10.5826/dpc.1303a194
text/xml
2160-9381
3094
en
Mariano Ara
https://creativecommons.org/licenses/by-nc/4.0
Dermatology Practical & Conceptual
digital dermatoscopy
Multiple Primary Melanoma in a CHEK2 Mutation Carrier
Text.Serial.Journal
https://dpcj.org/index.php/dpc
Research Letter
2023-07-31
2022-12-16
2023-07-31
2023-08-24
e2023194
Dermatol Pract Concept
Mariano Ara
2023/07/31
10.5826/dpc.1303a194
e2023194
Department of Dermatology, Hospital Clínico Universitario Lozano Blesa, Zaragoza, Spain
2160-9381
digital dermatoscopy
en
e2023194
Weischer M, Heerfordt IM, Bojesen SE, et al. CHEK2*1100delC and risk of malignant melanoma: Danish and German studies and meta-analysis. J Invest Dermatol. 2012;132(2):299-303. DOI: 10.1038/jid.2011.303. PMID: 21956126.
Multiple Primary Melanoma in a CHEK2 Mutation Carrier
https://dpcj.org/index.php/dpc/article/download/3094/2223
                 Multiple Primary Melanoma in a CHEK2
                            Mutation Carrier
            Marcial Álvarez-Salafranca1, Francesc Felipo-Berlanga2, Mar García-García2,
                             Beatriz Aldea-Manrique1, Mariano Ara1


1 Department of Dermatology, Hospital Clínico Universitario Lozano Blesa, Zaragoza, Spain
2 Department of Pathology, Hospital Clínico Universitario Lozano Blesa, Zaragoza, Spain



Key words: melanoma, CHEK2, p53, digital dermatoscopy
Citation: Álvarez-Salafranca M, Felipo-Berlanga F, García-García M, Aldea-Manrique B, Ara M. Multiple Primary Melanoma in a CHEK2
Mutation Carrier. Dermatol Pract Concept. 2023;13(3):e2023194. DOI: https://doi.org/10.5826/dpc.1303a194
Accepted: March 14, 2023; Published: July 2023
Copyright: ©2023 Álvarez-Salafranca et al. This is an open-access article distributed under the terms of the Creative Commons Attribution-
NonCommercial License (BY-NC-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use,
distribution, and reproduction in any medium, provided the original authors and source are credited.
Funding: None.
Competing Interests: None.
Authorship: All authors have contributed significantly to this publication.
Corresponding Author: Marcial Álvarez-Salafranca, Department of Dermatology, Hospital Clínico Universitario Lozano Blesa, Avenida San
Juan Bosco 15, CP 50009, Zaragoza, Spain. Telephone: 976 76 57 00 Email: malvarezs@salud.aragon.es




Introduction                                                             her left lumbar region (Figure 1, A and B). Histopathological
                                                                         examination revealed a non-ulcerated nevus-associated mel-
Checkpoint kinase 2 (CHEK2) gene (22q12.1) encodes                       anoma with a Breslow thickness of 1mm (pT1b). Relevant
the protein CHEK2, a cell cycle checkpoint regulator that                familial history included a history of breast carcinoma in
acts as a tumor suppressor. CHEK2 is activated by signals                her mother at the age of 76 years and a possible history of
from ataxia-telangiectasia, ataxia-telangiectasia mutated                melanoma in her maternal grandmother. Neither the patient
and Rad3-related proteins in the setting of double-stranded              brother nor her son had a history of cancer.
DNA breaks. Then, it phosphorylates and activates p53                         Considering her personal and familial history, germline
and BRCA1 proteins, inducing cell cycle arrest/apoptosis or              genetic testing for melanoma and breast cancer was offered.
DNA repair [1]. Patients with pathogenic mutations affect-               Written informed consent was obtained from patient for
ing CHEK2 may not correctly recognize UV-induced DNA                     ­genetic study of a peripheral blood sample. A c.349A>G
breaks and, therefore, it could be hypothesized that these               (p.Arg117Gly) heterozygous mutation in the CHEK2 gene
mutations may increase the risk of melanoma [1,2].                       was identified by Ion Torrent TM Next Generation Sequenc-
                                                                         ing (Thermo Fisher Scientific). No pathogenic variants were

Case Presentation                                                        found in CDKN2A, CDK4, BAP1, MiTF, BRCA1, BRCA2
                                                                         or PTEN genes. The same pathogenic mutation was found
A 51-year-old woman with more than 150 nevi, a previous                  in her mother.
history of multiple sunburns and a nevus-associated mela-                     The patient was included in a surveillance program with
noma in situ, presented with an atypical pigmented lesion on             total body photography and digital dermatoscopy. Sixteen




