Abstract
Background:
Increasing evidence suggests that Duchenne muscular dystrophy (DMD) gene is involved in the occurrence of different types of cancer. Moreover, development of sarcomas was reported in mdx mice, the murine model of DMD, in older age. So far, nine isolated DMD patients were reported with concomitant cancer, four of whom with rhabdomyosarcoma (RMS), but no systematic investigation was performed about the true incidence of cancer in DMD.
Methods:
All members of the Italian Association of Myology were asked about the occurrence of cancer in their DMD patients in the last 30 years.
Results:
Four DMD patients with cancer were reported after checking 2455 medical records. One developed brain tumour at the age of 35 years. Two patients had alveolar RMS at 14 and 17 years of age. The fourth patient had a benign enchondroma when 11-year-old.
Conclusion:
Prevalence of cancer in general in the Italian DMD patients does not seem to be different from that in the general population with the same age range. Although the small numbers herein presented do not allow definitive conclusion, the frequent occurrence of RMS in DMD patients raises an alert for basic researchers and clinicians. The role of DMD gene in cancer merits further investigations.
INTRODUCTION
Duchenne muscular dystrophy (DMD) is the most common muscular dystrophy affecting 1:3500–1:6000 live male births. The disease presents in childhood and is caused by the absence of dystrophin protein (Dp) coded by the DMD gene located on chromosome Xp21 [1]. A review has been recently published about the involvement of DMD gene in tumourigenesis, reporting that protein products of DMD gene, possibly the ratio of Dp427 to Dp71, may play a role in the development of soft tissue sarcomas, neuroblastomas, meningiomas, glioblastomas, melanomas, lymphomas, leukaemia, and carcinomas [2]. The review also cites nine cases reported in the literature between 1986 and 2014 with cancer occurring in DMD patients: 4 with rhabdomyosarcoma (RMS), 2 with medulloblastoma, 1 with neuroblastoma, 1 with Wilms tumour, 1 with acute lymphoblastic leukaemia (Table 1) [3–11].
Summary of DMD patients with concomitant cancer
Reduced life span has been reported in mdx mice, the murine model of DMD, and old mdx mice were found prone to develop sarcomas, such as lymphosarcoma, osteosarcoma, hemangiosarcoma and particularly RMS. The mean age at which RMS were detected was 20 months, with a range 16.5 to 24 months. No RMS were observed in any wild-type mice. A possible origin of RMS was postulated from an over-activation and proliferation of satellite cells and an increased risk of spontaneous mutations [12]. Spontaneous development of RMS was then reported in 9%of mdx mice aged to over one-year-old, whilst none of the 450 similarly aged wild-type mice developed tumours [13]. These data were confirmed by another study reporting a much higher incidence of mixed soft tissue tumours, including embryonal RMS, in almost 40%of mdx mice [14]. So far, no systematic investigation has been performed about the true incidence of cancer in DMD patients.
METHODS AND CASE REPORTS
We were particularly impressed by the hypothesis that DMD patients, who have gained a significant increase of life expectancy in the last decades because of improved respiratory support and standards of care, so that many of them may now expect to live into their fourth decade of life [15], in the same time can have an augmented risk to develop a cancer. So, since all Italian Neuromuscular Centres are grouped in an active clinical and scientific network and they monitor regularly DMD patients along their lives, we asked all members of the Italian Association of Myology about the occurrence of cancer in their DMD patients. Twenty neuromuscular clinics including all the main centres in the country answered the questionnaire. They reviewed their database containing clinical information on all DMD patients followed in the last 30 years. Two thousand, four hundred, and fifty-five medical records were checked and only 4 DMD patients with cancer were found (Table 1).
The first patient was a 35-year-old man who was on H24 non-invasive ventilation (NIV) for more than fifteen years and had dilatative cardiomyopathy treated with ACE-inhibitors and anticoagulant. He had an exon 46-47 deletion of DMD gene. Because of severe headache and behavioural disturbances with apathy and abulia for one month, he underwent a brain magnetic resonance imaging (MRI) demonstrating a T1 iso-hypointense lesion at the pineal region, diffusing at quadrigeminal and superior cerebellar cistern, splenium of corpus callosum, the third ventricle, posterior portion of thalamus and pressing posterior portion of mesencephalon, quadrigeminal lamina and sylvian aqueduct, being the last two not anymore recognizable. There were triventricular hydrocephalus and signs of trans-ependymal reabsorption of cerebrospinal fluid. On the basis of neuroimaging, a possible diagnosis of germinoma or teratoma was done. He was admitted to a neurological ward. A chest CT showed a left massive pneumothorax and a catheter drainage was inserted with iv antibiotics. A consultation with neurosurgeon, anaesthetist and neurologist together with his parents led to the decision of not to operate and the patient was treated with betamethasone, furosemide and mannitol. He worsened in the following days and died twenty days after admission.
The second patient was a 14-year-old boy with exon 48–50 deletion. He was treated with deflazacort since the age of 4.5 years and was still walking. Heart examination was normal. He noticed a painless swelling in the right forearm with rapid growth. Histological examination confirmed the diagnosis of alveolar RMS. He was treated with chemotherapy but was unresponsive and died after nine months.
