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Nevus Distribution in a Utah Melanoma Kindred with a Temperature-Sensitive CDKN2A Mutation

2005; Elsevier BV; Volume: 125; Issue: 6 Linguagem: Inglês

10.1111/j.0022-202x.2005.23945.x

1523-1747

Scott R. Florell, Laurence J. Meyer, Kenneth M. Boucher, Marybeth Hart, Lisa Cannon‐Albright, Ronald M. Harris, Douglas Grossman, Wolfram E. Samlowski, John J. Zone, Jason Philip Brinton, Sancy A. Leachman,

melanin and skin pigmentation

total nevus density total nevus number To the Editor: We recently reported in the Journal our longitudinal phenotypic observations of a well-characterized Utah melanoma kindred carrying a temperature-sensitive mutation (V126D) in CDKN2A (Florell et al., 2004Florell S.R. Meyer L.J. Boucher K.M. et al.Longitudinal assessment of the nevus phenotype in a melanoma kindred.J Invest Dermatol. 2004; 123: 576-582Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar). The V126D mutation, which co-segregates with melanoma susceptibility (Kamb et al., 1994Kamb A. Shattuck-Eidens D. Eeles R. et al.Analysis of the p16 gene (CDKN2) as a candidate for the chromosome 9p melanoma susceptibility locus.Nat Genet. 1994; 8: 23-26Crossref PubMed Scopus (739) Google Scholar), results in a p16 protein with diminished capacity to bind CDK4/CDK6, inhibit Rb phosphorylation, and induce exit from the cell cycle (G1 arrest) at physiologic temperatures (Parry and Peters, 1996Parry D. Peters G. Temperature-sensitive mutants of p16CDKN2 associated with familial melanoma.Mol Cell Biol. 1996; 16: 3844-3852Crossref PubMed Scopus (93) Google Scholar). As this mutation was associated with increased nevus size and number in this family (Meyer et al., 1992Meyer L.J. Goldgar D.E. Cannon-Albright L.A. Piepkorn M.W. Zone J.J. Risman M.B. Skolnick M.H. Number, size, and histopathology of nevi in Utah kindreds.Cytogenet Cell Genet. 1992; 59: 167-169Crossref PubMed Scopus (14) Google Scholar; Florell et al., 2004Florell S.R. Meyer L.J. Boucher K.M. et al.Longitudinal assessment of the nevus phenotype in a melanoma kindred.J Invest Dermatol. 2004; 123: 576-582Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar), we hypothesized that given its temperature sensitivity it might also be associated with excess formation of nevi and/or melanomas on warmer regions of the body, defined as the head, neck, and trunk. Here we report nevus and melanoma distribution data derived from 29 family members and 11 spouse control subjects over an average interval of 15 y. This study was approved by the Institutional Review Board at the University of Utah and was conducted according to Declaration of Helsinki principles. All subjects agreed to participate and informed written consent was obtained. The subjects were not aware of their CDKN2A mutation status. A total of 13 V126D mutation carriers and 16 non-carriers were examined, with 11 married-in spouses serving as a control group. All participants were examined in this study and initially 15 y ago by the same dermatologist (L. J. M.), who was also unaware of subject mutational status. The initial and follow-up examinations were conducted in a similar fashion and included a total body skin exam in which location and size of all nevi ≥2 mm in diameter were recorded on a body map diagram as described (Florell et al., 2004Florell S.R. Meyer L.J. Boucher K.M. et al.Longitudinal assessment of the nevus phenotype in a melanoma kindred.J Invest Dermatol. 2004; 123: 576-582Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar). The head, neck, and trunk were considered "warm" regions and the extremities "cold" regions. Invasive melanomas were confirmed by the Utah Cancer Registry, by obtaining the pathology report, and/or by review of histologic slides by dermatopathologists (S. R. F. and R. M. H.). The nevus count and nevus density data were analyzed using multiple linear regression with appropriate differences, constructed for each subject, as response variables. Carrier status, age at first visit, and gender were used as explanatory variables in the multiple regression analysis. Nevus distribution data were analyzed by absolute number of nevi and by the mean change of nevi in warm and cold regions over time. As shown in Figure 1, mutation carriers developed more nevi on warm regions than non-carrier or spouse control subjects (p=0.004), but the carriers, non-carriers, and spouse control subjects showed a similar rate of nevus development on cold regions (p=0.07). Because CDKN2A mutation carriers are more prone to nevus development in this family (Meyer et al., 1992Meyer L.J. Goldgar D.E. Cannon-Albright L.A. Piepkorn M.W. Zone J.J. Risman M.B. Skolnick M.H. Number, size, and histopathology of nevi in Utah kindreds.Cytogenet Cell Genet. 