Antonetti, Paolo

Brancati, Francesco

Bruni, Manfredo

Castiglia, Daniele

De Luca, Chiara

Fargnoli, Maria Concetta

Mastrangelo, Mirco

Pellegrini, Cristina

IRIS Università degli Studi dell'Aquila

CASE REPORTFrom theScienceDepartmsity of LBiologyItalyc; Dand HuRoma,Funding sPatient cooral anobtaineand meand wpubliclythe jou134Occurrence of multiple melanomas in apatient with punctate palmoplantarkeratoderma type-1A associated to alpha and gammaadaptin binding proteinMirco Mastrangelo, PhD,a Cristina Pellegrini, PhD,a Chiara De Luca, MD,b Manfredo Bruni, MD,aDaniele Castiglia, PhD,c Paolo Antonetti, MD,a,d Francesco Brancati, MD,b,e and Maria Concetta Fargnoli, MDa,dKey words: AAGAB gene; multiple primary melanoma; PPPK1.Abbreviations used:AAGAB: alpha and gamma adaptin bindingproteinMPM: multiple primary melanomaPPPK1: punctate palmoplantar keratodermatype-1INTRODUCTIONPatients with cutaneous melanoma are at anincreased risk of developing 1 or more additional(multiple) primary cutaneous melanomas (multipleprimary melanoma [MPM]). A genetic predisposi-tion has been suggested for MPM, with germlinevariants identified in high-risk/intermediate-riskgenes, including cyclin-dependent kinase inhibitor2A, cyclin-dependent kinase 4, protection oftelomeres 1, ACD, TERF2 interacting protein,telomerase reverse transcriptase, melanocyteinducing transcription factor, and melanocortin 1receptor.1Punctate palmoplantar keratoderma type-1(PPPK1) is a rare genodermatosis characterized bymultiple hyperkeratotic papules with a centralindentation, irregularly distributed on the palmsand soles. The inheritance pattern is autosomaldominant with mutations in alpha and gammaadaptin binding protein (AAGAB) (PPPK1A) andCOL14A1 genes (PPPK1B).2 AAGAB encodes for anadaptin binding protein (p34) involved inmembranetrafficking.2Department of Biotechnological and Applied Clinicals, University of L’Aquila, L’Aquila, Italya; Human Genetics,ent of Life, Health, and Environmental Sciences, Univer-’Aquila, L’Aquila, Italyb; Laboratory of Molecular and Cell, Istituto Dermopatico dell’Immacolata, IDI-IRCCS, Rome,ermatology Unit, Ospedale San Salvatore, L’Aquila, Italyd;man Functional Genomics Laboratory, IRCCS San RaffaeleRome, Italy.eources: None.nsent: The patient signed a written consent after specificd written information for this research. The authorsd written consent from patients for their photographsdical information to be published in print and onlineith the understanding that this information may beavailable. Patient consent forms were not provided tornal but are retained by the authors.CASE REPORTHerein, we report the finding of 2 primarycutaneous melanomas in a patient with PPPK1 andexplore the literature on a possible associationbetween PPPK1 and malignancy.A man in his late 60s was referred to ourDermatology Unit after 3 months from the excisionof an ulceratedmelanoma, 2.1 mm in thickness (pT3bwith 10/mm2mitosis), on his left forearm (Fig 1,A). Atthe time of patient admission, the total number of nevi[2 mm was 191 (122 on the lower extremities, 36 onthe upper extremities, 32 on the back, 29 on the chestand abdomen, and 4 on the face); no clinicallyatypical nevi were observed. The patient presentedan intense recreational sun exposure both in child-IRB approval status: The patient included in the study has beenenrolled in the context of the MPM study approved byInstitutional Review Boards.Availability of data and materials: The data and material thatsupport the findings of this study are available from thecorresponding author upon reasonable request.Correspondence