Lack of association between CDKN2A germline mutations and survival in patients with melanoma: A retrospective cohort study

• DOI: 10.1016/j.jaad.2021.10.024
• Publication Date: 2021-10-25T13:16:43Z
• Authors: Norbertus Anton I...; Mary-Ann El Sharouni; Remco van Doorn; Paul J. van Diest; Monique E. van Le...; Jasper I. van der...; Jelle Goeman; Nicole A. Kukutsch; Dyon G.C.T.M. Snels; Sybren Dekker; Robert L. van Lee...; Tondo van Rijssen; Erik Honig; Jacqueline Vink; Marianne B. Crijns; Ineke Bruynzeel; Francis P.K. Wu; Biljana Zupan-Kaj...; Jacqueline Schuur
• Keywords: 03 medical and health sciences; Skin Neoplasms; 0302 clinical medicine; Genes, p16; Humans; Genetic Predisposition to Disease; Melanoma; Cyclin-Dependent Kinase Inhibitor p16; Germ-Line Mutation; Pedigree; Retrospective Studies

To the Editor: Approximately 10% of patients with cutaneous melanomas have a positive melanoma family history. Germline mutation CDKN2A gene is most common cause familial melanoma.1Read J. Wadt K.A.W. Hayward N.K. Melanoma genetics.J Med Genet. 2016; 53: 1-14https://doi.org/10.1136/jmedgenet-2015-103150Crossref PubMed Scopus (133) Google Scholar Mutation carriers lifetime risk approximately 70%, and many develop at younger age.2van der Rhee J.I. Krijnen P. Gruis N.A. et al.Clinical histologic characteristics malignant in families germline CDKN2A.J Am Acad Dermatol. 2011; 65: 281-288https://doi.org/10.1016/j.jaad.2010.06.044Abstract Full Text PDF (36) For other cancer types, there evidence that hereditary tumors different prognoses than sporadic tumors. However, it uncertain whether carriership (CDKN2A-mut) affects prognosis.3Helgadottir H. Höiom V. Tuominen R. al.Germline status survival cases.J Natl Cancer Inst. 108: djw135https://doi.org/10.1093/jnci/djw135Crossref (30) Scholar, 4Helgadottir Olsson Hansson risks multiple primary melanomas: association history status.J 2017; 77: 893-901https://doi.org/10.1016/j.jaad.2017.05.050Abstract (24) 5Dalmasso B. Pastorino L. Ciccarese G. al.CDKN2A mutations are not associated poor an Italian cohort patients.J 2019; 80: 1263-1271https://doi.org/10.1016/j.jaad.2018.07.060Abstract (11) The aim this study was to compare CDKN2A-mut melanoma.All adults newly diagnosed invasive, clinically localized, between January 1, 2000, December 31, 2014, were included. Data 89 extracted from database Netherlands Foundation for Detection Hereditary Tumors. A population-based 56,929 PALGA (the Dutch Nationwide Network Registry Histopathology Cytopathology) Registry. Ethical approval granted by ethical review boards Leiden University Medical Center . Cox proportional hazards regression analyses performed. See Supplementary (available via Mendeley https://doi.org/10.17632/h4m4zwdysx.1) all statistical analyses.CDKN2A-mut more often developed (MPMs) (42.7% vs 4.0%; P < .0001). median age diagnosis first 15 years lower (42 57 years; had thinner (median Breslow thickness, 0.6 mm 0.9 mm; .0001) (Table I). After correcting gender, melanoma, site, ulceration, sentinel node status, subtype, year diagnosis, overall (OS) recurrence-free (RFS) significantly without (OS hazard ratio [HR], 1.44; 95% CI, 0.85-2.43; RFS HR, 0.91; 0.45-1.83) II).Table IBaseline mutation–positive patientsCharacteristicsCDKN2A-mut (N = 89)Sporadic 56,929)P valueGender, n (%).13 Female57 (64.0)31,916 (56.1) Male32 (36.0)25,013 (43.9)Median y (IQR)42 (31-50)57 (44-68)<.0001Year diagnosis<.0001 2000/200115 (16.9)4928 (8.7) 2002/200317 (19.1)5459 (9.6) 2004/200513 (14.6)6396 (11.2) 2006/200715 (16.9)6979 (12.3) 2008/200910 (11.2)810 (14.2) 2010/201111 (12.4)9308 (16.4) 2012/2013/20148 (9.0)15,759 (27.7)Primary (%).04 Head neck5 (5.6)7127 (12.5) Trunk35 (39.3)23,892 (42.0) Upper limb18 (20.2)8327 (14.6) Lower limb31 (34.8)15,725 (27.6) Not known0 (0.0)1858 (3.3)Median (IQR)0.6 (0.4-0.9)0.9 (0.5-1.8)<.0001Breslow mm, (%)<.0001 <0.853 (60.9)23,270 (40.9) ≤0.8-1.016 (18.4)9311 