Cancer phenotype in myotonic dystrophy patients: Results from a meta‐analysis

Emparanza, José Ignacio; Munáin, Adolfo López de; Greene, Mark H.; Matheu, Ander; Fernández‐Torrón, Roberto; Gadalla, Shahinaz M.

doi:10.1002/mus.26194

Cited by 30 publications

(22 citation statements)

References 26 publications

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“…Previous studies found DM1 patients to be at elevated risk of developing specific cancers including melanoma and basal cell carcinoma of the skin, as well as cancers of the thyroid, uterus, ovary, and possibly colon, testis, and brain . Here, we identified a similar organ profile for benign tumors, suggesting that DM1 pathogenesis could include a selective proliferative cellular growth advantage in those same organs.…”

Section: Discussionsupporting

confidence: 60%

“…Clinically, the DM1 phenotype varies widely and is classified into three major subtypes: congenital/childhood (most severe), classic, and late‐onset (mild) . Recent quantitative studies have shown that DM1 patients are at increased risk of cancers arising in the skin, thyroid, uterus, and possibly colon, testis, and brain . We have previously shown that the excess risk of cancer in DM1 may be restricted to patients with the classic subtype (diagnosed between ages 11–40 years) …”

Section: Introductionmentioning

confidence: 99%

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Benign tumors in myotonic dystrophy type I target disease‐related cancer sites

Alsaggaf

George

Zhan

et al. 2019

Ann Clin Transl Neurol

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Objectives Recent evidence showed that myotonic dystrophy type I (DM1) patients are at increased risk of certain cancers, but the risk of benign tumors is unknown. We compared the risk of benign tumors in DM1 patients with matched DM1‐free individuals and assessed the association between benign tumors and subsequent cancers. Methods We identified 927 DM1 patients and 13,085 DM1‐free individuals matched on gender, birth‐year, clinic, and clinic‐registration year from the UK Clinical Practice Research Datalink, a primary care records database. We used Cox regression models for statistical analyses. Results DM1 patients had elevated risks of thyroid nodules (Hazard Ratio [HR] = 10.4; 95% Confidence Interval [CI] = 3.91–27.52; P < 0.001), benign tumors of the brain or nervous system (HR = 8.4; 95% CI = 2.48–28.47; P < 0.001), colorectal polyps (HR = 4.3; 95% CI = 1.76–10.41; P = 0.001), and possibly uterine fibroids (HR = 2.7; 95% CI = 1.22–5.88; P = 0.01). Pilomatricomas and salivary gland adenomas occurred almost exclusively in DM1 patients (Fisher's exact P < 0.001). The HR for colorectal polyps was elevated in DM1 males but not in females (HR = 8.2 vs. 1.3, respectively; P‐heterogeneity < 0.001), whereas endocrine and brain tumors occurred exclusively in females. The data suggested an association between benign tumors and subsequent cancer in classic DM1 patients (HR = 2.7; 95% CI = 0.93–7.59; P = 0.07). Interpretation Our study showed a similar site‐specific benign tumor profile to that previously reported for DM1‐associated cancers. The possible association between benign tumors and subsequent cancer in classic DM1 patients warrants further investigation as it may guide identifying patients at elevated risk of cancer. Our findings underscore the importance of following population‐based screening recommendations in DM1 patients, for example, for colorectal cancer.

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Section: Discussionsupporting

confidence: 60%

Section: Introductionmentioning

confidence: 99%

Benign tumors in myotonic dystrophy type I target disease‐related cancer sites

Alsaggaf

George

Zhan

et al. 2019

Ann Clin Transl Neurol

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“…Although myotonia and progressive muscle weakness are the primary symptoms of DM1, prevalent extramuscular manifestations include early‐onset cataracts, cognitive impairment, cardiac conduction defects, thyroid dysfunction and insulin resistance . More recently, DM1 patients have been shown to have excess risks of certain cancers including those originating in the endometrium, brain, ovary, thyroid, skin and possibly colon, testes and eye . Accumulating evidence has shown that DM1 pathogenesis is largely RNA‐mediated; the transcription of the expanded repeats produces mutant RNA that alters the splicing of various target transcripts leading to the complex clinical manifestations of DM1 .…”