to: Cristina Pellegrini, PhD, Department ofBiotechnological and Applied Clinical Sciences, University ofL’Aquila, Via Vetoio, Coppito 2, L’Aquila, Italy. E-mail: cristina.pellegrini@univaq.it.JAAD Case Reports 2025;59:134-7.2352-5126 2025 Published by Elsevier Inc. on behalf of the AmericanAcademy of Dermatology, Inc. This is an open access articleunder the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).https://doi.org/10.1016/j.jdcr.2025.02.010Fig 1. A, Clinical images of the 2 melanomas. Left panel: first melanoma located on the leftforearm. Molecular status: NRAS Q61L mutation. Right panel: second melanoma on the pubicregion. Molecular status: BRAF V600E mutation. B, Punctate palmoplantar keratoderma type-1A. Multiple hyperkeratotic papules on the palms and soles. C, Pedigree of the family. Patientsaffected by PPPK1 are reported by black fill; proband is showed by black arrow.JAAD CASE REPORTSVOLUME 59Mastrangelo et al 135hood and adult age never using sunscreens, while notherapeutic and occupational ultraviolet radiationhistory was referred. Instrumental staging andsentinel node biopsy were negative (stage IIB,American Joint Committee on Cancer eighth edition).After a complete dermatological examination, wediagnosed a second synchronous melanoma of thesuperficial spreading histotype on the pubic region,1.9 mm in thickness, without ulceration (pT2a with 3/mm2 mitosis) (Fig 1, A).Sentinel node biopsy revealed micrometastases in3 right and 1 left inguinal lymph nodes (stage IIIC,American Joint Committee on Cancer eighth edi-tion). Molecular analysis, performed by competitiveallele-specific TaqMan PCR Mutation Detection kit(ThermoFisher), revealed a somatic discordancebetween the 2 melanomas, harboring the NRASQ61L and the BRAF V600E substitution, respectively.In addition, we also observed multiple hyperkera-totic papules on the palms and soles, suggestive ofPPPK1 (Fig 1, B). Family pedigree revealed PPPK1 inat least 5 relatives, including the father of ourproband, 1 aunt with pancreatic carcinoma, and nofamily history of melanoma (Fig 1, C ). Clinicalexome sequencing on genomic DNA of the probandwas performed using the Trusight One panel(Illumina), run on the NextSeq500 platform(Illumina) with 303 average coverage. VariantTable I. Literature evidence of the co-occurrence of hereditary PPPK1 and cancerNumber offamilies withhereditary PPPK1Number ofmembersNumber ofpatients withPPPK1 and cancer Country Cancers in the family Reference1 35 3 US Colon and pancreas Bennion et al33 Not specified Not specified Italy Colon Ena et al41 320 10 UK Bladder, colon, kidney,ovary, pancreas, andHodgkin diseaseStevens et al53 4 1 Germany Breast Kiritsi et al68 61 1 China Unknown site Cui et al78 18 1 Tunisia Prostate Charfeddine et al818 277 9 Canada Bone, bowel, brain, breastcolon, esophagus,kidney, melanoma,multiple myeloma,prostate, and throatElhaji. et al9Only studies with detailed information proving the hereditary (not sporadic) PPPK1 disease have been included.Excluded keratinocyte cancers.JAAD CASE REPORTSMAY 2025136 Mastrangelo et alannotation and prioritization were performed usingthe eVai platform (enGenome).We identified a heterozygous c.370 C[T(p.Arg124*) variant in the AAGAB gene (NM_024666.5; NP_078942.3), predicted to result in lossof function and already reported in Human GeneMutation Database and ClinVar as pathogenic andassociated with the PPPK1A phenotype. Segregationanalysis of this variant was not possible. The germ-line profile for melanoma susceptibility genes(cyclin-dependent kinase inhibitor 2A, cyclin-dependent