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Prevalent somatic BRCA1 mutations shape clinically relevant genomic patterns of nasopharyngeal carcinoma in Southeast Europe
Author(s) -
Fountzilas George,
Psyrri Amanda,
Giannoulatou Eleni,
Tikas Ioannis,
Manousou Kyriaki,
Rontogianni Dimitra,
Ciuleanu Elisabeta,
Ciuleanu Tudor,
Resiga Liliana,
Zaramboukas Thomas,
Papadopoulou Kyriaki,
Bobos Mattheos,
Chrisafi Sofia,
Tsolaki Eleftheria,
Markou Konstantinos,
Giotakis Evangelos,
Koutras Angelos,
Psoma Elsa,
KalogeraFountzila Anna,
Skondra Maria,
Bamia Christina,
Pectasides Dimitrios,
Kotoula Vassiliki
Publication year - 2017
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.31023
Subject(s) - nasopharyngeal carcinoma , germline , kras , germline mutation , biology , cancer research , genome instability , somatic cell , mutation , gene , genetics , medicine , dna damage , radiation therapy , dna
Genomic patterns of nasopharyngeal carcinomas (NPCs) have as yet been studied in Southeast Asian (SEA) patients. Here, we investigated genomic patterns of locally advanced NPC Southeast European (SEE) patients treated with chemoradiotherapy. We examined 126 tumors (89% EBV positive) from Greek and Romanian NPC patients with massively parallel sequencing. Paired tumor‐cell‐rich (TC) and infiltrating‐lymphocyte‐rich (TILs) samples were available in 19 and paired tumor‐germline samples in 68 cases. Top mutated genes were BRCA1 (54% of all tumors); BRCA2 (29%); TP53 (22%); KRAS (18%). Based on the presence and number of mutations and mutated genes, NPC were classified as stable (no mutations, n = 27); unstable (>7 genes with multiple mutations, all BRCA1 positive, n = 21); and of intermediate stability (1–7 singly mutated genes, n = 78). BRCA1 p.Q563* was present in 59 tumors (48%), more frequently from Romanian patients ( p < 0.001). No pathogenic germline mutations were identified. NPC exhibited APOBEC3A/B and nucleotide‐excision‐repair‐related mutational signatures. As compared to TC, TILs demonstrated few shared and a higher number of low frequency private mutations ( p < 0.001). In multivariate analysis models for progression‐free survival, EBV positivity was a favorable prognosticator in stable tumors; BRCA1 mutations were unfavorable only in tumors of intermediate stability. In conclusion, other than described for SEA NPC, somatic BRCA1 mutations were common in SEE NPC; these were shared between TC and TILs, and appeared to affect patient outcome according to tumor genomic stability status. Along with the identified mutational signatures, these novel data may be helpful for designing new treatments for locally advanced NPC.