By Adam MarcusReviewed by Julia M. Cunningham, MD, Assistant Professor, Division of Hematology and Oncology, Lombardi Comprehensive Cancer Center, Georgetown University

The presence of moles and a sensitivity to sunlight appear to be linked to an increased risk for certain forms of blood cancer, new research shows. The authors, who published their findings

in a recent issue of Cancer Medicine, said the results point to a potential genetic link between skin features and the risk for blood cancers.1

Skin cancers are the most common form of malignancy, and pigmentation features, such as nevi and sun sensitivity, are established risk factors for these tumors. Studies also have identified

Besson and colleagues sought to investigate whether pigmentation features and sun exposure are associated with risk of CLL/NHL using the E3N prospective database, a French repository of

nearly 99,000 urban women aged 40-65 years followed between 1990 and 2014. Of the total cohort, the researchers excluded approximately 7000 women who had been diagnosed with cancer (except

basal cell carcinoma and in situ colorectal tumor) prior to inclusion in the database or who had been lost to follow-up, leaving 92,097 for their analysis. The E3N baseline questionnaire

asked women a range of questions about pigmentation, including their hair color, complexion, number of moles and freckles, and whether they were prone to sunburns.1

Results of this study showed that women who self-reported being highly sensitive to sunburn, and those who said they had many nevi, were 2 to 3 times more likely to be diagnosed with CLL,

respectively, than women less prone to burning and those without moles. The presence of many nevi, but not sensitivity to sunburn, was also linked to a modestly increased risk for NHL, the

researchers reported, but the association of risk is mostly limited to CLL.1

During the 24-year study period, 622 women received a diagnosis of either CLL (n=144) or NHL (n=478). Women who self-reported having any nevi were more likely to be diagnosed with CLL/NHL

than women who said they had no nevi. The risk was greater among women who reported having many or very many moles (hazard ratio [HR]=1.56; 95% CI, 1.15–2.11) than for those with few such

skin features (HR=1.42; 95% CI, 1.04–1.94; P-trend=.007).1

The association between nevi and blood cancers, however, appeared to be limited to CLL, and the authors observed a linear increase in risk of CLL with number of nevi. Women with few nevi had

an 86% greater risk for CLL than those with no nevi (HR=1.86; 95% CI, 0.84-4.15), while those with many or very many had a 3-fold higher risk for the disease (HR=3.00; 95% CI, 1.38-6.52;

P-trend=.0003). After multivariable analysis, this association remained highly significant. By contrast, associations with NHL were not statistically significant.1

The association between high skin sensitivity to sunlight and risk of CLL or NHL was less clear. In fact, the authors found no significant association overall; however, women with skin that

is highly sensitive to sunburn were at increased risk of CLL (HR=1.96; 95% CI, 1.21-3.18). These women showed no increase in risk of NHL. “Skin or hair color, number of freckles, and average

daily ultraviolet (UV) dose during spring and summer in location of residence at birth or at inclusion (kJ/m2) were not associated with CLL/NHL risk,” the study authors noted.

“Our study is the first study, based on a large prospective cohort, that showed a relationship between the number of nevi or skin sensitivity to sunlight and the risk of developing CLL.

These data support the hypothesis that there are partially common genetic or pathophysiological mechanisms between these 2 tumors,” Caroline Besson, MD, PhD, a hematologist/oncologist at the

Centre Hospitalier de Versailles and the senior author of the study, said. “With this in mind, it may be prudent to prescribe a complete blood count of these patients in order to detect a

possible CLL at an early stage since the diagnosis of CLL is easily suggested by a simple blood test (lymphocytosis >5 g/L). This approach should be further evaluated.”

“The significant associations found in our study concern the CLL subgroup,” Besson added. Although the 2 conditions share a proliferation of malignant lymphoid cells, they have different

pathways of pathogenesis. “From now on, it might be more judicious to study each NHL entity separately to gain homogeneity. In our study, it is precisely with 1 of the subtypes of NHL, the

CLL, that the association could be highlighted.”

The French group said their findings suggest that a common genetic pathway may help explain the link between certain skin features and the development of lymphoid malignancies. “Potentially

common genetic mechanisms between nevi and CLLs have not been clearly identified. However, 1 gene seems to be involved in certain pigmentary features of the skin as well as in the

pathogenesis of skin carcinomas and CLLs: the IRF4 gene,” Louis-Marie Garcin, MD, of the Université Paris-Saclay, Villejuif and the lead author of the paper, told MedPage Today.

Previous research found a strong association between IRF4 variants and risk of CLL.3 “IRF4 belongs to the interferon family of regulatory factors, and is implicated in a range of biological

functions,” she said. “Also known as multiple myeloma oncogene-1 (MUM1), it is widely expressed in both lymphocytes and skin cells. It is a key factor in the regulation of lymphocyte

differentiation and activation. It is also thought to play a role in cutaneous carcinomas by reducing the host immune response against atypical skin keratinocytes,” Garcin said.

Besson said future studies could look for shared pathophysiological pathways implicated in skin cancers and CLL. “Certain polymorphisms of the IRF4 gene appear to be involved in the

pathogenesis of both diseases,” Besson said. “They could then constitute an element of risk prediction or even a therapeutic target.”