Mitochondrial-rich oncocytic thyroid tumors frequently show near-haploidization and endoreduplication (masked haploidization), which manifests as a near-homozygous genome (NHG). We now extend this investigation to include adrenocortical cancer and parathyroid carcinoma (PaTC), which we studied for a NHG in association with mitochondrial DNA mutations. Sixty endocrine tumors from 59 patients were studied, including 46 thyroid tumor samples of varying histology, 11 adrenocortical cancers, and 3 PaTCs. Genome-wide SNP array analysis and DNA content analysis were combined to determine the chromosomal dosage (allelic state). The entire mitochondrial genome was also studied for mutations. In addition, tumors were characterized for somatic mutations in a subset of genes that are directly or indirectly implicated in cellular metabolism. In addition to a subset of thyroid cancers (n = 5), a NHG was also observed in 1 of 3 PaTCs and 6 of 11 adrenocortical cancers. All but one of the tumors with a NHG (n = 12) showed oncocytic metaplasia (P = 0.0001, two-tailed Fisher's exact). One or more damaging or disrupting mtDNA mutations were found in 68% (41/60) of tumor samples. No correlation was found between mtDNA mutations and the oncocytic phenotype or a NHG, and none of the mutations in nuclear encoded genes correlated with the oncocytic phenotype or a NHG. A subset of oncocytic tumors of the thyroid, parathyroid, and adrenocortical carcinomas carries a NHG. Although damaging/disrupting mtDNA mutations are frequently found in oncocytic and nononcocytic endocrine tumors, neither correlates with a NHG phenotype nor with an oncocytic phenotype.

Objective: Gene alterations leading to activation of the MAPK pathway are of interest for targeted therapy in patients with advanced radioactive iodine refractory (RAI-R) thyroid carcinoma. Due to technical reasons gene fusion analysis in RNA isolated from formalin-fixed tumor tissues has till now been limited. The objective of the present study was to identify targetable gene rearrangements in RNA isolated from formalin-fixed RAI-R thyroid carcinomas. Design: Retrospective study in 132 patients with RAI-R thyroid carcinoma (59 papillary-, 24 follicular-, 35 Hürthle cell-and 14 anaplastic thyroid carcinoma). Methods: Total nucleic acid (undivided DNA and RNA) was isolated from formalin-fixed tissue. Extensive gene fusion analysis was performed in all samples that tested negative for pathogenic BRAF, NRAS, HRAS and KRAS variants. Results: Seven targetable gene fusions were identified in the remaining 60 samples without known DNA variants. This includes frequently reported gene fusions such as CCDC6/RET (PTC1), PRKAR1A/RET (PTC2) and ETV6/NTRK3 , and gene fusions that are less common in thyroid cancer (TPM3/NTRK1, EML4/ALK and EML4/NTRK3). Of note, most gene fusions were detected in papillary thyroid carcinoma and MAPK-associated alterations in Hürthle cell carcinomas are rare (2/35). Conclusion: Targetable gene fusions were found in 12% of RAI-R thyroid carcinoma without DNA variants and can be effectively identified in formalin-fixed tissue. These gene fusions might provide a preclinical rationale to include specific kinase inhibitors in the treatment regimen for these patients. The latter intends to restore iodine transport and/or take advantage of the direct effect on tumor cell vitality once progressive disease is seen.

Treatment choices for cervical cancer are primarily based on clinical FIGO stage and the post-operative evaluation of prognostic parameters including tumor diameter, parametrial and lymph node involvement, vaso-invasion, infiltration depth, and histological type. The aim of this study was to evaluate genomic changes in bulky cervical tumors and their relation to clinical parameters, using single nucleotide polymorphism (SNP)-analysis.Flow-sorted tumor cells and patient-matched normal cells were extracted from 81 bulky cervical tumors. DNA-index (DI) measurement and whole genome SNP-analysis were performed. Data were analyzed to detect copy number alterations (CNA) and allelic balance state: balanced, imbalanced or pure LOH, and their relation to clinical parameters.The DI varied from 0.92–2.56. Pure LOH was found in ≥40% of samples on chromosome-arms 3p, 4p, 6p, 6q, and 11q, CN gains in >20% on 1q, 3q, 5p, 8q, and 20q, and losses on 2q, 3p, 4p, 11q, and 13q. Over 40% showed gain on 3q. The only significant differences were found between histological types (squamous, adeno and adenosquamous) in the lesser allele intensity ratio (LAIR) (p = 0.035) and in the CNA analysis (p = 0.011). More losses were found on chromosome-arm 2q (FDR = 0.004) in squamous tumors and more gains on 7p, 7q, and 9p in adenosquamous tumors (FDR = 0.006, FDR = 0.004, and FDR = 0.029).Whole genome analysis of bulky cervical cancer shows widespread changes in allelic balance and CN. The overall genetic changes and CNA on specific chromosome-arms differed between histological types. No relation was found with the clinical parameters that currently dictate treatment choice.