MAX Mutations in Endometrial Cancer: Clinicopathologic Associations and Recurrent MAX p.His28Arg Functional Characterization

Walker, Christopher J.; Rush, Craig M.; Dama, Paola; O’Hern, Matthew J.; Cosgrove, Casey; Gillespie, J.; Zingarelli, Roman A.; Smith, B.; Stein, Maggie; Mutch, David G.; Shakya, Reena; Chang, C.-S.; Selvendiran, Karuppaiyah; Song, Jonathan W.; Cohn, David E.; Goodfellow, Paul J.

doi:10.1093/jnci/djx238

Cited by 9 publications

(3 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition, among the top candidates an important factor with a negative β value was FOXA2, the Forkhead Box A2, an essential TF for fertility and uterine function ( 25 , 26 ). In addition, other top TFs with high β values were Max Dimerization Protein MGA, a negative regulator of MYC pathway and implicated in endometrial cancers ( 27 , 28 ), and PAX5 is involved in gene regulation in many tissues. Overall, we found that differences in TFBS numbers could explain variation in gene expression to a modest extent overall, while there are also many TFs explaining a large extent of interspecies variation for specific genes.…”

Section: Resultsmentioning

confidence: 99%

Tracing the cis-regulatory changes underlying the endometrial control of placental invasion

Suhail

Maziarz

Novin

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Significance Cellular invasion into adjacent tissue is observed in pregnancy, where the fetal placenta invades the mother’s endometrium, and in cancer, where tumor dissemination into stroma is a necessary step before metastasis. The behavior of the surrounding tissue, and its role in either facilitating or resisting this invasion, has not been as deeply studied as the role of the invading cells. The degree of placental invasion into the endometrium varies significantly between different eutherian mammals. Having previously shown that the endometrium of different mammals is significantly responsible for these differences, we identify cis-regulatory elements underlying these differences and show the functional effect of the corresponding transcriptional factors in regulating invasion.

show abstract

Section: Resultsmentioning

confidence: 99%

Tracing the cis-regulatory changes underlying the endometrial control of placental invasion

Suhail

Maziarz

Novin

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…In addition, among the top candidates an important factor with a negative β value was FOXA2, the Forkhead Box A2, an essential transcription factor for fertility and uterine function 25,26 . In addition, other top transcription factors with high β values were Max Dimerization Protein MGA, a negative regulator of MYC pathway and implicated in endometrial cancers 27,28 , PAX5 involved in gene regulation in many tissues.…”

Section: Resultsmentioning

confidence: 99%

Cis-Regulatory Differences Explaining Evolved Levels of Endometrial Invasibility in Eutherian Mammals

Suhail

Maziarz

Dighe

et al. 2020

Preprint

View full text Add to dashboard Cite

Eutherian (placental) mammals exhibit great differences in the degree of placental invasion into the maternal endometrium, with humans being on the most invasive end. Previously, we have shown that these differences in invasiveness is largely controlled by the stromal fibroblasts of the maternal endometrium, with secondary effect on stroma of other tissues resulting in correlated differences in cancer malignancy. Here, we present a statistical investigation of the second dogma linking the phenotypic and transcriptional differences to the genomic changes across species, revealing the regulatory genomic sequence differences underlying these inter-species differences. We show that gain or loss of specific transcription factor binding site sequences are connected to the inter-species gene-expression differences in a statistically significant manner, with a particularly larger effect on stromal genes related to invasibility. We also uncover transcriptional factors differentially regulating genes related to pro- and anti- invasible property of stroma. This work extends the understanding of inter-species differences in stromal invasion to the causal genomic sequence differences paving new avenues to target stromal characteristics to regulate placental, or cancer invasion.

show abstract

“…Germline MAX variants have been implicated in PPGL and renal oncocytoma and somatic variants have been identified in small cell carcinoma of the lung (Kurschner, et al 2017;Romero, et al 2014). Other tumours reported in association with MAX variants include endometrial carcinoma, ganglioneuromas, neuroblastoma, pancreatic cancer, lung adenocarcinoma and breast cancer (Seabrook, et al 2021;Walker, et al 2018). In one study, germline MAX variants accounted for approximately 1% of PPGLs in patients with a negative RET, VHL, SDHB, SDHC, SDHD, and TMEM127 genetic screen, thus making it very rare cause of PPGL (Burnichon, et al 2012).…”

Section: Introductionmentioning

confidence: 99%

Succinate dehydrogenase and MYC-associated factor X mutations in pituitary neuroendocrine tumours

Loughrey

Roncaroli

Healy

et al. 2022

Endocrine-Related Cancer

View full text Add to dashboard Cite

Pituitary neuroendocrine tumours (PitNETs) associated with paragangliomas or phaeochromocytomas are rare. SDHx variants are estimated to be associated with 0.3-1.8% of PitNETs. Only a few case reports have documented the association with MAX variants. Prolactinomas are the most common PitNETs occurring in patients with SDHx variants, followed by somatotrophinomas, clinically non-functioning tumours and corticotrophinomas. One pituitary carcinoma has been described. SDHC, SDHB and SDHA mutations are inherited in an autosomal dominant fashion and tumorigenesis seems to adhere to the Knudson’s two hit hypothesis. SDHD and SDHAF2 mutations most commonly have paternal inheritance. Immunohistochemistry for SDHB or MAX and loss of heterozygosity analysis can support assessment of pathogenicity of the variants. Metabolomics is promising in the diagnosis of SDHx-related disease. Future research should aim to further clarify the role of SDHx and MAX variants or other genes in the molecular pathogenesis of PitNETs including pseudohypoxic and kinase signalling pathways along with elucidating epigenetic mechanisms to predict tumour behaviour.

show abstract

MAX Mutations in Endometrial Cancer: Clinicopathologic Associations and Recurrent MAX p.His28Arg Functional Characterization

Abstract: These data highlight the importance of MAX mutations in EC and point to increased vascularity as one mechanism contributing to clinical aggressiveness of EC.

Cited by 9 publications

References 43 publications

Tracing the cis-regulatory changes underlying the endometrial control of placental invasion

Tracing the cis-regulatory changes underlying the endometrial control of placental invasion

Cis-Regulatory Differences Explaining Evolved Levels of Endometrial Invasibility in Eutherian Mammals

Succinate dehydrogenase and MYC-associated factor X mutations in pituitary neuroendocrine tumours

Contact Info

Product

Resources

About