1.1-2.015 (17.2)12,614 (22.2) 2.1-4.03 (3.4)7668 (13.5) >4.00 (0.0)4066 (7.1)Subtype, (%).03 Nonnodular84 (94.4)49,248 (86.5) Nodular5 (5.6)7679 (13.5)Ulceration, No53 (59.6)39,030 (68.6) Yes1 (1.1)7587 (13.3) Unknown35 (39.3)10,312 (18.1)Mitoses, (%).05 No14 (15.7)9914 (17.4) Yes29 (32.6)12,522 (22.0) Unknown46 (51.7)34,493 (60.6)Multiple melanoma<.0001 No (SPM)51 (57.3)54,645 (96.0) Yes (MPM)38 (42.7)2284 (4.0)SN (%).50 Negative7 (87.5)9162 (77.5) Positive1 (12.5)2666 (22.5) performed8145,099Median follow-up, (IQR)11.5 (9.4-15.7)6.3 (3.6-10.3)<.0001CDKN2A-mut, mutation-positive patients; IQR, interquartile range; MPM, melanoma; SN, node; SPM, single melanoma. Open table new tab Table IIUni- multivariable 51,921)VariableClassOverall (10,457 events)Recurrence-free (6865 events)UnivariableMultivariableUnivariableMultivariableHR (95% CI)P valueHR valueCDKN2ANot mutated1111Mutated0.52 (0.31-0.88).011.44 (0.85-2.43).180.48 (0.24-0.98).040.91 (0.45-1.83).78GenderMale1111Female0.58 (0.55-0.60)<.00010.69 (0.66-0.72)<.00010.59 (0.57-0.63)<.00010.72 (0.68-0.75)<.0001Breslow thicknessPer mm1.11 (1.10-1.11)<.00011.06 (1.06-1.07)<.00011.11 (1.11-1.11)<.00011.08 (1.08-1.09)<.0001Age melanoma18-27111128-370.16 (0.94-1.45).171.14 (0.91-1.41).260.98 (0.82-1.16).801.00 (0.84-1.19).9938-471.67 (1.36-2.05)<.00011.61 (1.31-1.97)<.00011.19 (1.01-1.40).041.24 (1.05-1.46).0148-572.54 (2.08-3.09)<.00012.30 (1.89-2.82)<.00011.54 (1.31-1.81)<.00011.43 (1.21-1.68)<.000158-674.32 (3.55-5.26)<.00013.66 (3.01-4.47)<.00011.90 (1.62-2.22)<.00011.66 (1.42-1.95)<.000168-778.49 (6.98-10.33)<.00017.00 (5.75-8.53)<.00012.30 (1.96-2.69)<.00011.83 (1.56-2.15)<.000178-8719.55 (16.07-23.79)<.000114.94 (12.25-18.22)<.00012.86 (2.42-3.38)<.00012.02 (1.71-2.40)<.000188+45.53 (37.03-55.97)<.000129.22 (23.65-36.10)<.00013.44 (2.74-4.31)<.00011.49 (1.17-1.91).001Primary siteHead neck1111Trunk0.53 (0.50-0.55)<.00010.95 (0.90-1.01).090.77 (0.71-0.82)<.00010.88 (0.82-0.95).001Upper limb0.52 (0.48-0.55)<.00010.78 (0.73-0.83)<.00010.52 (0.48-.58)<.00010.61 (0.55-0.67)<.0001Lower limb0.46 (0.43-0.48)<.00010.83 (0.78-0.88)<.00010.81 (0.76-0.88)<.00011.01 (0.93-1.09).83UlcerationNo1111Yes4.25 (4.08-4.42)<.00012.18 (2.08-2.28)<.00015.42 (5.16-5.69)<.00012.97 (2.81-3.14)<.0001SN statusNegative1111Positive2.87 (2.64-3.11)<.00012.42 (2.23-2.63)<.00013.20 (2.95-3.47)<.00012.39 (2.20-2.60)<.0001Not performed1.21 (1.15-1.28)<.00011.15 (1.09-1.22)<.00010.71 (0.66-0.75)<.00010.96 (0.90-1.02).17SubtypeNonnodular1111Nodular2.83 (2.71-2.95)<.00011.41 (1.34-1.48)<.00013.61 (3.43-3.80)<.00011.80 (1.70-1.91)<.0001Year diagnosis2000/200111112002/20030.94 (0.88-1.01).120.87 (0.81-0.94)<.00010.92 (0.84-1.01).090.84 (0.76-0.93)<.00012004/20050.93 (0.86-0.99).030.87 (0.81-0.94)<.00010.93 (0.85-1.02).110.89 (0.81-0.98).022006/20070.99 (0.92-1.06).680.93 (0.87-1.01).070.98 (0.89-1.07).610.98 (0.89-1.07).642008/20090.93 (0.87-1.01).070.82 (0.76-0.88)<.00010.85 (0.78-0.94).0010.85 (0.77-0.93).0012010/20110.94 (0.87-1.02).120.79 (0.73-0.86)<.00010.89 (0.81-0.98).010.88 (0.80-0.97).0072012/2013/20140.91 (0.84-0.98).010.71 (0.65-0.76)<.00010.94 (0.86-1.02).150.91 (0.83-0.99).04HR, Hazard ratio; node. Our finding worse OS or line study.5Dalmasso In contrast, 2 Swedish studies showed patients.3Helgadottir Scholar,4Helgadottir aims design differed. We used nationwide control group almost 60,000 patients, which made possible confounders. Previous did status.3Helgadottir Scholar,5Dalmasso 1 study, only MPM included.4Helgadottir assessed 4 studies, while our studied instead melanoma-specific survival.3Helgadottir accordance earlier prone developing MPM.2van Scholar,3Helgadottir Close surveillance probably one reasons why less advanced stages. retrospective design, relatively small number missing survival, ascertainment bias, longevity bias limitations study.In conclusion, presence present study. All analyses. II). CDKN2A-mut, None disclosed.