Skip to Main content Skip to Navigation
Journal articles

Mathematical modeling of disease dynamics in SDHB- and SDHD-related paraganglioma: Further step in understanding hereditary tumor differences and future therapeutic strategies

Abstract : Succinate dehydrogenase subunit B and D (SDHB and SDHD) mutations represent the most frequent cause of hereditary pheochromocytoma and paraganglioma (PPGL). Although truncation of the succinate dehydrogenase complex is thought to be the disease causing mechanism in both disorders, SDHB and SDHD patients exihibit different phenotypes. These phenotypic differences are currently unexplained by molecular genetics. The aim of this study is to compare disease dynamics in these two conditions via a Markov chain model based on 4 clinically-defined steady states. Our model corroborates at the population level phenotypic observations in SDHB and SDHD carriers and suggests potential explanations associated with the probabilities of disease maintenance and regression. In SDHB-related syndrome, PPGL maintenance seems to be reduced compared to SDHD (p = 0.04 vs 0.95) due to higher probability of tumor cell regression in SDHB vs SDHD (p = 0.87 vs 0.00). However, when SDHB-tumors give rise to metastases, metastatic cells are able to thrive with decreased probability of regression compared with SDHD counterparts (p = 0.17 vs 0.89). By constrast, almost all SDHD patients develop PGL (mainly head and neck) that persist throughout their lifetime. However, compared to SDHB, maintenance of metastatic lesions seems to be less effective for SDHD (p = 0.83 vs 0.11). These findings align with data suggesting that SDHD-related PPGL require less genetic events for tumor initiation and maintenance compared to those related to SDHB, but fail to initiate biology that promotes metastatic spread and metastatic cell survival in host tissues. By contrast, the higher number of genetic abnormalities required for tumor initiation and maintenance in SDHB PPGL result in a lower penetrance of PGL, but when cells give rise to metastases they are assumed to be better adapted to sustain survival. These proposed differences in disease progression dynamics between SDHB and SDHD diseases provide new cues for future exploration of SDHx PPGL behavior, offering considerations for future specific therapeutic and prevention strategies.
Document type :
Journal articles
Complete list of metadatas

Cited literature [32 references]  Display  Hide  Download

https://hal-amu.archives-ouvertes.fr/hal-02143661
Contributor : Ghislain Bidaut <>
Submitted on : Tuesday, October 22, 2019 - 2:32:47 PM
Last modification on : Thursday, October 24, 2019 - 3:37:08 PM
Long-term archiving on: : Thursday, January 23, 2020 - 7:21:02 PM

File

journal.pone.0201303.pdf
Publisher files allowed on an open archive

Licence


Distributed under a Creative Commons Attribution 4.0 International License

Identifiers

Collections

Citation

Dominique Barbolosi, Joakim Crona, Raphael Serre, Karel Pacak, David Taieb. Mathematical modeling of disease dynamics in SDHB- and SDHD-related paraganglioma: Further step in understanding hereditary tumor differences and future therapeutic strategies. PLoS ONE, Public Library of Science, 2018, 13 (8), pp.e0201303. ⟨10.1371/journal.pone.0201303⟩. ⟨hal-02143661⟩

Share

Metrics

Record views

111

Files downloads

98