1992; 59: 167-169Crossref PubMed Scopus (14) Google Scholar; Florell et al., 2004Florell S.R. Meyer L.J. Boucher K.M. et al.Longitudinal assessment of the nevus phenotype in a melanoma kindred.J Invest Dermatol. 2004; 123: 576-582Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar), we also evaluated nevus distribution based on the mean change of nevi and nevus density in warm and cold regions over the 15 y follow-up period. In this way, we minimized the possibility that the preponderance of warm-region nevi in CDKN2A mutation carriers was merely reflective of a nevogenic effect of CDKN2A mutation. Mutation carriers demonstrated a significant increase in the mean change of nevus number and density on the warm regions, as compared with the non-carriers and spouse control subjects. The mean change in these parameters was not significantly different in the cold regions (Table I). Four V126D CDKN2A mutation carriers developed 11 invasive melanomas, six on warm regions (55%) and five on cold regions (45%), which was not statistically significant. A significant difference in nevus distribution was not observed in a second Utah melanoma kindred with a promoter-region CDKN2A mutation (-34 G>T) over a 15-interval (12 mutation carriers, 11 non-carriers, and 11 spouse control subjects; Figure 1).Table IMean change in nevus number and density in V126D CDKN2A mutation kindredRegionaWarm regions of the body were defined as the head, neck, and trunk, and cold regions were defined as the upper and lower extremities.GroupbSubject mutation status was verified by sequencing the promoter region and exons 1α–3 of CDKN2A and exon 1β (ARF). A total of 13 V126D mutation carriers and 16 non-carriers were examined, with 11 spouses serving as a control group.TNNcChange in TNN represents difference in number of clinically detectable nevi≥2 mm in diameter (# nevi at follow-up–# nevi at initial visit). mean change initial versus F/U95% CIpdThe analysis used a square-root transformation to normalize the data, which were adjusted for age and sex. Statistical analysis was performed using Statistica 6.0 (StatSoft Inc., Tulsa, Oklahoma).TNDeChange in TND calculated by dividing area of all nevi by estimated body surface area (nevus density at follow-up–nevus density at first visit) (Goldgar et al, 1991; Meyer et al, 1992). mean change initial versus F/U95% CIpdThe analysis used a square-root transformation to normalize the data, which were adjusted for age and sex. Statistical analysis was performed using Statistica 6.0 (StatSoft Inc., Tulsa, Oklahoma).WarmCarrier102–250.0026115–1380.005Non-carrier-1-6 to 00-15 to 7Spouse0-4 to 40-14 to 24ColdCarrier20–110.36151–500.26Non-carrier0-2 to 31-3 to 12Spouse0-4 to 417–18TNN, total nevus number; TND, total nevus density.a Warm regions of the body were defined as the head, neck, and trunk, and cold regions were defined as the upper and lower extremities.b Subject mutation status was verified by sequencing the promoter region and exons 1α–3 of CDKN2A and exon 1β (ARF). A total of 13 V126D mutation carriers and 16 non-carriers were examined, with 11 spouses serving as a control group.c Change in TNN represents difference in number of clinically detectable nevi≥2 mm in diameter (# nevi at follow-up–# nevi at initial visit).d The analysis used a square-root transformation to normalize the data, which were adjusted for age and sex. Statistical analysis was performed using Statistica 6.0 (StatSoft Inc., Tulsa, Oklahoma).e Change in TND calculated by dividing area of all nevi by estimated body surface area (nevus density at follow-up–nevus density at first visit) (Goldgar et al., 1991Goldgar D.E. Cannon-Albright L.A. Meyer L.J. Piepkorn M.W. Zone J.J. Skolnick M.H. Inheritance of nevus number and size in melanoma and dysplastic nevus syndrome kindreds.J Natl Cancer Inst. 1991; 83: 1726-1733Crossref PubMed Scopus (38) Google Scholar; Meyer et al., 1992Meyer L.J. Goldgar D.E. Cannon-Albright L.A. Piepkorn M.W. Zone J.J. Risman M.B. Skolnick M.H. Number, size, and histopathology of nevi in Utah kindreds.Cytogenet Cell Genet. 