Comparison of 2SC, AKR1B10, and FH Antibodies as Potential Biomarkers for FH-deficient Uterine Leiomyomas

Ahvenainen, Terhi; Kaukomaa, Jaana; Kämpjärvi, Kati; Uimari, Outi; Ahtikoski, Anne; Mäkinen, Netta; Heikinheimo, Oskari; Aaltonen, Lauri A.; Karhu, Auli; Bützow, Ralf; Vahteristo, Pia

doi:10.1097/pas.0000000000001826

Cited by 15 publications

(14 citation statements)

References 42 publications

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“…Aldo-Keto Reductase Family 1 Member B10 (AKR1B10), an NADPH-dependent reductase that catalyzes the reduction of a wide variety of carbonyl-containing compounds, is often overexpressed in FH deficient tumors, including LM [4]. A recent study showed that AKR1B10 can be a specific and sensitive marker of FH-LM [24]. Our IHC assay confirmed the previous report and detected a high expression of AKR1B10 only in FH-LM but not in other LM subtypes (Fig 4A).…”

Section: Resultsmentioning

confidence: 99%

Patient-derived xenograft studies of fumarate hydratase (FH)-deficient uterine leiomyoma subtype

Kajimura¹,

Serna²,

Amurgis³

et al. 2022

Preprint

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Uterine leiomyoma (LM) is the most common benign gynecological tumor in premenopausal women. Our previous patient-derived xenograft (PDX) studies established that 17ß-estradiol (E2) and progesterone (P4) stimulate the growth of the two most prevalent subtypes, MED12 mutant (MED12-LM) and HMGA2 overexpressing LMs (HMGA2-LM), via proliferation and hypertrophy of smooth muscle tumor cells (SMTCs). In addition, tumor-associated fibroblasts (TAFs) that do not carry MED12 mutations also contribute to the growth of MED12-LM by secreting extracellular matrix (ECM) proteins. In this study, we investigated the growth control of the fumarate hydratase (FH) deficient LM (FH-LM) subtype, utilizing the PDX model. We identified an FH-negative case with conventional leiomyoma histology. The overexpression of aldo-keto reductase family 1 member B10 (AKR1B10) confirmed the FH deficiency. Like MED12-LM, FH-LM comprised two major cell types: 54.4% SMTCs and 43.3% TAFs. Furthermore,the TAFs expressed FH. The FH-LM PDXs grew in response to E2 and P4 via proliferation and hypertrophy of SMTCs, similar to MED12-LM and HMGA2-LM. While E2 alone did not stimulate growth, E2 was essential for sensitizing FH-deficient SMTCs to P4 by upregulating progesterone receptor (PGR). Our current study established that the growth of the three most prevalent LM subtypes, MED12-LM, HMGA2-LM, and FH-LM, depends on E2 and P4. Thus, selective progesterone receptor modulators (SPRMs) should be an effective treatment option for most symptomatic LM patients.

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Section: Resultsmentioning

confidence: 99%

Patient-derived xenograft studies of fumarate hydratase (FH)-deficient uterine leiomyoma subtype

Kajimura¹,

Serna²,

Amurgis³

et al. 2022

Preprint

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“…Indeed, we recently analyzed publicly available leiomyoma data and reclassified two leiomyomas as FH-deficient partly based on the expression of AKR1B10 [ 16 ]. Using FH-deficient tumors derived from HLRCC patients and sporadic leiomyomas with biallelic loss of FH , we recently showed that AKR1B10 immunohistochemistry can act as a biomarker on protein-level as well [ 17 ]. In this study, we present a novel uterine leiomyoma subtype that is FH-proficient but displays AKR1B10 protein expression.…”