Section: Introductionmentioning

confidence: 99%

Diabetes, metformin and cancer risk in myotonic dystrophy type I

Alsaggaf

Pfeiffer

Wang

et al. 2019

Intl Journal of Cancer

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Myotonic dystrophy type I (DM1) is an autosomal dominant multisystem disorder characterized by myotonia and muscle weakness. Type 2 diabetes (T2D) and cancer have been shown to be part of the DM1 phenotype. Metformin, a well-established agent for the management of T2D, is thought to have cancer-preventive effects in the general population. In our study, we aimed to assess the association between T2D, metformin use and the risk of cancer in DM1 patients. We identified a cohort of 913 DM1 patients and an age-, sex-and clinic-matched cohort of 12,318 DM1-free controls from the UK Clinical Practice Research Datalink, a large primary care records database. We used Cox regression models to assess cancer risk in T2D patients who were metformin users or nonusers compared to patients without T2D. Separate analyses were conducted for DM1 patients and controls. T2D was more prevalent in DM1 than in controls (8% vs. 3%, p < 0.0001). DM1 patients with T2D, compared to those without T2D, were more likely to develop cancer (hazard ratio [HR] = 3.60, 95% confidence interval [CI] = 1.18-10.97; p = 0.02), but not if they were treated with metformin (HR = 0.43, 95% CI = 0.06-3.35; p = 0.42). Among controls, we observed no significant associations between T2D and cancer risk in either users or nonusers of Metformin (HR = 1.28, 95% CI = 0.91-1.79; p = 0.16 and HR = 1.13, 95% CI = 0.72-1.79; p = 0.59, respectively). These results show an association between T2D and cancer risk in DM1 patients and may provide new insights into the possible benefits of Metformin use in DM1.

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“…For example, although hypogammaglobulinemia and low lymphocyte counts occur in both DM types, they are especially prevalent in DM2 and are associated with an increased risk of autoimmune disease in DM2 18,19 . In addition, thymic hyperplasia and thymoma, as well as increased risk for other cancer types, have been reported in DM [20][21][22][23] . Although the immune phenotype contributes to DM1 and DM2 complexity, the consequence of MBNL depletion on adaptive immunity has not been investigated.…”

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confidence: 99%

Loss of MBNL1 induces RNA misprocessing in the thymus and peripheral blood

et al. 2020

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The thymus is a primary lymphoid organ that plays an essential role in T lymphocyte maturation and selection during development of one arm of the mammalian adaptive immune response. Although transcriptional mechanisms have been well documented in thymocyte development, co-/post-transcriptional modifications are also important but have received less attention. Here we demonstrate that the RNA alternative splicing factor MBNL1, which is sequestered in nuclear RNA foci by C(C)UG microsatellite expansions in myotonic dystrophy (DM), is essential for normal thymus development and function. Mbnl1 129S1 knockout mice develop postnatal thymic hyperplasia with thymocyte accumulation. Transcriptome analysis indicates numerous gene expression and RNA mis-splicing events, including transcription factors from the TCF/LEF family. CNBP, the gene containing an intronic CCTG microsatellite expansion in DM type 2 (DM2), is coordinately expressed with MBNL1 in the developing thymus and DM2 CCTG expansions induce similar transcriptome alterations in DM2 blood, which thus serve as disease-specific biomarkers.

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Cancer phenotype in myotonic dystrophy patients: Results from a meta‐analysis

Abstract: Our data refine the DM cancer phenotype, which may guide patient clinical management and inform plans for molecular investigations to understand DM-related carcinogenesis. Muscle Nerve 58: 517-522, 2018.

Cited by 30 publications

References 26 publications

Benign tumors in myotonic dystrophy type I target disease‐related cancer sites

Benign tumors in myotonic dystrophy type I target disease‐related cancer sites

Diabetes, metformin and cancer risk in myotonic dystrophy type I

Loss of MBNL1 induces RNA misprocessing in the thymus and peripheral blood

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