Abstract
The incidence of thyroid cancer is increasing worldwide. Whilst outcome
in thyroid cancer is generally good, up to 25% of patients develop
recurrence, and have a significantly reduced life expectancy.
We hypothesise those thyroid tumours which subsequently recur display
a distinct pattern of driver events. Whole exome sequencing
data were downloaded from The Cancer Genome Atlas (TCGA). Bioinformatic
analysis of data on N=43 patients whose tumours recurred
was performed, using a Platypus, Annovar and SIFT/PolyPhen2/MutationTaster
filtering pipeline. This identified mutations in biologically
significant genes, including Inosine-5′-monophosphate dehydrogenase
2 (IMPDH2), 6-Phosphofructo-2-Kinase/Fructose-2,6-Biphosphatase
4 (PFKFB4) and Dicer 1 ribonuclease type III (DICER1). As in-silico
analysis suggested these variants to be pathogenic, we recreated
these mutations. Subcellular localisation, proliferation, cellular migration
and invasion were investigated in cell lines which represent the
most common background driver mutations of papillary thyroid cancer
(TPC1: RET/PTC; SW1736: BRAF; Cal62: Ras). In TPC1 cells IMPDH2
mutation significantly increased cell migration at 4, 8 and 24hrs vs.
WT (p=0.0068, p=0.0008, p=0.0088 respectively) and DICER1 mutation
induced increased cell migration at 24 hours vs. vector-only (p=
0.0094). Overexpression of IMPDH2 resulted in altered intracellular localisation
into intracellular discrete bodies known as rods and rings.
As recurrence may also reflect altered gene expression, we analysed
the RNA and microRNA profile of the recurrent patients (N=43) compared
to the non-recurrent (N=457). In particular, genes involved in
matrix adhesion and thyroid cancer pathogenesis were most differentially
expressed in recurrence patients, including fibronectin 1
(FN1), thyroglobulin (TG), α3 integrin (ITGA3), SPARC-like protein 1
(SPARCL1), and the proto-oncogene mesenchymal-epithelial transition
factor (MET) (p=0.00376, p=0.00311, p=0.00757, p=0.01874, p=
0.00003, p=0.00003 respectively). Overall, we propose that rare somatic
mutations on top of established driver events, as well as specifically
altered RNA expression levels, may be key to predicting thyroid
cancer recurrence.
in thyroid cancer is generally good, up to 25% of patients develop
recurrence, and have a significantly reduced life expectancy.
We hypothesise those thyroid tumours which subsequently recur display
a distinct pattern of driver events. Whole exome sequencing
data were downloaded from The Cancer Genome Atlas (TCGA). Bioinformatic
analysis of data on N=43 patients whose tumours recurred
was performed, using a Platypus, Annovar and SIFT/PolyPhen2/MutationTaster
filtering pipeline. This identified mutations in biologically
significant genes, including Inosine-5′-monophosphate dehydrogenase
2 (IMPDH2), 6-Phosphofructo-2-Kinase/Fructose-2,6-Biphosphatase
4 (PFKFB4) and Dicer 1 ribonuclease type III (DICER1). As in-silico
analysis suggested these variants to be pathogenic, we recreated
these mutations. Subcellular localisation, proliferation, cellular migration
and invasion were investigated in cell lines which represent the
most common background driver mutations of papillary thyroid cancer
(TPC1: RET/PTC; SW1736: BRAF; Cal62: Ras). In TPC1 cells IMPDH2
mutation significantly increased cell migration at 4, 8 and 24hrs vs.
WT (p=0.0068, p=0.0008, p=0.0088 respectively) and DICER1 mutation
induced increased cell migration at 24 hours vs. vector-only (p=
0.0094). Overexpression of IMPDH2 resulted in altered intracellular localisation
into intracellular discrete bodies known as rods and rings.
As recurrence may also reflect altered gene expression, we analysed
the RNA and microRNA profile of the recurrent patients (N=43) compared
to the non-recurrent (N=457). In particular, genes involved in
matrix adhesion and thyroid cancer pathogenesis were most differentially
expressed in recurrence patients, including fibronectin 1
(FN1), thyroglobulin (TG), α3 integrin (ITGA3), SPARC-like protein 1
(SPARCL1), and the proto-oncogene mesenchymal-epithelial transition
factor (MET) (p=0.00376, p=0.00311, p=0.00757, p=0.01874, p=
0.00003, p=0.00003 respectively). Overall, we propose that rare somatic
mutations on top of established driver events, as well as specifically
altered RNA expression levels, may be key to predicting thyroid
cancer recurrence.
| Original language | English |
|---|---|
| Article number | O5 |
| Pages (from-to) | 3 |
| Number of pages | 1 |
| Journal | Thyroid Research |
| Volume | 12(Suppl 1) |
| Issue number | 11 |
| Publication status | Published - 19 Nov 2019 |
| Event | 67th Annual British Thyroid Association Meeting - London, United Kingdom Duration: 10 May 2019 → 10 May 2019 |
