Identification of genetic modifiers for PC and melanoma risk in
p16-Leiden carriers could possibly explain the variability of cancer occurrence within
p16-Leiden positive families and ultimately favor individualized surveillance and clinical management of those patients [
4,
12]. Herein, we sought to estimate the risk of developing PC and melanoma more accurately in carriers of the pathogenic variant
p16-Leiden. This was tested by determining whether a previously published associated risk variant for PC and melanoma, rs36115365-C [
13], could explain modified risk in a homogeneous population of
p16-Leiden carriers.
The MAF of rs36115365-C in the general European (Non-Finnish) population is 0.18 [
18] and in the Netherlands specifically, it is 0.20 [
19] indicating a common variant with high chances of detection. In this case, the second most-common allele (C) was detected with MAFs ranging from 0.21 to 0.29 in 283
p16-Leiden carriers, slightly higher than in the general population. A limitation of this study however is the small cohort size that could limit possibilities of detecting statistical associations. Moreover, selecting subjects older than 55 years of age not only reduced the control group size but also the possibility of developing PC or melanoma in the future was not fully excluded. A GEE statistical procedure was applied as it is appropriated for studying family based associations [
17,
20]. There was no significant association between rs36115365-C presence and PC risk in
p16-Leiden carriers.
Several efforts in scientific literature focused on identifying genetic modifiers of PC risk in
CDKN2A-mutation carriers. Yang et al., applied Whole Exome Sequencing (WES) in 66 PC patients with/without a
CDKN2A mutation [
21]. The combined data from five research groups, including 13 pancreatic
CDKN2A mutated (
p16-Leiden) cases from the Netherlands identified 35 variants in PC-related genes. Nominally significant associations were obtained for mismatch repair genes (
MLH1, MSH2, MSH6, PMS2) in all PC patients, however, variants in
ATM, CPA1, and
PMS2 were only observed in
CDKN2A wild-type PC patients. Further, nine
CDKN2A mutated and four
CDKN2A wild-type PC patients had rare potentially deleterious variants in multiple PC-related genes. These results, therefore, suggest that a subset of PC patients may have increased risk because of germline mutations in multiple PC-related genes [
21]. Nonetheless,
p16-Leiden carriers described in the study by Yang were not included in the current study. In addition, the same group showed that sequencing analysis of
PALB2, another high susceptibility gene for PC, did not reveal any deleterious mutations in PC patients from
CDKN2A-mutated families [
22]. Potjer et al. who studied the same cohort of
p16-Leiden carriers as in the current study, did not identify an association of seven PC-associated SNPs with PC risk [
12]. Therefore, consideration of other genetic modifiers yet unknown could be an additional explanation of the variability in occurrence of PC within
p16-Leiden families. Moreover, epidemiological studies suggest that non-genetic factors may also contribute to PC development specifically in
p16-Leiden carriers, with the most significant one being smoking [
23] as well as alcohol use and obesity in the general population [
24]. Collectively these data suggest that rs36115365-C risk variant could not be used to estimate the risk of PC in
p16-Leiden mutation carriers more accurately unlike in the European population published previously [
13].
Modifier genes for melanoma have been well described in literature for
CDKN2A mutation carriers [
10,
11,
25,
26]. The variant rs36115365-C, previously published to be negatively correlated with melanoma risk [
13] had a significantly negative association with melanoma development in this study. This effect did not remain however, when excluding probands from the analysis suggesting that ascertainment of melanoma cases influenced the results.