Genome Haploidisation with Chromosome 7 Retention in Oncocytic Follicular Thyroid Carcinoma

Abstract

BackgroundRecurrent non-medullary thyroid carcinoma (NMTC) is a rare disease. We initially characterized 27 recurrent NMTC: 13 papillary thyroid cancers (PTC), 10 oncocytic follicular carcinomas (FTC-OV), and 4 non-oncocytic follicular carcinomas (FTC). A validation cohort composed of benign and malignant (both recurrent and non-recurrent) thyroid tumours was subsequently analysed (n = 20).MethodsData from genome-wide SNP arrays and flow cytometry were combined to determine the chromosomal dosage (allelic state) in these tumours, including mutation analysis of components of PIK3CA/AKT and MAPK pathways.ResultsAll FTC-OVs showed a very distinct pattern of genomic alterations. Ten out of 10 FTC-OV cases showed near-haploidisation with or without subsequent genome endoreduplication. Near-haploidisation was seen in 5/10 as extensive chromosome-wide monosomy (allelic state [A]) with near-haploid DNA indices and retention of especially chromosome 7 (seen as a heterozygous allelic state [AB]). In the remaining 5/10 chromosomal allelic states AA with near diploid DNA indices were seen with allelic state AABB of chromosome 7, suggesting endoreduplication after preceding haploidisation. The latter was supported by the presence of both near-haploid and endoreduplicated tumour fractions in some of the cases. Results were confirmed using FISH analysis. Relatively to FTC-OV limited numbers of genomic alterations were identified in other types of recurrent NMTC studied, except for chromosome 22q which showed alterations in 6 of 13 PTCs. Only two HRAS, but no mutations of EGFR or BRAF were found in FTC-OV. The validation cohort showed two additional tumours with the distinct pattern of genomic alterations (both with oncocytic features and recurrent).ConclusionsWe demonstrate that recurrent FTC-OV is frequently characterised by genome-wide DNA haploidisation, heterozygous retention of chromosome 7, and endoreduplication of a near-haploid genome. Whether normal gene dosage on especially chromosome 7 (containing EGFR, BRAF, cMET) is crucial for FTC-OV tumour survival is an important topic for future research.MicroarraysData are made available at GEO (GSE31828).

Response and Acquired Resistance to Everolimus in Anaplastic Thyroid Cancer

“…Genomewide copy-number analysis showed near-haploidization of the cancer genome with retention of chromosome 7, a feature that appears to be pathognomonic of oncocytic follicular thyroid carcinoma, 16 This finding is consistent with the putative origin of this anaplastic thyroid cancer (Fig. S2 in Supplementary Appendix 1).…”

Molecular pathogenesis and mechanisms of thyroid cancer

“…In Hürthle-cell thyroid carcinoma (HCTC), mutations of NADH dehydrogenase (ubiquinone) 1α subcomplex 13 ( NDUFA13 ; also known as GRIM19 ) are fairly common 45 . Unlike other types of thyroid cancers, HCTC does not harbour classical genetic alterations, such as BRAF and RAS mutations or RET– PTC 46,47 , but commonly harbours DNA haploidization in recurrent disease 47 .…”

Loss of Heterozygosity and Copy Number Alterations in Flow-Sorted Bulky Cervical Cancer

“…The resolution of this assay is relatively low, but in contrast with other SNP assays it can be used with FFPE derived DNA [24], [25]. These SNP analyses on FFPE tissue were extensively validated previously by FISH analysis [15], [24]–[26]. Samples were processed in 6 batches of 48 samples, and samples of the same patient were always processed in the same batch.…”