Investigating heredity in cutaneous T-cell lymphoma in a unique cohort of Danish twins

Cutaneous T-cell lymphomas (CTCLs) are uncommon but potentially fatal malignancies. The most prevalent clinical forms of CTCL are mycosis fungoides (MF) and the more aggressive leukemic variant, Sézary syndrome (SS). 1 , 2 Although the etiology is largely unknown, some lines of evidence indicate that genetic factors and heredity play a role in CTCL. Thus, independent studies reported on strong linkage disequilibrium between MF/SS and specific HLA-class II allotypes in Caucasians and Ashkenazi, indicating the existence of a significant genetic predisposition to CTCL. 3 , 4 Moreover, examples of CTCL occurring conjointly in monozygotic twin pairs have been reported 5 , 6 further suggesting a possible relevance of genetic factors in the CTCL etiology. However, genetic studies in multi-generation families and larger cohorts of twins have never been conducted. Accordingly, we have taken advantage of the Danish Twin Register and other nationwide population-based registers, to study heritability, predisposition to infectious diseases, comorbidity, hospitalizations and mortality for a 30+-year period in a cohort of 42 twins with CTCL (case twins) and their 42 co-twins, 420 age- and sex-matched twin controls (case controls) and their 420 co-twin controls. The 42 twin pairs comprised 13 monozygotic and 27 dizygotic twin pairs, whereas two twin pairs were of unknown zygosity. Patient characteristics of the CTCL case twin cohort are shown in Supplementary Table 1 . Female–male ratio was 1:1.8 and the average age at time of the CTCL diagnosis was 53 years (range: 5–85 years) showing that case twins with CTCL did not differ in terms of age at onset and female–male ratio from what has been described in other cohorts of Caucasian patients with CTCL. 7 , 8 , 9 Likewise, the mortality was 2.7-fold increased in the case twins compared with the case–controls, adjusted HR 2.65 (95% confidence interval (CI) 1.66–4.24) ( Table 1 ), further indicating that the CTCL cases represented a typical CTCL cohort. 9 Surprisingly, all twin pairs were discordant for CTCL, that is, none of the co-twins were diagnosed with CTCL. Importantly, all co-twins were monitored from birth until 1 June 2015 or death and none were lost to follow-up. On average, the co-twins that were alive at the time of case diagnosis were monitored for 20 years (range: 3–40 years) after the case twins were initially diagnosed with CTCL. As none of the co-twins were diagnosed with CTCL within a period of minimum 3 years and up to a maximum of 40 years after the corresponding case twin was diagnosed with CTCL, our findings indicated that the complete absence of CTCL in the co-twins was not a result of a short observation time.