The third patient was a 17-year-old man with unknown mutation. He developed an enlargement of the anterior part of right leg. A surgical biopsy showed an alveolar RMS and excision was performed with complete removal of the anterior part of the leg, of the fibula after distal osteotomy and of the triceps sural muscle, including the external popliteal sciatic nerve and the anterior tibial artery. Surgery was followed by local radiotherapy. The patient died 12 months later for respiratory failure due to lung metastases.
The fourth patient was an 11-year-old boy with an exon 45–54 deletion of DMD gene. He presented with a pain localized to the left humerus. X-ray documented the presence of a benign enchondroma, which regressed after calcium and vitamin D supplementation. The boy died at the age of 24 years from DMD-related respiratory failure.
DISCUSSION
There is conspicuous evidence for a role of DMD gene in the development of major tumour types, suggesting that both full-length Dp427 and short Dp71 gene products may act as tumour suppressor. A dysregulation between them has been postulated so that a future approach of DMD-targeted therapy has been hypothesized in cancer, for example by restoring Dp427 expression or by reducing/abolishing the expression of Dp71 [2]. Moreover, some cellular pathways involved in cancer development are perturbed in DMD. One of these is the Hippo signalling pathway, which is a key regulator of tissue homeostasis, cell proliferation and apoptosis. The expression of the downstream target of the Hippo pathway, Yes-associated protein 1 (YAP), is decreased in DMD muscle [16]. Activation of YAP could be beneficial to promote tissue repair and regeneration in DMD patients, whereas its inhibition has been proposed as an anticancer strategy [16]. Another example comes from studies on telomeres, which are involved in replicative senescence, apoptosis and neoplastic transformation. A telomere shortening occurs in DMD muscle in an age-dependent manner and also in muscle stem cells and cardiac tissue from dystrophic mice. In DMD muscle, telomere shortening is associated with increased expression of telomeric repeat binding factor-1 (TRF1) and poly (ADP-ribose) polymerase-1 (PARP1), which modulate telomere elongation [17–19].
Although aged mdx mice have a dramatically increased rate of sarcoma and particularly RMS [12–14], the risk and incidence of cancer in DMD patients are unknown. The aim of this retrospective study was to collect clinical information of DMD patients followed in a 30-year period by all neuromuscular centres in Italy. A prevalence of cancer of approx. 1/614 (0.16%) was found. Even considering the possible underestimation of our assessment, the value is lower than the reported prevalence of cancer in Italy in 2017 of 0.43%in the age group 5–14 years old and of 1.37%in age group 15–49 years old [20]. When considering the 9 patients reported by Jones et al. [2] and the 4 patients reported herein, 7 had cancer in their first decade of age, 4 in their second decade, 1 in the fourth decade and for 1 it is unknown. Thereby our data do not suggest increased prevalence of cancer in DMD patients in general or in aged DMD patients. Furthermore, among all 13 patients, 6 had unknown DMD gene mutation, 5 had exon deletions in the mid-distal hotspot of the gene, and 1 (plus 1 unconfirmed) had a point mutation. The small number with many undetermined type of mutation does not allow any comment about a possible relationship between cancer and the mutation site.
A more interesting matter is the type of cancer found in DMD patients. Considering all 13 patients, twelve tumours were malignant and one benign, 6 had RMS (3 alveolar, 1 embryonal, and 2 not specified), 4 had brain tumours (2 medulloblastoma, 1 neuroblastoma, and 1 not specified), 1 enchondroma, 1 acute lymphoblastic leukaemia (ALL), and 1 Wilms tumour. Medulloblastoma, neuroblastoma, Wilms tumour, enchondroma and ALL primarily or commonly develop in children or teens. RMS, which resulted herein the most common cancer in DMD patients, is the most common soft tissue sarcoma in children. Although they are small numbers, the occurrence of RMS in half of DMD patients so far reported with cancer (all in the age range 4–17 years) and in half of the Italian DMD patients observed with cancer in the last 30 years merits a particular attention. The Annual Cancer Reports of the Italian Association of Medical Oncology state that soft tissue sarcomas represent 1%of all tumours and 7.4%of the malignant tumours in the childhood. Rhabdomyosarcomas are 60%of all sarcomas in the childhood and have an annual incidence of 4.5 per million [21]. Therefore, our data suggest that DMD patients may have an increased risk to develop RMS, but not broadly other cancers. It has been already postulated that the occurrence of RMS in DMD patients is related to the degenerative muscle environment associated to increased muscle stem cells activation, which may promote RMS development through increased tissue turnover [22]. Another possible explanation is related to proposed tumour suppressor role of DMD gene products. Without functional tumour suppressor genes, there is a high risk of dysregulated cell growth that is a well-known mechanism for the development of cancers and most genes may increase risk in only a few cancer types, pertinent to function of that specific gene [23].
Although the small numbers herein presented do not allow definitive conclusion, the present report raises an alert for basic researchers and clinicians. The role of DMD gene in cancer merits further investigations. A multinational survey across a much larger network of neuromuscular centres may help in unravelling the link between DMD and cancer, perhaps also opening a new therapeutic window for both diseases.
Footnotes
ACKNOWLEDGMENTS
The authors received no financial support for this manuscript and have no potential conflicts. G.L. Vita, L. Politano and G. Vita are members of the European Reference Network for Rare Neuromuscular Diseases (ERN EURO-NMD).