Survival patterns and cancer determinants in families with myotonic dystrophy type 1

Best, A. de; Hilbert, JE; Wood, Libby; Martens, WB; Nikolenko, Nikoletta; Marini‐Bettolo, Chiara; Lochmüller, Hanns; Rosenberg, Philip S.; Moxley, RT; Greene, MH; Gadalla, S. M.

doi:10.1111/ene.13763

Cited by 10 publications

(10 citation statements)

References 33 publications

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“…Nevertheless, further studies are required to fully elucidate EGFR activity in DM1, because altered EGFR signaling is associated with human cancers [48]. Several publications have indexed the overall risk of cancers in DM1 patients [4,49], with the most prevalent being skin cancers, specifically basal cell carcinoma [50,51]. To that end, we cannot exclude endocytic pathway alterations from the mechanism underlying the onset of cancers and/or metabolic diseases [52] in DM1 patients.…”

Section: Discussionmentioning

confidence: 99%

“…Unaffected individuals have 5-37 CTG repeats that remain stable over generations, whereas DM1 patients display more than 40 CTG repeats that tend to increase in successive generations [3]. DM1 is a multisystemic disorder that affects many organs and tissues and can result in endocrine system dysfunction, cataracts, respiratory failure, cancer, and cardiac defects, leading to sudden death in many cases [2,4]. Depending on the onset of the first clinical symptoms, DM1 is classified into five clinical forms: congenital (neonatal), infantile (1 month-10 years), juvenile (11-20 years), adult (21-40 years), and late-onset (40 years and older).…”

Section: Introductionmentioning

confidence: 99%

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Delay of EGF-Stimulated EGFR Degradation in Myotonic Dystrophy Type 1 (DM1)

Alegre-Cortés

Gimenez-Bejarano

Uribe-Carretero

et al. 2022

Cells

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Myotonic dystrophy type 1 (DM1) is an autosomal dominant disease caused by a CTG repeat expansion in the 3′ untranslated region of the dystrophia myotonica protein kinase gene. AKT dephosphorylation and autophagy are associated with DM1. Autophagy has been widely studied in DM1, although the endocytic pathway has not. AKT has a critical role in endocytosis, and its phosphorylation is mediated by the activation of tyrosine kinase receptors, such as epidermal growth factor receptor (EGFR). EGF-activated EGFR triggers the internalization and degradation of ligand–receptor complexes that serve as a PI3K/AKT signaling platform. Here, we used primary fibroblasts from healthy subjects and DM1 patients. DM1-derived fibroblasts showed increased autophagy flux, with enlarged endosomes and lysosomes. Thereafter, cells were stimulated with a high concentration of EGF to promote EGFR internalization and degradation. Interestingly, EGF binding to EGFR was reduced in DM1 cells and EGFR internalization was also slowed during the early steps of endocytosis. However, EGF-activated EGFR enhanced AKT and ERK1/2 phosphorylation levels in the DM1-derived fibroblasts. Therefore, there was a delay in EGF-stimulated EGFR endocytosis in DM1 cells; this alteration might be due to the decrease in the binding of EGF to EGFR, and not to a decrease in AKT phosphorylation.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Delay of EGF-Stimulated EGFR Degradation in Myotonic Dystrophy Type 1 (DM1)

Alegre-Cortés

Gimenez-Bejarano

Uribe-Carretero

et al. 2022

Cells

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“…Details describing the methodology of data collection and information obtained have been published previously (18, 21, 22). Briefly, a self-administered questionnaire was sent to DM patients enrolled in the US ( via mail) or UK (primarily via email, followed by mail for non-responders) DM registries.…”

Section: Methodsmentioning

confidence: 99%

“…Research activities of the US DM registry were approved by the University of Rochester's Institutional Review Board, and those of the UK DM Registry were approved by the UK Research Ethics Service. This report is part of our comprehensive effort aimed at more detailed characterization of the recently-recognized cancer susceptibility in DM patients (18, 21–23).…”