1992; 59: 167-169Crossref PubMed Scopus (14) Google Scholar). Open table in a new tab TNN, total nevus number; TND, total nevus density. There is precedent for temperature-sensitive mutations resulting in a demonstrable clinical phenotype. The well-known temperature-sensitive tyrosinase mutation ("Siamese cat mutation") occurs in both cats and mice, producing an increased relative pigmentation in the cooler areas of the body such as the tips of the ears, tail, and paws (Searle, 1968Searle A.G. Comparative Genetics of Coat Colour in Mammals. Academic Press Inc., New York1968Google Scholar). An analogous human tyrosinase mutation confers a temperature-dependent distribution of pigmentation in human carriers (Giebel et al., 1991Giebel L.B. Tripathi R.K. King R.A. Spritz R.A. A tyrosinase gene missense mutation in temperature-sensitive type I oculocutaneous albinism. A human homologue to the Siamese cat and the Himalayan mouse.J Clin Invest. 1991; 87: 1119-1122Crossref PubMed Scopus (73) Google Scholar; King et al., 1991King R.A. Townsend D. Oetting W. Summers C.G. Olds D.P. White J.G. Spritz R.A. Temperature-sensitive tyrosinase associated with peripheral pigmentation in oculocutaneous albinism.J Clin Invest. 1991; 87: 1046-1053Crossref PubMed Scopus (64) Google Scholar). In addition, although skin temperature regulation is complex and depends on thermoregulatory and environmental factors (Houdas and Ring, 1982Houdas Y. Ring E.F.J. Temperature distribution.Human Body Temperature. Its Measurement and Regulation. Plenum Press, London1982: 81-103Crossref Google Scholar; Wenger, 1995Wenger C.B. The regulation of body temperature.in: Rhodes R.A. Tanner G.A. Medical Physiology. Little, Brown and Company, Boston1995: 587-613Google Scholar), the normal fluctuations in body temperature appear to encompass a range that would impact V126D CDKN2A function. Studies measuring skin temperature in warm, neutral, and cold conditions suggest that core regions (head and trunk) are, on average, warmer than the extremities in neutral (26°C–27°C) and cold environments (Folk, 1974Folk G.E. Principles of temperature regulation.Textbook of Environmental Physiology. Lea & Febiger, Philadelphia1974: 88-132Google Scholar; Webb, 1992Webb P. Temperatures of skin, subcutaneous tissue, muscle and core in resting men in cold, comfortable and hot conditions.Eur J Appl Physiol Occup Physiol. 1992; 64: 471-476Crossref PubMed Scopus (109) Google Scholar; Wenger, 1995Wenger C.B. The regulation of body temperature.in: Rhodes R.A. Tanner G.A. Medical Physiology. Little, Brown and Company, Boston1995: 587-613Google Scholar), but skin temperature in warm environments (34°C) is similar over the entire integument (Folk, 1974Folk G.E. Principles of temperature regulation.Textbook of Environmental Physiology. Lea & Febiger, Philadelphia1974: 88-132Google Scholar). Temperature measurements of skin in a comfortable environment are slightly higher in warm body regions and have been measured at 34°C–35°C as compared with 31°C–34°C in the cooler extremities (Houdas and Ring, 1982Houdas Y. Ring E.F.J. Temperature distribution.Human Body Temperature. Its Measurement and Regulation. Plenum Press, London1982: 81-103Crossref Google Scholar; Webb, 1992Webb P. Temperatures of skin, subcutaneous tissue, muscle and core in resting men in cold, comfortable and hot conditions.Eur J Appl Physiol Occup Physiol. 1992; 64: 471-476Crossref PubMed Scopus (109) Google Scholar). Thus, the temperature range at which the V126D CDKN2A mutation is functionally impaired coincides with the range of normal fluctuations of cutaneous temperature. Our data demonstrate a statistically significant disparity in the nevus distribution between mutation carriers and non-carriers, suggesting that the V126D temperature-sensitive mutation may influence the distribution of nevi in these subjects. We considered other explanations for the discrepancy observed in mutation carriers. Distribution of nevi is known to correlate with UV exposure, sunburn history, and phenotypic constitutional features (Kopf et al., 1985Kopf A.W. Lindsay A.C. Rogers G.S. Friedman R.J. Rigel D.S. Levenstein M. Relationship of nevocytic nevi to sun exposure in dysplastic nevus syndrome.J Am Acad Dermatol. 