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

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 5 27); unstable (>7 genes with multiple mutations, all BRCA1 positive, n 5 21); and of intermediate stability (1-7 singly mutated genes, n 5 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 progressionfree 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.

Enhanced expression of SETDB1 possesses prognostic value and promotes cell proliferation, migration and invasion in nasopharyngeal carcinoma

“…It is widely accepted that NPC is a complicated disease associated with multiple factors including genetics (27,28), Epstein-Barr virus infection (29)(30)(31) and the environment (32). Thus far, researchers have mainly focused on improving our understanding of NPC pathogenesis (33)(34)(35)(36). However, we still need further insight into the underlying molecular genetics of NPC, which would enable future tailored patient prognostication and treatment strategies.…”

Pathogenic mutations and overall survival in 3,084 patients with cancer: the Hellenic Cooperative Oncology Group Precision Medicine Initiative

“…Genotyping data from 3,084 tumors were retrieved from 14 NGS datasets obtained from 2013 to 2017 in the context of HeCOG translational projects [7][8][9][10][11][12][13][14][15]. Eight tumor types were genotyped on the basis of tissue sample availability, research interests of the respective investigators, and funding opportunities: breast, colorectal, pancreatic, nasopharyngeal, glioma, gastric, biliary, and ovarian.…”

“…HeCOG has previously investigated the genomic profiles of different tumor types using cancer-specific panels designed on the basis of available published data [7][8][9][10][11][12][13][14][15]. From 2013 to 2017, NGS was performed in the Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research, Aristotle University of Thessaloniki, to assess clinically relevant molecular alterations in patients with cancer.…”

“…Research cohorts included patients with adequate tumor tissue for NGS and annotated clinical data. The studies found that mutations in breast and colorectal tumors were associated with survival [7,9,12,16], and mutations in nasopharyngeal and biliary tumors occurred in clinically relevant genes [13,15].…”

Downregulation of ribophorin II suppresses tumor growth, migration, and invasion of nasopharyngeal carcinoma

“…Nasopharyngeal carcinoma (NPC), an epithelial malignancy of the head and neck, is one of the most common malignant tumors in Southeast Asia and southern China, where the incidence rate is approximately 25 cases per 100,000 individuals. 1 – 3 Approximately 80,000 new cases and 50,000 deaths are reported annually all over the world. 4 , 5 Although the overall survival has improved by using intensity-modulated radiation therapy or chemotherapy, prognosis for patients with NPC remains very poor, due to disease recurrence and distant metastasis.…”