A hypothesis concerning deficiency of sunlight, cold temperature, and influenza epidemics associated with the onset of acute lymphoblastic leukemia in northern Finland

Abstract

Research to detect new factors contributing to the etiology of acute leukemia (AL) is urgently needed. Located between latitudes 65 degrees and 70 degrees north, the population in northern Finland is exposed to extreme seasonal alterations of ultraviolet-B light and temperature. There is also a seasonal variation of both the 25(OH)- and 1,25(OH)2-D3 vitamin serum concentrations. In the present work, the frequencies of different types and age-groups at diagnosis of AL were compared during the dark and light months of the year, to uncover seasonality. Between January 1972 and December 1986, 300 consecutive patients aged >/=16 years and diagnosed as having AL were enrolled. The observed mean monthly global solar radiation, temperature measurements, and influenza epidemics were compared with the monthly occurrence of AL. Both acute lymphoblastic leukemia (ALL) (p=0.006) and total AL (p=0.015) were diagnosed excessively in the dark and cold compared with light and warm period of the year. There was a tendency for de novo leukemia to increase also in the dark and cold, but for acute myeloid leukemia (AML) patients the excess was not significant. Age >/=65 was strongly associated with the dark and cold season (p=0.003). Significantly more ALL (p=0.005) and de novo leukemias (p=0.029) were observed during influenza epidemics than during nonepidemic periods. However, a seasonality, i. e., the fluctuation of numbers of AL cases, was not determined, either monthly or during different photo- and temperature periods or influenza epidemics; this might be due to the small numbers of patients studied. Nevertheless, it is hypothesized that sunlight deprivation in the arctic winter can lead to a deficiency of the 1, 25(OH)2D3 vitamin, which might stimulate leukemic cell proliferation and block cell differentiation through dysregulation of growth factors in the bone marrow stromal cells, causing one mutation and an overt ALL in progenitor cells damaged during the current or the previous winter by influenza virus, the other mutation.

Evidence of seasonality in the diagnosis of monocytic leukaemia

“…Many recent studies have focused on acute lymphocytic leukaemia and/or leukaemia in childhood but the results remain inconsistent (Harris et al, 1987;Badrinath et al, 1997;Westerbeek et al, 1998;Ross et al, 1999;Timonen, 1999;Higgins et al, 2001).…”

Are sunlight deprivation and influenza epidemics associated with the onset of acute leukemia?

“…6 In 86% of these, the month of diagnosis was the same or within one month before or after that in the FCR record, and in 9% the difference was 2-4 months. …”

“…1-3 However, the alleged viral origin of leukemia [3][4][5] and the possible role of vitamin D deficiency associated with winter darkness 6 have prompted further studies. Two well-known hypotheses suggest that childhood leukemia could arise as a rare abnormal response to common infections either due to low herd immunity (the population mixing hypothesis) 5 or with a delayed exposure to infections.…”

“…4 It has been hypothesized that vitamin D deficiency associated with winter darkness might stimulate leukemic proliferation and block differentiation through dysregulation of growth factors. 6 This would cause one mutation, followed by influenza causing another mutation and manifest leukemia. 6 In view of Gilliland's 7 two-hit hypothesis proposing a combined effect of two mutations, a short latency period of leukemia would therefore be a possibility.…”

“…6 This would cause one mutation, followed by influenza causing another mutation and manifest leukemia. 6 In view of Gilliland's 7 two-hit hypothesis proposing a combined effect of two mutations, a short latency period of leukemia would therefore be a possibility. Situated in the far North, between the 60 and 70°N latitudes, Finland has wide annual variations in sunlight.…”