Section: Introductionmentioning

confidence: 99%

A novel uterine leiomyoma subtype exhibits NRF2 activation and mutations in genes associated with neddylation of the Cullin 3-RING E3 ligase

et al. 2022

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Uterine leiomyomas, or fibroids, are the most common tumors in women of reproductive age. Uterine leiomyomas can be classified into at least three main molecular subtypes according to mutations affecting MED12, HMGA2, or FH. FH-deficient leiomyomas are characterized by activation of the NRF2 pathway, including upregulation of the NRF2 target gene AKR1B10. Here, we have identified a novel leiomyoma subtype showing AKR1B10 expression but no alterations in FH or other known driver genes. Whole-exome and whole-genome sequencing revealed biallelic mutations in key genes involved in neddylation of the Cullin 3-RING E3 ligase, including UBE2M, NEDD8, CUL3, and NAE1. 3′RNA sequencing confirmed a distinct molecular subtype with activation of the NRF2 pathway. Most tumors displayed cellular histopathology, perivascular hypercellularity, and characteristics typically seen in FH-deficient leiomyomas. These results suggest a novel leiomyoma subtype that is characterized by distinct morphological features, genetic alterations disrupting neddylation of the Cullin 3-RING E3 ligase, and oncogenic NRF2 activation. They also present defective neddylation as a novel mechanism leading to aberrant NRF2 signaling. Molecular characterization of uterine leiomyomas provides novel opportunities for targeted treatment options.

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“…[15][16][17][18][19][20][21] Although these morphologic features prove to be relevant for the detection of HLRCC, 2 immunohistochemical stains, 2-succinocysteine (2SC), and FH can be applicable to identify FH deficiency. 22,23 In this study, the relationship between the characteristic morphologic findings of leiomyomas thought to be FH-deficient and the expression of FH and 2SC immunohistochemistry (IHC), and the frequency of FH and 2SC IHC expression in uterine leiomyomas detected in young patients are aimed to be scrutinized. a database search at the Pathology Department of Istanbul Medical Faculty during the period of 2018 to 2022.…”

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confidence: 99%

The Role of Morphology in Predicting Fumarate Hydratase–deficient Uterine Leiomyomas in Young Women

Bayram,

Bagbudar,

Sozen

et al. 2023

Applied Immunohistochemistry &Amp; Molecular Morphology

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Hereditary leiomyomatosis and renal cell carcinoma is caused by germline mutations in the fumarate hydratase (FH) gene and is associated with an increased incidence of leiomyomas and a potentially aggressive variant of renal cell carcinoma. Pathologic evaluation of uterine leiomyoma can provide an opportunity for early recognition of the syndrome. We reviewed all archived slides of the cases to identify the characteristic morphologic features described for FH-deficient leiomyomas. We performed immunohistochemistry on whole sections of patients with uterine leiomyoma to evaluate for both FH and 2-succinocysteine (2SC) expression. Of the 106 cases, 19 showed the characteristic eosinophilic nucleoli with perinuclear halos, and 24 revealed a characteristic eosinophilic cytoplasmic inclusion consisting of pink globules present within the cytoplasm. Both of these morphologic findings were present together in 15 cases, and hemangiopericytomatous vessels were detected in 23 cases. The loss of FH protein expression was detected in 14 out of 106 cases (13%), and 13 out of 106 cases (12%) were positive for 2SC. We detected 10 cases with both 2SC-positive and FH expression loss. The presence of eosinophilic nucleoli with perinuclear halos and eosinophilic cytoplasmic inclusion was associated with both loss of FH protein expression and 2SC positivity (P < 0.001). These findings underscore the importance of hematoxylin and eosin–based predictive morphology in FH-deficient uterine leiomyomas. Therefore, morphologic assessment of uterine leiomyomas for features of FH deficiency can serve as a screening tool for hereditary leiomyomatosis and renal cell carcinoma syndrome, allowing patients to be divided according to their hereditary risk assessment.

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Comparison of 2SC, AKR1B10, and FH Antibodies as Potential Biomarkers for FH-deficient Uterine Leiomyomas

Cited by 15 publications

References 42 publications

Patient-derived xenograft studies of fumarate hydratase (FH)-deficient uterine leiomyoma subtype

Patient-derived xenograft studies of fumarate hydratase (FH)-deficient uterine leiomyoma subtype

A novel uterine leiomyoma subtype exhibits NRF2 activation and mutations in genes associated with neddylation of the Cullin 3-RING E3 ligase

The Role of Morphology in Predicting Fumarate Hydratase–deficient Uterine Leiomyomas in Young Women

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