scholarly journals Abnormal Cystic Tumor in a Patient with Hereditary Leiomyomatosis and Renal Cell Cancer Syndrome: Evidence of a Precursor Lesion?

2015 ◽  
Vol 2015 ◽  
pp. 1-5 ◽  
Author(s):  
Benjamin T. Ristau ◽  
Sonal N. Kamat ◽  
Tatum V. Tarin
Keyword(s):  
Growth Factor ◽  
Renal Cell Cancer ◽  
Renal Cell ◽  
Cell Cancer ◽  
Fumarate Hydratase ◽  
Cystic Tumor ◽  
Precursor Lesion ◽  
Glucose Transporter 1 ◽  
Hereditary Leiomyomatosis

The hereditary leiomyomatosis and renal cell cancer (HLRCC) association is a rare syndrome caused by mutation of the Kreb’s cycle enzyme, fumarate hydratase (FH). It is characterized by unusually aggressive type 2 papillary renal cell histology. FH is responsible for catalyzing the conversion of fumarate to malate. Its absence leads to a state of “pseudohypoxia,” inducing hypoxia inducible factor 1α(HIF-1α) and leading to increased growth factor transcription (e.g., vascular endothelial growth factor, VEGF; glucose transporter 1, GLUT1). Ultimately, this results in tumorigenesis. We present a patient who was diagnosed with HLRCC and underwent bilateral nephrectomies. One of the nephrectomy specimens was notable for benign cystic lesions that stained positive immunohistochemically for succinated proteins, a finding only noted in FH-deficient cells. Thus, we posit a potential precursor lesion to type 2 papillary renal cell carcinoma in the HLRCC syndrome.

Hereditary leiomyomatosis and renal cell cancer syndrome (HLRCC): Genotype and phenotype characteristics in a cohort of 197 patients.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 1580-1580
Author(s):  
Ana Beatriz Sanchez-Heras ◽  
Adela Castillejo ◽  
Juan de Dios García-Diaz ◽  
Mercedes Robledo ◽  
Alex Teule ◽  
...  
Keyword(s):  
Renal Cell Cancer ◽  
Renal Cell ◽  
Cell Cancer ◽  
Fumarate Hydratase ◽  
Stage Iv ◽  
Renal Cysts ◽  
Loss Of Function ◽  
Cancer Syndrome ◽  
Pathogenic Variants

1580 Background: HLRCC is a hereditary condition with autosomal dominant inheritance due to germline mutations in the fumarate-hydratase gene ( FH). It is characterized by skin leiomyomas (SLM) in 48-84% of individuals, uterine leiomyomas (ULM) in 30-72%, renal cysts (RCy) and renal cell cancer (RCC) in 15-34%. We aimed to describe the genetics, the clinical features and the potential genotype-phenotype associations in the largest cohort of FH mutation carriers from Spain. Methods: We performed a multicenter, observational, retrospective study of individuals with genetic or clinical diagnosis of HLRCC. We collected clinical information from medical records. We analyzed genetic variants and looked for genotype-phenotype associations. Statistical analyses were performed by IBM-SPSS Statistics-v.22. Results: We included 197 individuals (113 women, 84 men), 74 index cases and 123 relatives. Twenty-seven different variants were detected, 26 pathogenic (12 missense, 5 frameshift, 4 large-deletions, 3 splice-site and 2 nonsense) and 1 variant of unknown significance (missense). Of 182 patients with full skin examination, 64.8% presented SLM (median age 36 years; range 8-85). ULM were diagnosed in 90.3% of 103 women with gynecologic exam (median age 30 years; range 17- 55). Hysterectomy was performed in 62.9% (median age 34 years; range 21-54). Of 153 patients with radiological records, 37.3 % presented RCy. Nineteen patients (10.9%) presented RCC, 11 males and 8 females (median age 37 years; range 10-67). The histological diagnoses were: 14 papillary, of which 10 were type 2; 3 clear cell carcinoma and 2 unclassified carcinoma. Six tumors had stage I, 2 stage II, 3 stage III, 4 stage IV, and 4 not available. The median overall survival among patients at stages 3-4 was 2.9 years [1.3-4.5]. Patients with missense pathogenic variants showed higher risk of developing SLM (p = 0.043) and ULM (p = 0.002) than those with loss of function variants. Conclusions: In our cohort, the frequency of RCC (10.9%) is lower than that published in cohorts of similar sample size. The most frequent histology was the papillary type-2; however, other histological patterns do not exclude HLRCC. Individuals with missense pathogenic variants show higher incidence of SLM and ULM.

First Presentation of Hereditary Leiomyomatosis and Renal Cell Cancer Syndrome in Pregnancy

2016 ◽  
Vol 20 (4) ◽  
pp. 334-336
Author(s):  
Kathryn Woolner ◽  
Ashley O’Toole ◽  
Lauren LaBerge
Keyword(s):  
Renal Cell Cancer ◽  
Renal Cell ◽  
Cell Cancer ◽  
Fumarate Hydratase ◽  
Case Series ◽  
Review Of The Literature ◽  
Cancer Syndrome ◽  
Cutaneous Lesions ◽  
Hereditary Leiomyomatosis ◽  
In Pregnancy

Background: Reed’s syndrome, also known as hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome, is an autosomal dominant condition in which affected individuals may develop cutaneous leiomyomas, uterine fibroids, and renal cell carcinoma. Objective: This report describes a unique case of HLRCC because it presented in pregnancy with development of cutaneous pilar leiomyomas. Methods: Review of the literature for previous cases of Reed’s syndrome during pregnancy including PubMed and Medline search. Results: Genetic testing of this patient demonstrated a mutation in the fumarate hydratase ( FH) gene. Review of the literature showed only 1 previous case series that described the onset of cutaneous lesions during pregnancy. Conclusion: This case serves as a reminder that there may exist a correlation between pregnancy and the first manifestation of cutaneous lesions in patients with HLRCC, and thus an increased clinical suspicion is warranted during this period.