1985; 12: 656-662Abstract Full Text PDF PubMed Scopus (46) Google Scholar,Kopf et al., 1986Kopf A.W. Gold R.S. Rogers G.S. Hennessey N.P. Friedman R.J. Rigel D.S. Levenstein M. Relationship of lumbosacral nevocytic nevi to sun exposure in dysplastic nevus syndrome.Arch Dermatol. 1986; 122: 1003-1006Crossref PubMed Scopus (34) Google Scholar; Slade et al., 1995Slade J. Marghoob A.A. Salopek T.G. Rigel D.S. Kopf A.W. Bart R.S. Atypical mole syndrome: Risk factor for cutaneous malignant melanoma and implications for management.J Am Acad Dermatol. 1995; 32: 479-494Abstract Full Text PDF PubMed Scopus (103) Google Scholar; Harrison et al., 1999Harrison S.L. Buettner P.G. MacLennan R. Body-site distribution of melanocytic nevi in young Australian children.Arch Dermatol. 1999; 135: 47-52Crossref PubMed Scopus (62) Google Scholar; Autier et al., 2001Autier P. Boniol M. Severi G. et al.The body site distribution of melanocytic naevi in 6–7 year old European children.Melanoma Res. 2001; 11: 123-131Crossref PubMed Scopus (40) Google Scholar; Carli et al., 2002Carli P. Naldi L. Lovati S. La Vecchia C. The density of melanocytic nevi correlates with constitutional variables and history of sunburns: A prevalence study among Italian schoolchildren.Int J Cancer. 2002; 101: 375-379Crossref PubMed Scopus (66) Google Scholar). Significant differences between the genotypic groups, however, were not identified with respect to markers of chronic UV radiation (rhytides, poikiloderma, actinic keratoses, solar lentigines, etc.), self-reported sunburn history, or phenotypic constitutional features (hair and eye color, skin type) (Florell et al., 2004Florell S.R. Meyer L.J. Boucher K.M. et al.Longitudinal assessment of the nevus phenotype in a melanoma kindred.J Invest Dermatol. 2004; 123: 576-582Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar). We also considered the possibility that nevogenic CDKN2A mutations might induce nevus formation on the head, neck, and trunk preferentially, unrelated to temperature sensitivity. Nevus distribution data from a second Utah melanoma kindred with a promoter region CDKN2A mutation (-34 G>T) over a 15-y interval, however, showed no significant differences in nevus distribution between the genotypic groups. In summary, we found that a temperature-sensitive CDKN2A mutation is associated with an altered nevus phenotype with increased rate of nevus development and density on warm body regions among mutation carriers. Although there were slightly more melanomas on the warm areas, the difference was not significant. These findings provide the first in vivo evidence that a temperature-sensitive CDKN2A mutation may confer a temperature-dependent nevus distribution. This work was supported by grants from The Skin Cancer Foundation (S. R. F.), the Dermatology Foundation Leaders Society Dermatologist Investigator Research Fellowship and Clinical Career Development Award (S. R. F.), National Institutes of Health grants K23 RR17525-01 (S. R. F.), R01 CA102422 (L. A. C.), K08 AR48618 (D. G.) and R01 AR50102 (D. G.), Doris Duke Charitable Foundation (S. A. L.), Fellowship-To-Faculty Transition Award from the University of Utah, funded in part by the Howard Hughes Medical Institute (S. A. L.), The Huntsman Cancer Foundation (S. A. L., D. G.), the Tom C. Mathews Jr. Familial Melanoma Research Clinic at Huntsman Cancer Institute, Huntsman General Clinical Research Center Public Health Service grant (MO1 RR00064), National Cancer Institute (NCI) Cancer Center Support grant 5P30CA420-14, and the Utah Cancer Registry, funded by Contract # NCI-CN-67000 from the NCI with additional support from the Utah Department of Health and the University of Utah. We wish to thank Huntsman Cancer Foundation for database support provided to the Pedigree and Population Resource of Huntsman Cancer Institute. We gratefully acknowledge the willing participation of all the family members in this study.