Section: Methodsmentioning

confidence: 99%

Reproductive Cancer Risk Factors in Women With Myotonic Dystrophy (DM): Survey Data From the US and UK DM Registries

et al. 2019

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Introduction: Recent evidence demonstrates that women with myotonic dystrophy type 1 are at increased risk of reproductive organ tumors. However, studies of reproductive cancer risk factors in those patients are lacking.Methods: Using questionnaires, we collected and analyzed personal history information related to cancer risk factors from women enrolled in a UK and US registry for myotonic dystrophy (dystrophia myotonica; DM) patients.Results: The survey was completed by 242 DM type 1 (DM1) and 44 DM type 2 (DM2) women enrolled in the UK Registry (N = 124) and the US National Registry (N = 162). The mean age at DM1 diagnosis was 33.8 years (standard deviation, SD = 13.2) and for DM2 was 49.2 (SD = 13.0). Mean age at survey was 48.7 (SD = 12.8) and 59.1 years (SD = 12.8) for DM1 and DM2, respectively. There were no statistically significant differences between DM1 and DM2 regarding menstrual history or fertility-related factors. Yet, women with DM2 were more likely to have used menopausal hormone therapy (HT) than women with DM1 (52.3 vs. 22.1%, p < 0.0001), and more women with DM2 had a hysterectomy (53.5 vs. 29.5%, p < 0.01). These differences were not statistically significant after age adjustment (OR = 2.00, p = 0.08, and OR = 1.40, p = 0.38, respectively). The frequency of self-reported reproductive organ tumors was not significantly different comparing DM1 to DM2 (p = 0.28). However, the data suggested that women with DM2 appear to have a lower risk of malignant tumors compared to those with DM1 (OR = 0.72, p = 0.69).Discussion: Our study is the first to characterize a wide range of reproductive risk factors in women with DM. We observed no significant differences between DM1 and DM2 in the factors that were evaluated, which suggests that the known excesses of ovarian and endometrial cancer previously reported in women with DM1 cannot be attributed to greater prevalence of standard cancer-related reproductive risk factors. Larger studies evaluating the possible link between reproductive cancer risk factors and risk of tumors in women with DM are needed.

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“…Part of the clinical spectrum of progeroid diseases is an increased risk of malignancy. DM1 is associated with an increased risk of certain cancers, for example, thyroid cancer (101, 102). Of note, hyperinsulinemia is also associated with an increased risk of thyroid cancer [reviewed in (23)].…”

Section: Clinical Evidence Of Insulin Signaling Involvement In Dm1mentioning

confidence: 99%

Insulin Signaling as a Key Moderator in Myotonic Dystrophy Type 1

et al. 2019

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Myotonic dystrophy type 1 (DM1) is an autosomal dominant genetic disease characterized by multi-system involvement. Affected organ system includes skeletal muscle, heart, gastro-intestinal system and the brain. In this review, we evaluate the evidence for alterations in insulin signaling and their relation to clinical DM1 features. We start by summarizing the molecular pathophysiology of DM1. Next, an overview of normal insulin signaling physiology is given, and evidence for alterations herein in DM1 is presented. Clinically, evidence for involvement of insulin signaling pathways in DM1 is based on the increased incidence of insulin resistance seen in clinical practice and recent trial evidence of beneficial effects of metformin on muscle function. Indirectly, further support may be derived from certain CNS derived symptoms characteristic of DM1, such as obsessive-compulsive behavior features, for which links with altered insulin signaling has been demonstrated in other diseases. At the basic scientific level, several pathophysiological mechanisms that operate in DM1 may compromise normal insulin signaling physiology. The evidence presented here reflects the importance of insulin signaling in relation to clinical features of DM1 and justifies further basic scientific and clinical, therapeutically oriented research.

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Survival patterns and cancer determinants in families with myotonic dystrophy type 1

Cited by 10 publications

References 33 publications

Delay of EGF-Stimulated EGFR Degradation in Myotonic Dystrophy Type 1 (DM1)

Delay of EGF-Stimulated EGFR Degradation in Myotonic Dystrophy Type 1 (DM1)

Reproductive Cancer Risk Factors in Women With Myotonic Dystrophy (DM): Survey Data From the US and UK DM Registries

Insulin Signaling as a Key Moderator in Myotonic Dystrophy Type 1

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