A phase II study of bevacizumab and erlotinib in subjects with advanced hereditary leiomyomatosis and renal cell cancer (HLRCC) or sporadic papillary renal cell cancer (RCC).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. TPS4680-TPS4680 ◽  
Author(s):  
Eric A. Singer ◽  
Julia C. Friend ◽  
Geri Hawks ◽  
Cathy Vocke ◽  
Adam R. Metwalli ◽  
...  
Keyword(s):  
Growth Factor ◽  
Phase Ii ◽  
Renal Cell Cancer ◽  
Renal Cell ◽  
Transforming Growth Factor ◽  
Phase Ii Study ◽  
Cell Cancer ◽  
Fumarate Hydratase ◽  
Genetic Alterations ◽  
Papillary Rcc

TPS4680 Background: There are currently no treatment options of proven efficacy for patients with advanced papillary RCC. The evaluation of families with inherited forms of RCC has allowed for the identification of genetic alterations associated with papillary RCC. HLRCC is one such familial condition with a propensity for the development of a clinically aggressive variant of papillary RCC characterized by unique histopathologic features. Germline mutations in the gene for the Krebs cycle enzyme fumarate hydratase (FH) are the genetic hallmark of HLRCC. Mutational inactivation of FH leads to von Hippel-Lindau-independent upregulation of hypoxia inducible factors (HIF) and their downstream transcriptional targets such as vascular endothelial growth factor (VEGF) and transforming growth factor-alpha (TGF-α) / epidermal growth factor receptor (EGFR). Upregulation of the HIF pathway may also be important in sporadic papillary RCC, although the prevalence of FH inactivation in these patients is unknown. We propose to evaluate the activity of dual VEGF/EGFR blockade with bevacizumab/erlotinib in patients with HLRCC-associated RCC and sporadic papillary RCC. Methods: This is a single arm phase II study based on an open label Simon two-stage minmax design with a maximum accrual of 20 patients in each of two cohorts: Cohort 1- patients with HLRCC; Cohort 2- patients with sporadic papillary RCC. The primary endpoint is RECIST overall response rate, assessed independently in each cohort. Patients will receive bevacizumab (10mg/Kg IV every 2 weeks) and erlotinib (150mg PO daily). Dose reductions and drug interruptions for toxicity are allowed. Patients will be evaluated for response every 8 weeks. Major eligibility criteria include: advanced RCC associated with HLRCC or sporadic papillary RCC; age >18 years; ECOG 0-2; measurable disease by RECIST; no brain metastases; no more than 2 prior regimens containing a VEGF inhibitor; and no prior therapy with bevacizumab. The prespecified activity goal for the first stage of accrual has been met for both cohorts. NCT01130519.

scholarly journals Mutations in the Fumarate Hydratase Gene Cause Hereditary Leiomyomatosis and Renal Cell Cancer in Families in North America

2003 ◽  
Vol 73 (1) ◽  
pp. 95-106 ◽  
Author(s):  
Jorge R. Toro ◽  
Michael L. Nickerson ◽  
Ming-Hui Wei ◽  
Michelle B. Warren ◽  
Gladys M. Glenn ◽  
...  
Keyword(s):  
North America ◽  
Renal Cell Cancer ◽  
Renal Cell ◽  
Cell Cancer ◽  
Fumarate Hydratase ◽  
Hereditary Leiomyomatosis

scholarly journals Proteogenomic landscape of uterine leiomyomas from hereditary leiomyomatosis and renal cell cancer patients

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Nicholas W. Bateman ◽  
Christopher M. Tarney ◽  
Tamara Abulez ◽  
Anthony R. Soltis ◽  
Ming Zhou ◽  
...  
Keyword(s):  
Renal Cell Cancer ◽  
Renal Cell ◽  
Target Genes ◽  
Cell Cancer ◽  
Fumarate Hydratase ◽  
Thioredoxin Reductase ◽  
Antioxidant Response ◽  
Suppressor Gene ◽  
Uterine Leiomyomas ◽  
Hereditary Leiomyomatosis

AbstractPathogenic mutations in fumarate hydratase (FH) drive hereditary leiomyomatosis and renal cell cancer (HLRCC) and increase the risk of developing uterine leiomyomas (ULMs). An integrated proteogenomic analysis of ULMs from HLRCC (n = 16; FH-mutation confirmed) and non-syndromic (NS) patients (n = 12) identified a significantly higher protein:transcript correlation in HLRCC (R = 0.35) vs. NS ULMs (R = 0.242, MWU p = 0.0015). Co-altered proteins and transcripts (228) included antioxidant response element (ARE) target genes, such as thioredoxin reductase 1 (TXNRD1), and correlated with activation of NRF2-mediated oxidative stress response signaling in HLRCC ULMs. We confirm 185 transcripts previously described as altered between HLRCC and NS ULMs, 51 co-altered at the protein level and several elevated in HLRCC ULMs are involved in regulating cellular metabolism and glycolysis signaling. Furthermore, 367 S-(2-succino)cysteine peptides were identified in HLRCC ULMs, of which sixty were significantly elevated in HLRCC vs. NS ULMs (LogFC = 1.86, MWU p < 0.0001). These results confirm and define novel proteogenomic alterations in uterine leiomyoma tissues collected from HLRCC patients and underscore conserved molecular alterations correlating with inactivation of the FH tumor suppressor gene.

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