Research Letter | Dermatol Pract Concept. 2023;13(3):e2023194                                                                           1
         Figure 1. (A) Irregularly pigmented macule on her left lumbar region. (B) Dermatoscopy revealed an atypical pigment
         network, irregularly distributed brown globules, negative network (asterisk) and dotted vessels. (C) The patient showed
         more than 150 melanocytic nevi, many of them atypical (baseline total body photograph image). (D) A striking growth
         and darkening of a previously inconspicuous lesion were notorious (arrow); dermatoscopy showed a homogeneous
         blue-gray area (FotoFinder Bodyscan ATBM®, x20) (inset). (E) Irregular proliferation of atypical melanocytes within the
         epidermis, some of them arranged in nests (haematoxylin and eosin, original magnification x 20); an atypical mitosis is
         observed (inset). (F) Extension of the atypical melanocytes down adnexal structures (H&E, original magnification x 20).


months after the beginning of the follow-up, a striking               (Figure 1, E and F). One year later, a previous stable lesion
growth and darkening of a previously inconspicuous lesion             on her lower abdomen showed a new pigmented blotch and
was detected (Figure 1, C and D). This lesion was surgically          a blue-gray area (Figure 2, A and B). Histopathologic ex-
removed, and its histopathologic examination revealed a               amination showed a new nevus-associated melanoma in situ
melanoma with a Breslow thickness of 0,18mm (pT1a)                    (Figure 2, C and D).



2                                                                          Research Letter | Dermatol Pract Concept. 2023;13(3):e2023194
    Figure 2. (A) Irregular 12mm-in-diameter pigmented lesion on the lower part of the abdomen. (B) Digital dermatoscopic follow-up
    showed a new pigmented blotch (arrow) and a blue-gray area (asterisk). (C) The extension of atypical melanocytes to an eccrine
    duct is easily seen (H&E, original magnification x 20). (D) The melanocytic proliferation is too crowded and with atypical melano-
    cytes above dermal papillae (H&E, original magnification x 10).




Conclusions                                                            References
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alterations in the p53 pathway, suggesting that p53 inducer                ­double-strand break formation upon UV-induced r­ eplication stress
and effector genes such as ATM, ATR, CHK1, CHEK2 or                         activates ATM and DNA-PKcs kinases. J Mol Biol. 2009;
Apaf1 represent potential alternative mutational targets in                 385(3):800-810.DOI:10.1016/j.jmb.2008.11.036.PMID:1907113.
melanoma [3]. Furthermore, a recent in vitro study suggests                 PMCID: PMC2662442.
                                                                        3. Papp T, Niemetz A, Dosdahl N, Kumar K, Schiffmann D.
that alterations in the ATM-CHEK2 signaling pathway may
                                                                            ­Mutational analysis of Chk1, Chk2, Apaf1 and Rb1 in human
induce genomic instability in melanoma [4].
                                                                             malignant melanoma cell lines. Oncol Rep. 2007;17(1):135-140.
   There is an association between CHEK2 mutations and                       PMID: 17143490.
hereditary breast and colorectal cancer [5]. Nevertheless,              4. Spoerri L, Brooks K, Chia K, et al. A novel ATM-dependent
there is a lack of studies exploring a possible association                  checkpoint defect distinct from loss of function mutation pro-
with melanoma. A case-control study with 1152 Danish                         motes genomic instability in melanoma. Pigment Cell Mela-
                                                                             noma Res. 2016;29(3):329-339. DOI: 10.1111/pcmr.12466.
and 752 German patients with melanoma compared with
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9142 and 3718 controls, identified a twofold risk of mela-
                                                                        5. Meijers-Heijboer H, Wijnen J, Vasen H, et al. The CHEK2
noma in CHEK2*1100delC heterozygotes compared with                           1100delC mutation identifies families with a hereditary breast
non-carriers. These results were ratified by a meta-analysis [6].            and colorectal cancer phenotype. Am J Hum Genet. 2003;72(5):
CHEK2 c.349A>G (p.Arg117Gly) is a rare missense variant,                     1308-1314. DOI: 10.1086/375121. PMID: 1269058. PMCID:
which affects an important domain for protein function and                   PMC1180284.
                                                                        6. Weischer M, Heerfordt IM, Bojesen SE, et al. CHEK2*1100delC
there is evidence of its association with breast cancer. Cur-
                                                                             and risk of malignant melanoma: Danish and German studies
rently, there is no strong evidence supporting an increased
                                                                             and meta-analysis. J Invest Dermatol. 2012;132(2):299-303.
risk of melanoma in CHEK2 mutation carriers. Nevertheless,                   DOI: 10.1038/jid.2011.303. PMID: 21956126.
the implication of the CHEK2 pathway in melanoma patho-
genesis is plausible. Until more evidence is available, patients
with CHEK2 mutations may benefit from sun protection
measures and periodic dermatologic examinations.




Research Letter | Dermatol Pract Concept. 2023;13(3):e2023194                                                                               3
