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Int J Cancer. 2018 Jan 1;142(1):66-80. doi: 10.1002/ijc.31023. Epub 2017 Sep 30.

Prevalent somatic BRCA1 mutations shape clinically relevant genomic patterns of nasopharyngeal carcinoma in Southeast Europe.

Author information

1
Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research/Aristotle University of Thessaloniki, Thessaloniki, Greece.
2
Faculty of Medicine, School of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece.
3
Division of Oncology, Second Department of Internal Medicine, Attikon University Hospital, Athens, Greece.
4
Victor Chang Cardiac Research Institute, Darlinghurst, NSW, Australia.
5
The University of New South Wales, Kensington, NSW, Australia.
6
Section of Biostatistics, Hellenic Cooperative Oncology Group, Data Office, Athens, Greece.
7
Department of Pathology, Evangelismos Hospital, Athens, Greece.
8
Radiotherapy Department, Ion Chiricuta Cancer Institute, Cluj, Romania.
9
Institute of Oncology Ion Chiricuta and UMF Iuliu Hatieganu, Cluj-Napoca, Romania.
10
Department of Pathology, Ion Chiricuta Cancer Institute, Cluj, Romania.
11
Department of Pathology, School of Health Sciences, Faculty of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece.
12
First Department of Otorhinolaryngology, AHEPA Hospital, School of Health Sciences, Faculty of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece.
13
Department of Otolaryngology Head and Neck Surgery, Hippokration Hospital, National and Kapodistrian University of Athens, Athens, Greece.
14
Division of Oncology, Department of Medicine, University Hospital, University of Patras Medical School, Patras, Greece.
15
Department of Radiology, AHEPA Hospital, School of Health Sciences, Faculty of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece.
16
Oncology Section, Second Department of Internal Medicine, Hippokration Hospital, Athens.
17
Department of Hygiene, Epidemiology and Medical Statistics, National and Kapodistrian University of Athens, Medical School, Athens, Greece.

Abstract

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.

KEYWORDS:

APOBEC3A/B; BRCA1; BRCA2; nasopharyngeal carcinoma; next generation sequencing; somatic mutation; tumor infiltrating lymphocytes

PMID:
28857155
DOI:
10.1002/ijc.31023
[Indexed for MEDLINE]

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