kinase 4, telomerase reverse transcrip-tase, protection of telomeres 1, melanocortin 1receptor, and melanocyte inducing transcriptionfactor) was wild-type.DISCUSSIONAn association between cancer and PPPK1 hasbeen hypothesized but not proven. Nevertheless,various malignancies have been reported in patientswith PPPK1, including those that are relatively com-mon in general populations, such as breast, colon,and prostate cancer (Table I).Melanoma was described in 3 of 18 Canadianfamilies9 with 2 cases developing a single melanomaand 1 patient with MPM who notably carried thesame p.Arg124* variant. Unfortunately, no informa-tion on the clinicopathological aspects of melanomaswas reported.The increased cancer risk in PPPK1 families mightbe explained by p34 deficiency, which wouldincrease growth factor signaling by altering endo-cytic recycling of epidermal growth factor receptor,thus promoting cellular proliferation.2,10 However,p34 also acts as a regulator of NEDD4-1-mediatedPTEN nuclear translocation; thus, the deficiencymight suppress cancer cell proliferation.11 Recently,the somatic level of AAGAB was identified as apotential on-treatment biomarker of treatmentoutcome in breast cancer;12 however, the exact roleof AAGAB in cancer still needs further investigation.Of interest is the study conducted on clear cell renalcell carcinoma, in which the AAGAB gene wasdescribed as a gene that could increase the risk ofthis tumor, but when the tumor is advanced it couldinhibit it. This seems to be explained by the fact thatAAGAB seems to be able to influence the tumormicroenvironment.13 In the systematic review byGram et al (2023), 45 studies were reviewed for theassociation of PPPK1 with cancer. Of these, 23studies in the literature show an association betweenPPPK1 and cancer, while in the other 22 there is noassociation. In the review, they point out that thisassociation cannot be defined for the few cases in theliterature, and that the possible associations betweenPPPK1 and cancer are diverse (colorectal, prostate,breast, and melanoma), so we propose this addi-tional case as further data.14The 2 synchronous melanomas of our patientpresented a discordant somatic profile (NRAS Q61Land BRAF V600E). The genetic diversity of multiplemelanomas has implications in clinical practice ifMPM patients need to be treated with BRAF in-hibitors.1 Indeed, our multidisciplinary team agreedon adjuvant immunotherapy with an anti-PD1 anti-body (nivolumab).In conclusion, we report the rare co-occurrenceof PPPK1A and multiple melanomas in a patientJAAD CASE REPORTSVOLUME 59Mastrangelo et al 137with p.Arg124* mutation in AAGAB. Consideringthe current lack of evidence for a link between the 2diagnoses, a larger cohort of patients is needed toinvestigate the significance of melanoma occur-rence in patients with PPPK1 and AAGAB geneticvariants.The authors are indebted to patients and families whosegenerosity and cooperation made this study possible.Conflicts of interestNone disclosed.REFERENCES1. Pellegrini C, Di Nardo L, Cipolloni G, et al. Heterogeneity ofBRAF, NRAS, and TERT promoter mutational status in multiplemelanomas and association with MC1R genotype: findings frommolecular and immunohistochemical analysis. J Mol Diagn.2018;20(1):110-122. https://doi.org/10.1016/j.jmoldx.2017.10.0022. Guerra L, Castori M, Didona B, Castiglia D, Zambruno G.Hereditary palmoplantar keratodermas. Part I. Non-syndromicpalmoplantar keratodermas: classification, clinical and geneticfeatures. J Eur Acad Dermatol Venereol. 