; 103(1):295-305. DOI: 10.1210/jc.2017-01702. View

10.

Fishbein L, Nathanson K . Pheochromocytoma and paraganglioma: understanding the complexities of the genetic background. Cancer Genet. 2012; 205(1-2):1-11. PMC: 3311650. DOI: 10.1016/j.cancergen.2012.01.009. View

11.

Casey R, Ten Hoopen R, Ochoa E, Challis B, Whitworth J, Smith P . SDHC epi-mutation testing in gastrointestinal stromal tumours and related tumours in clinical practice. Sci Rep. 2019; 9(1):10244. PMC: 6629852. DOI: 10.1038/s41598-019-46124-9. View

12.

Moog S, Lussey-Lepoutre C, Favier J . Epigenetic and metabolic reprogramming of SDH-deficient paragangliomas. Endocr Relat Cancer. 2020; 27(12):R451-R463. DOI: 10.1530/ERC-20-0346. View

13.

Lasota J, Miettinen M . KIT and PDGFRA mutations in gastrointestinal stromal tumors (GISTs). Semin Diagn Pathol. 2006; 23(2):91-102. DOI: 10.1053/j.semdp.2006.08.006. View

14.

Udager A, Magers M, Goerke D, Vinco M, Siddiqui J, Cao X . The utility of SDHB and FH immunohistochemistry in patients evaluated for hereditary paraganglioma-pheochromocytoma syndromes. Hum Pathol. 2017; 71:47-54. DOI: 10.1016/j.humpath.2017.10.013. View

15.

Abo R, Ducar M, Garcia E, Thorner A, Rojas-Rudilla V, Lin L . BreaKmer: detection of structural variation in targeted massively parallel sequencing data using kmers. Nucleic Acids Res. 2014; 43(3):e19. PMC: 4330340. DOI: 10.1093/nar/gku1211. View

16.

Moreno C, Santos R, Burns R, Zhang W . Succinate Dehydrogenase and Ribonucleic Acid Networks in Cancer and Other Diseases. Cancers (Basel). 2020; 12(11). PMC: 7693138. DOI: 10.3390/cancers12113237. View

17.

Papathomas T, Oudijk L, Persu A, Gill A, van Nederveen F, Tischler A . SDHB/SDHA immunohistochemistry in pheochromocytomas and paragangliomas: a multicenter interobserver variation analysis using virtual microscopy: a Multinational Study of the European Network for the Study of Adrenal Tumors (ENS@T). Mod Pathol. 2015; 28(6):807-21. DOI: 10.1038/modpathol.2015.41. View

18.

Brcic I, Kashofer K, Skone D, Liegl-Atzwanger B . KIT mutation in a naïve succinate dehydrogenase-deficient gastric GIST. Genes Chromosomes Cancer. 2019; 58(11):798-803. PMC: 6771634. DOI: 10.1002/gcc.22768. View

19.

Manning D, Shivdasani P, Koeller D, Schwartz A, Rana H, Garber J . Assessment of genomic alterations in non-syndromic von Hippel-Lindau: Insight from integrating somatic and germline next generation sequencing genomic data. Data Brief. 2021; 39:107653. PMC: 8661471. DOI: 10.1016/j.dib.2021.107653. View

20.

Santi R, Rapizzi E, Canu L, Ercolino T, Baroni G, Fucci R . Potential Pitfalls of SDH Immunohistochemical Detection in Paragangliomas and Phaeochromocytomas Harbouring Germline Gene Mutation. Anticancer Res. 2017; 37(2):805-812. DOI: 10.21873/anticanres.11381. View