Differentiated thyroid cancer – Evaluation of contemporary management and novel risk assessment

Introduction Differentiated thyroid cancer (DTC) is a heterogeneous disease with a spectrum of phenotypes ranging from indolent to aggressive variants. The incidence of DTC has increased by 300% over the past 15 years in Ireland. Current best practice guidelines recommend a “personalised decision making” approach for a large cohort of patients with intermediate size tumours where there is a paucity of sufficient quality evidence to support specific recommendations for their management. This cohort may be over treated due to equivocal guidelines. An improved understanding of the molecular mechanisms of thyroid tumourigenesis, and knowledge of low risk mutant alleles which contribute to DTC susceptibility and impact disease phenotype may improve our ability to individualise treatment for these patients. We ascertain the effect of equivocal guidance, particularly for patients with intermediate size 1-4cm tumours, on contemporary practice patterns. With a view to improving risk stratification for those subject to equivocal guidelines, we validate the effect of single nucleotide polymorphisms in genes affecting thyroid biology for patients with DTC, and investigate the role of these genotypes in modifying DTC risk. We also examine the impact of mutations in miRNA, or in miRNA-mRNA binding sites on DTC susceptibility and phenotype. Methods Patients were recruited from thyroid cancer treatment clinics at tertiary centres in the West of Ireland and South of France as part of a collaborative multicentre study to establish a thyroid cancer biobank at the Discipline of Surgery in the Lambe Institute for Translational Research, based in University Hospital Galway. Patient demographics and clinico-pathological data were recorded. Controls were recruited from community volunteers and were >60 years old, without a current or previous diagnosis of cancer, and without a first-degree family history of thyroid cancer. Patterns of DTC presentation and therapeutic approaches were assessed and compared to current British Thyroid Association clinical practice guidelines. We ascertained those subgroups subject to equivocal guidance. Germline DNA was extracted from blood or buccal swabs using crystallisation precipitation, and genotyped using Taqman-based PCR. A case–control analysis was undertaken, comparing genotypic and allelic frequencies of the FOXE1 variant in patients with DTC, to frequencies in unaffected controls. Three miRNA-associated mutations (miR146a, KIT and KRAS) were also genotyped among cases and controls, and the effect on DTC susceptibility assessed. Results Of 178 patients assessed, an equivocal “personalised decision making” approach was the recommended strategy for 32 and 80 patients for surgery and RRA respectively; almost all proceeded to the more aggressive options of completion surgery and RRA. 277 patients with confirmed DTC and 309 non-cancer controls were genotyped for the FOXE1 variant. We demonstrated a significant association between the mutation and DTC susceptibility. An allele dosage effect was observed with odds ratios (OR) of 1.66 and 2.93 for heterozygous and rare homozygous genotypes respectively. Amongst Irish patients alone, presence of the rare homozygous genotype conferred an odds ratio of 3.9 (p<0.00001) for DTC risk. Three miRNA-associated variants were assessed for their impact on DTC susceptibility. The miR146a variant exhibited a per allele OR of 1.64 (p<0.001) for DTC cases (n=175), compared to controls (n=637). For those with one copy of the mutant allele at the locus, a genotypic OR of 1.62 (p=0.008) was observed, rising to 2.51 (p=0.006) for rare homozygous carriers. The KIT variant rs17084733 is associated with a reduced risk for development of DTC. The variant allele was evident in 54% of cases (n=275) and 61% of controls (n=440), with an associated per allele odds ratio of 0.65 (p=0.012). Rare homozygous carriers exhibited a lower genotypic OR compared to heterozygous carriers (OR=0.72, p=0.077 vs OR=0.24, p=0.046). The minor allele frequency of a novel germline T>G polymorphism in the 3' UTR of KRAS was observed to be 8% for both cases (n=274) and controls (n=669). No significant association was evident between presence of the mutant allele and DTC susceptibility (per allele OR=1.03, p=0.869). Conclusions Current best practice guidelines for the management of patients with DTC do not adequately delineate the appropriate management for large subgroups of patients for which there is a paucity of high quality evidence to guide clinical practice. This work demonstrates the significant extent to which patients treated in tertiary referral centres are subject to equivocal guidelines.

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NUI Galway

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Attribution-NonCommercial-NoDerivs 3.0 Ireland

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University of Galway Theses (PhD Theses)