Alterations in the genome that lead to changes in DNA sequence copy number are characteristic features of solid tumors. We used CGH+SNP microarray and HPV-FISH techniques for detailed screening of copy number alterations (CNAs) in a cohort of 26 patients with cervical carcinoma (CC). This approach identified CNAs in 96.2% (25/26) of tumors. Array-CGH discovered CNAs in 73.1% (19/26) of samples, HPV-FISH experiments revealed CNAs in additional 23.1% (6/26) of samples. Common gains of genetic sequences were observed in 3q (50.0%), 1q (42.4%), 19q (23.1%), while losses were frequently found in 11q (30.8%), 4q (23.1%) and 13q (19.2%). Chromosomal regions involved in loss of heterozygosity were observed in 15.4% of samples in 8q21, 11q23, 14q21 and 18q12.2. Incidence of gain 3q was associated with HPV 16 and HPV 18 positive samples and simultaneous presence of gain 1q (P = 0.033). We did not found a correlation between incidence of CNAs identified by array-CGH and HPV strain infection and incidence of lymph node metastases. Subsequently, HPV-FISH was used for validation of array-CGH results in 23 patients for incidence of hTERC (3q26) and MYC (8q24) amplification. Using HPV-FISH, we found chromosomal lesions of hTERC in 87.0% and MYC in 65.2% of specimens. Our findings confirmed the important role of HPV infection and specific genomic alterations in the development of invasive cervical cancer. This study also indicates that CGH+SNP microarrays allow detecting genome-wide CNAs and copy-neutral loss of heterozygosity more precisely, however, it may be less sensitive than FISH in samples with low level clonal CNAs.

• Keywords
• CGH+SNP microarrays, Cervical carcinoma, HPV-FISH, copy number alterations, whole-genome profiling,
• MeSH
• Adult MeSH
• In Situ Hybridization, Fluorescence MeSH
• Papillomavirus Infections complications   genetics   MeSH
• Carcinoma genetics   virology   MeSH
• Middle Aged MeSH
• Humans MeSH
• Uterine Cervical Neoplasms genetics   virology   MeSH
• Oligonucleotide Array Sequence Analysis methods   MeSH
• Aged MeSH
• Sensitivity and Specificity MeSH
• Comparative Genomic Hybridization methods   MeSH
• Gene Expression Profiling methods   MeSH
• DNA Copy Number Variations MeSH
• Loss of Heterozygosity genetics   MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

Adenoid cystic carcinomas (AdCC) of salivary gland origin have long been categorized as fusion-defined carcinomas owing to the almost universal presence of the gene fusion MYB::NFIB , or less commonly MYBL1::NFIB. Sinonasal AdCC is an aggressive salivary gland malignancy with no effective systemic therapy. Therefore, it is urgent to search for potentially targetable genetic alterations associated with AdCC. We have searched the authors' registries and selected all AdCCs arising in the sinonasal tract. The tumors were examined histologically, immunohistochemically, by next generation sequencing (NGS) and/or fluorescence in situ hybridization (FISH) looking for MYB/MYBL1 and/or NFIB gene fusions or any novel gene fusions and/or mutations. In addition, all tumors were tested for HPV by genotyping using (q)PCR. Our cohort comprised 88 cases of sinonasal AdCC, predominantly characterized by canonical MYB::NFIB (49 cases) and MYBL1::NFIB (9 cases) fusions. In addition, noncanonical fusions EWSR1::MYB ; ACTB::MYB; ESRRG::DNM3 , and ACTN4::MYB were identified by NGS, each of them in 1 case. Among nine fusion-negative AdCCs, FISH detected rearrangements in MYB (7 cases) , NFIB (1 case), and EWSR1 (1 case). Six AdCCs lacked fusions or gene rearrangements, while 11 cases were unanalyzable. Mutational analysis was performed by NGS in 31/88 (35%) AdCCs. Mutations in genes with established roles in oncogenesis were identified in 21/31 tumors (68%), including BCOR (4/21; 19%), NOTCH1 (3/21; 14%), EP300 (3/21; 14%), SMARCA4 (2/21; 9%), RUNX1 (2/21; 9%), KDM6A (2/21; 9%), SPEN (2/21; 9%), and RIT1, MGA, RB1, PHF6, PTEN, CREBBP, DDX41, CHD2, ROS1, TAF1, CCD1, NF1, PALB2, AVCR1B, ARID1A, PPM1D, LZTR1, GEN1 , PDGFRA , each in 1 case (1/21; 5%). Additional 24 cases exhibited a spectrum of gene mutations of uncertain pathogenetic significance. No morphologic differences were observed between AdCCs with MYBL1::NFIB and MYB::NFIB fusions. Interestingly, mutations in the NOTCH genes were seen in connection with both canonical and noncanonical fusions, and often associated with high-grade histology or metatypical phenotype, as well as with poorer clinical outcome. Noncanonical fusions were predominantly observed in metatypical AdCCs. These findings emphasize the value of comprehensive molecular profiling in correlating morphologic characteristics, genetic landscape, and clinical behavior in AdCC.

• MeSH
• Carcinoma, Adenoid Cystic * genetics   pathology   MeSH
• Adult MeSH
• Phenotype MeSH
• Gene Fusion MeSH
• Oncogene Proteins, Fusion genetics   MeSH
• Genetic Predisposition to Disease MeSH
• In Situ Hybridization, Fluorescence * MeSH
• Immunohistochemistry MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Mutation * MeSH
• DNA Mutational Analysis MeSH
• Biomarkers, Tumor * genetics   MeSH
• Paranasal Sinus Neoplasms * genetics   pathology   MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• NFI Transcription Factors genetics   MeSH
• High-Throughput Nucleotide Sequencing * MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Oncogene Proteins, Fusion MeSH
• MYB-NFIB fusion protein, human MeSH Browser
• Biomarkers, Tumor * MeSH
• NFIB protein, human MeSH Browser
• NFI Transcription Factors MeSH