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. 2022 Aug;7(4):100525.
doi: 10.1016/j.esmoop.2022.100525. Epub 2022 Jun 28.

Predictors of germline status for hereditary melanoma: 5 years of multi-gene panel testing within the Italian Melanoma Intergroup

W Bruno  1 , B Dalmasso  2 , M Barile  2 , V Andreotti  2 , L Elefanti  3 , M Colombino  4 , I Vanni  5 , E Allavena  6 , F Barbero  2 , E Passoni  7 , B Merelli  8 , S Pellegrini  9 , F Morgese  10 , R Danesi  11 , V Calò  12 , V Bazan  13 , A V D'Elia  14 , C Molica  15 , F Gensini  16 , E Sala  17 , V Uliana  18 , P F Soma  19 , M Genuardi  20 , A Ballestrero  5 , F Spagnolo  21 , E Tanda  21 , P Queirolo  22 , M Mandalà  23 , I Stanganelli  24 , G Palmieri  4 , C Menin  3 ; Italian Melanoma Intergroup (IMI)  25 ; L Pastorino  5 , P Ghiorzo  5
Affiliations

Predictors of germline status for hereditary melanoma: 5 years of multi-gene panel testing within the Italian Melanoma Intergroup

W Bruno et al. ESMO Open. 2022 Aug.

Abstract

Background: The incidence of cutaneous melanoma is increasing in Italy, in parallel with the implementation of gene panels. Therefore, a revision of national genetic assessment criteria for hereditary melanoma may be needed. The aim of this study was to identify predictors of susceptibility variants in the largest prospective cohort of Italian high-risk melanoma cases studied to date.

Materials and methods: From 25 Italian centers, we recruited 1044 family members and germline sequenced 940 cutaneous melanoma index cases through a shared gene panel, which included the following genes: CDKN2A, CDK4, BAP1, POT1, ACD, TERF2IP, MITF and ATM. We assessed detection rate according to familial status, region of origin, number of melanomas and presence and type of non-melanoma tumors.

Results: The overall detection rate was 9.47% (5.53% analyzing CDKN2A alone), ranging from 5.14% in sporadic multiple melanoma cases (spoMPM) with two cutaneous melanomas to 13.9% in familial cases with at least three affected members. Three or more cutaneous melanomas in spoMPM cases, pancreatic cancer and region of origin predicted germline status [odds ratio (OR) = 3.23, 3.15, 2.43, P < 0.05]. Conversely, age > 60 years was a negative independent predictor (OR = 0.13, P = 0.008), and was the age category with the lowest detection rate, especially for CDKN2A. Detection rate was 19% when cutaneous melanoma and pancreatic cancer clustered together.

Conclusions: Gene panel doubled the detection rate given by CDKN2A alone. National genetic testing criteria may need a revision, especially regarding age cut-off (60) in the absence of strong family history, pancreatic cancer and/or a high number of cutaneous melanomas.

Keywords: CDKN2A; gene panel; germline; melanoma; predictors; susceptibility.

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Figures

Figure 1
Figure 1
Forest plot presenting the results of multiple logistic regression analysis for detection rate of all genes. (A) Panel genes, (B) CDKN2A and (C) non-CDKN2A genes. Significant values are marked with asterisks. ∗P < 0.05, ∗∗P < 0.01, ∗∗∗P < 0.001. CM, cutaneous melanoma; MPM, multiple primary melanoma.
See this image and copyright information in PMC

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