Our study is the first to quantify cancer risk in patients with MMD. In this large population-based study, we observed an excess cancer risk compared with the general population, first among Swedish MMD patients, and then among the replication cohort of Danish patients. Due to the close similarity in the results and to improve statistical power, we combined the findings from these two cohorts. The elevated overall cancer risk was primarily due to excess malignancies of the endometrium, brain, ovary, and colon.
Case reports have suggested a strong association between MMD and pilomatricoma, a rare benign skin neoplasm (which is not registered in the Swedish Cancer Registry and incompletely registered in the Danish Cancer Registry)and also included reports of a number of rare malignancies13
. Published case reports tend to present a biased sample of unusual cases, and therefore cannot provide conclusive evidence of a genuine association. This methodological shortcoming led to the current study, which provides strong evidence that MMD may in fact be a cancer susceptibility disorder.
Several biological mechanisms for the apparent increased cancer risk have been proposed including possible RNA-mediated alterations in tumor suppressor genes or oncogene expression, modification of the coding features of proteins 27
, and/or up-regulation of the Wnt/β-catenin
signaling pathway 13
. Of note, alteration in RNA binding proteins, suggested as a key player in MMD pathogenesis, have been observed in human carcinogenesis28
. On the other hand, it is worth noting that the DM1
gene product – DMPK (MIM #605377) – is a protein kinase, i.e.,
a member of a large gene family which contains numerous examples of cancer susceptibility genes, such as RET
(Peutz-Jeghers syndrome), PRKAR1A
(Carney complex), RAF1
(Noonan syndrome), ALK
(neuroblastoma) and PDGFRA
The absence of an excess cancer risk in other repeat disorders, e.g.,
and Huntington disease 31
is noteworthy. It is possible that repeat expansion size may be a key determinant of cancer risk in this context, since nucleotide repeat expansions are much longer in MMD patients compared with Huntington disease or fragile-X patients 32
, and several case reports have demonstrated longer nucleotide repeat expansion in tumor tissue from MMD patients compared with their normal tissue 33;34
. If proven true, we would expect that patients with MMD2, who are known to have the longest repeat sizes, would have higher risk of cancer, a hypothesis that needs further investigation. The observed cancer risk differences between various repeat disorders might also be related to the precise repeat expansion location within the affected gene. MMD differs from Huntington disease by having expansion in a non-coding region, which is more likely to produce a toxic RNA mediated gain-of-function that can affect downstream effector genes5;35
, some of which maybe tumor suppressor genes, e.g.,
mismatch repair genes (MMR). Additional analyses of paired normal tissue and tumor samples from well-characterized MMD patients could shed further light on the relationship between expansion repeat length and cancer risk in MMD.
Surprisingly, the cancer spectrum we observed in MMD patients included many of the same excess cancers observed in patients with hereditary non-polyposis colorectal cancer (HNPCC)36
colon, brain, ovary and endometrium. In that context, MMD-related pilomatricoma may be analogous to the increased risk of sebaceous adenoma in the Muir-Torre variant of HNPCC. Inherited DNA mismatch repair (MMR) abnormalities are the genetic basis for HNPCC, a prototypic cancer susceptibility disorder 36
. Defective MMR may play a role in the formation of unstable nucleotide repeats, perhaps through a disease-specific mechanism 37;38
. The nexus between the nucleotide repeat expansion pathway and MMR warrants further investigation in this context, because in vitro
and mouse models 39–41
suggest that abnormal MMR plays a major role in mediating the biological effects of MMD-related nucleotide repeat instability. eTable 2
summarizes the observed cancer profile in MMD patients versus
HNPCC patients. The occurrence of a similar spectrum of malignancies in both raises the possibility of shared causal pathways.
Our study has several strengths. We used population-based registries, minimizing selection bias and maximizing complete cancer ascertainment. Both MMD and cancer diagnoses were derived from registry-based records, rather than self-report, minimizing recall bias. The study included MMD patients identified from both inpatient and outpatient registries, broadening the generalizability of our results. However, the severely-affected MMD subset is still likely to be over-represented, since the majority of patients in the study were identified from inpatient hospitalization records. The remarkable similarity of findings obtained from the Swedish and Danish components of the study provides substantial reassurance that our observations are genuine. The absence of excess screening-related cancers such as breast, cervical, and prostate in our analysis argues against a possible influence of surveillance bias on our results. Most of the excess cancers observed in the present study were lethal cancers that would be diagnosed regardless of whether a person had prior contact with the health care system. Thus, surveillance bias did not appear to influence our results. Furthermore, we found MMD patients with a similarly increased risk of cancer when restricting the analyses to more than five years after first MMD discharge diagnosis, to those with MMD as main diagnosis, and to those with no other diagnoses besides MMD at the first MMD admittance, arguing against the possibility that our results may be confounded by cause of hospitalization or increased surveillance.
Due to the under-reporting of non-melanoma skin cancer in the Swedish cancer registry, we were not able to fully evaluate its risk in MMD. However, data available from the Danish registry only, suggested a possible excess risk of non-melanoma skin cancer (SIR= 2.08, 95% CI=1.2–3.4), an association that needs further confirmation. Of note, our combined data suggested an excess risk of cutaneous melanoma, although not statistically significant.
The lack of information regarding known cancer risk factors, e.g., smoking, which prevented evaluating them as possible confounders, represents one important study limitation. In addition, our data did not permit identifying which specific MMD subtype each subject had, so we could not determine if the increased cancer risk observed in MMD was common to all patients or confined to a specific subtype. We expect that most of the cases in this study were MMD1, because it is more prevalent, and it was identified and molecularly-characterized before MMD 2. Furthermore, we did not have data on gene repeat length. Thus, it remains to be evaluated in future studies to what extent gene repeat length modifies the cancer risk. Finally, we acknowledge that the point estimates for some of the cancer sites had wide confidence intervals, which make firm conclusions for these sites less reliable.
In conclusion, our study provides quantitative epidemiologic evidence of an increased risk of cancer in MMD patients. The specific cancer patterns observed in our study raise the possibility of a role for aberrant mismatch repair in the etiology of MMD-related cancer. Further research is needed to explore whether the observed associations are similar in both MMD1 and 2, to determine whether cancer risk correlates with disease severity and/or repeat length, and to understand the biological mechanisms which might explain the associations we have reported. Our findings have significant implications for the clinical management of MMD patients, including at a minimum the implementation of appropriate validated routine population-based cancer screening strategies, and careful assessment of therapy-related risks and benefits. The incidence rates for a number of the excess cancers are relatively low, despite their large relative risks. Screening for these uncommon cancers should not be implemented in the absence of demonstrated clinical utility. The evaluation of persistent CNS and abdominopelvic symptoms or dysfunctional uterine bleeding warrants clinical consideration with a higher prior probability of neoplasm, in light of our new findings.