D Shitara1,2, G Tell-Martí2,3, C Badenas2,3, M M S S Enokihara1,4, L Alós5, A B Larque5, N Michalany1,4, J A Puig-Butille2,3, C Carrera2,3,6, J Malvehy2,3,6, S Puig2,3,6, E Bagatin1. 1. Department of Dermatology, Federal University of São Paulo, São Paulo, Brazil. 2. Melanoma Unit, Dermatology, Biochemistry and Molecular Genetics Departments, Hospital Clinic of Barcelona, IDIBAPS, Barcelona, Spain. 3. CIBER de Enfermedades Raras, Instituto de Salud Carlos III, Barcelona, Spain. 4. Department of Pathology, Federal University of São Paulo, São Paulo, Brazil. 5. Melanoma Unit, Pathology Service, Hospital Clinic of Barcelona, IDIBAPS, Barcelona, Spain. 6. University of Barcelona, Barcelona, Spain.
Abstract
BACKGROUND: The origin of melanoma has always been a debated subject, as well as the role of adjacent melanocytic naevi. Epidemiological and histopathological studies point to melanomas arising either de novo or from a naevus. OBJECTIVES: To evaluate the presence of mutations in genes from well-known melanomagenesis pathways in a large series of naevus-associated melanomas. MATERIALS AND METHODS: Sixty-one melanomas found in association with a pre-existing naevus were microdissected, after careful selection of cell subpopulations, and submitted to Sanger sequencing of the BRAF, NRAS, c-KIT, PPP6C, STK19 and RAC1 genes. Each gene was evaluated twice in all samples by sequencing or by sequencing and another confirmation method, allele-specific fluorescent polymerase chain reaction (PCR) and capillary electrophoresis detection or by SNaPshot analysis. Only mutations confirmed via two different molecular methods or twice by sequencing were considered positive. RESULTS: The majority of cases presented concordance of mutational status between melanoma and the associated naevus for all six genes (40 of 60; 66.7%). Nine cases presented concomitant BRAF and NRAS mutations, including one case in which both the melanoma and the adjacent naevus harboured V600E and Q61K double mutations. In two cases, both melanoma and associated naevus located on acral sites were BRAF mutated, including an acral lentiginous melanoma. CONCLUSIONS: To our knowledge this is the largest naevus-associated melanoma series evaluated molecularly. The majority of melanomas and adjacent naevi in our sample share the same mutational profile, corroborating the theory that the adjacent naevus and melanoma are clonally related and that the melanoma originated within a naevus.
BACKGROUND: The origin of melanoma has always been a debated subject, as well as the role of adjacent melanocytic naevi. Epidemiological and histopathological studies point to melanomas arising either de novo or from a naevus. OBJECTIVES: To evaluate the presence of mutations in genes from well-known melanomagenesis pathways in a large series of naevus-associated melanomas. MATERIALS AND METHODS: Sixty-one melanomas found in association with a pre-existing naevus were microdissected, after careful selection of cell subpopulations, and submitted to Sanger sequencing of the BRAF, NRAS, c-KIT, PPP6C, STK19 and RAC1 genes. Each gene was evaluated twice in all samples by sequencing or by sequencing and another confirmation method, allele-specific fluorescent polymerase chain reaction (PCR) and capillary electrophoresis detection or by SNaPshot analysis. Only mutations confirmed via two different molecular methods or twice by sequencing were considered positive. RESULTS: The majority of cases presented concordance of mutational status between melanoma and the associated naevus for all six genes (40 of 60; 66.7%). Nine cases presented concomitant BRAF and NRAS mutations, including one case in which both the melanoma and the adjacent naevus harboured V600E and Q61K double mutations. In two cases, both melanoma and associated naevus located on acral sites were BRAF mutated, including an acral lentiginous melanoma. CONCLUSIONS: To our knowledge this is the largest naevus-associated melanoma series evaluated molecularly. The majority of melanomas and adjacent naevi in our sample share the same mutational profile, corroborating the theory that the adjacent naevus and melanoma are clonally related and that the melanoma originated within a naevus.
Authors: Vikas K Goel; Alexander J F Lazar; Carla L Warneke; Mark S Redston; Frank G Haluska Journal: J Invest Dermatol Date: 2006-01 Impact factor: 8.551
Authors: Chandrani Chattopadhyay; Julie A Ellerhorst; Suhendan Ekmekcioglu; Victoria R Greene; Michael A Davies; Elizabeth A Grimm Journal: Int J Cancer Date: 2012-01-11 Impact factor: 7.396
Authors: Amir S Yazdi; Gabriele Palmedo; Michael J Flaig; Ursula Puchta; Andrea Reckwerth; Arno Rütten; Thomas Mentzel; Heino Hügel; Markus Hantschke; Monika-Hildegard Schmid-Wendtner; Heinz Kutzner; Christian A Sander Journal: J Invest Dermatol Date: 2003-11 Impact factor: 8.551
Authors: Nancy E Thomas; Sharon N Edmiston; Audrey Alexander; Robert C Millikan; Pamela A Groben; Honglin Hao; Dawn Tolbert; Marianne Berwick; Klaus Busam; Colin B Begg; Dianne Mattingly; David W Ollila; Chiu Kit Tse; Amanda Hummer; Julia Lee-Taylor; Kathleen Conway Journal: Cancer Epidemiol Biomarkers Prev Date: 2007-05 Impact factor: 4.254
Authors: Jeffrey Zhao; Carlos Galvez; Kathryn Eby Beckermann; Douglas B Johnson; Jeffrey A Sosman Journal: Expert Rev Precis Med Drug Dev Date: 2021-08-11
Authors: S Polubothu; N McGuire; L Al-Olabi; W Baird; N Bulstrode; J Chalker; D Josifova; D Lomas; J O'Hara; J Ong; D Rampling; P Stadnik; A Thomas; E Wedgeworth; N J Sebire; V A Kinsler Journal: Br J Dermatol Date: 2019-08-09 Impact factor: 9.302