Περίληψη:
Purpose Ataxia-Telangiectasia Mutated (ATM) has been implicated in the
risk of several cancers, but establishing a causal relationship is often
challenging. Although ATM single-nucleotide polymorphisms have been
linked to melanoma, few functional alleles have been identified.
Therefore, ATM impact on melanoma predisposition is unclear. Methods
From 22 American, Australian, and European sites, we collected 2,104
familial, multiple primary (MPM), and sporadic melanoma cases who
underwent ATM genotyping via panel, exome, or genome sequencing, and
compared the allele frequency (AF) of selected ATM variants classified
as loss-of-function (LOF) and variants of uncertain significance (VUS)
between this cohort and the gnomAD non-Finnish European (NFE) data set.
Results LOF variants were more represented in our study cohort than in
gnomAD NFE, both in all (AF = 0.005 and 0.002, OR = 2.6, 95% CI =
1.56-4.11, p < 0.01), and familial + MPM cases (AF = 0.0054 and 0.002,
OR = 2.97, p < 0.01). Similarly, VUS were enriched in all (AF = 0.046
and 0.033, OR = 1.41, 95% CI = 1.6-5.09, p < 0.01) and familial + MPM
cases (AF = 0.053 and 0.033, OR = 1.63, p < 0.01). In a case-control
comparison of two centers that provided 1,446 controls, LOF and VUS were
enriched in familial + MPM cases (p = 0.027, p = 0.018). Conclusion This
study, describing the largest multicenter melanoma cohort investigated
for ATM germline variants, supports the role of ATM as a melanoma
predisposition gene, with LOF variants suggesting a moderate-risk.
Συγγραφείς:
Dalmasso, B.
Pastorino, L.
Nathan, V
Shah, N. N.
Palmer,
J. M.
Howlie, M.
Johansson, P. A.
Freedman, N. D. and
Carter, B. D.
Beane-Freeman, L.
Hicks, B.
Molven, A. and
Helgadottir, H.
Sankar, A.
Tsao, H.
Stratigos, A. J. and
Helsing, P.
Van Doorn, R.
Gruis, N. A.
Visser, M.
Wadt,
K. A. W.
Mann, G.
Holland, E. A.
Nagore, E.
Potrony, M.
and Puig, S.
Menin, C.
Peris, K.
Fargnoli, M. C. and
Calista, D.
Soufir, N.
Harland, M.
Bishop, T.
Kanetsky,
P. A.
Elder, D. E.
Andreotti, V
Vanni, I
Bruno, W. and
Hoiom, V
Tucker, M. A.
Yang, X. R.
Andresen, P. A. and
Adams, D. J.
Landi, M. T.
Hayward, N. K.
Goldstein, A. M.
and Ghiorzo, P.
GenoMEL
MelaNostrum Consortia