2018;32(5):704-719.https://doi.org/10.1111/jdv.149023. Bennion SD, Patterson JW. Keratosis punctata palmaris etplantaris and adenocarcinoma of the colon. A possible familialassociation of punctate keratoderma and gastrointestinalmalignancy. J Am Acad Dermatol. 1984;10(4):587-591. https://doi.org/10.1016/s0190-9622(84)80262-54. Ena P, Cottoni F, Cerimele D, Saccabusi S, Retanda G.Associazione della cheratodermia palmo-plantare punctatacon altre condizioni morbose (canizie precoce, carcinomadel colon). Studio su tre famiglie [Association of keratodermapunctata palmaris et plantaris with other morbid conditions(early grayness, carcinoma of the colon). Study of 3 families]. GItal Dermatol Venereol. 1986;121:45-54. Italian.5. Stevens HP, Kelsell DP, Leigh IM, Ostlere LS, MacDermot KD,Rustin MH. Punctate palmoplantar keratoderma and malig-nancy in a four-generation family. Br J Dermatol. 1996;134(4):720-726.6. Kiritsi D, Chmel N, Arnold AW, Jakob T, Bruckner-Tuderman L,Has C. Novel and recurrent AAGAB mutations: clinicalvariability and molecular consequences. J Invest Dermatol.2013;133(10):2483-2486. https://doi.org/10.1038/jid.2013.1717. Cui H, Gao M, Wang W, et al. Six mutations in AAGAB confirmits pathogenic role in Chinese punctate palmoplantar kerato-derma patients. J Invest Dermatol. 2013;133(11):2631-2634.https://doi.org/10.1038/jid.2013.1988. Charfeddine C, Ktaifi C, Laroussi N, et al. Clinical and molecularinvestigation of Buschke-Fischer-Brauer in consanguineousTunisian families. J Eur Acad Dermatol Venereol. 2016;30(12):2122-2130. https://doi.org/10.1111/jdv.137879. Elhaji Y, Hedlin C, Nath A, et al. AAGAB mutations in 18Canadian families with punctate palmoplantar keratodermaand a possible link to cancer. J Cutan Med Surg. 2020;24(1):28-32. https://doi.org/10.1177/120347541987816110. P€ohler E, Zamiri M, Harkins CP, et al. Heterozygous mutationsin AAGAB cause type 1 punctate palmoplantar keratodermawith evidence for increased growth factor signaling. J InvestDermatol. 2013;133(12):2805. https://doi.org/10.1038/jid.2013.24311. Dai C, Wu B, Chen Y, et al. Aagab acts as a novel regulator ofNEDD4-1-mediated Pten nuclear translocation to promoteneurological recovery following hypoxic-ischemic brain dam-age. Cell Death Differ. 2021;28(8):2367-2384. https://doi.org/10.1038/s41418-021-00757-412. Bownes RJ, Turnbull AK, Martinez-Perez C, Cameron DA,Sims AH, Oikonomidou O. On-treatment biomarkers canimprove prediction of response to neoadjuvant chemotherapyin breast cancer. Breast Cancer Res. 2019;21(1):73. https://doi.org/10.1186/s13058-019-1159-313. Chen Y, He J, Jin T, Zhang Y, Ou Y. Functional enrichmentanalysis of LYSET and identification of related hub genesignatures as novel biomarkers to predict prognosis andimmune infiltration status of clear cell renal cell carcinoma. JCancer Res Clin Oncol. 2023;149(18):16905. https://doi.org/10.1007/S00432-023-05280-214. Gram SB, Bjerrelund J, Jelsig AM, Bygum A, Leboeuf-Yde C,Ousager LB. Is punctate palmoplantar keratoderma type 1associated with malignancy? A systematic review of theliterature. Orphanet J Rare Dis. 2023;18(1):290. https://doi.org/10.1186/S13023-023-02862-8

Occurrence of multiple melanomas in a patient with punctate palmoplantar keratoderma type-1A associated to alpha and gamma adaptin binding protein

https://ricerca.univaq.it/bitstream/11697/265765/1/18.%20Mastrangelo_2025%20-%20AAGAB.pdf

Occurrence of multiple melanomas in a patient with punctate palmoplantar keratoderma type-1A associated to alpha and gamma adaptin binding protein

Abstract

Similar works

Full text

Available Versions

IRIS Università degli Studi dell'Aquila