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. 2016 May;239(1):72-83.
doi: 10.1002/path.4696. Epub 2016 Apr 1.

Clonality Analysis of Multifocal Papillary Thyroid Carcinoma by Using Genetic Profiles

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Free PMC article

Clonality Analysis of Multifocal Papillary Thyroid Carcinoma by Using Genetic Profiles

Zheming Lu et al. J Pathol. .
Free PMC article

Abstract

Papillary thyroid carcinoma (PTC) is the most common adult thyroid malignancy and often presents with multiple anatomically distinct foci within the thyroid, known as multifocal papillary thyroid carcinoma (MPTC). The widespread application of the next-generation sequencing technologies in cancer genomics research provides novel insights into determining the clonal relationship between multiple tumours within the same thyroid gland. For eight MPTC patients, we performed whole-exome sequencing and targeted region sequencing to identify the non-synonymous point mutations and gene rearrangements of distinct and spatially separated tumour foci. Among these eight MPTCs, completely discordant mutational spectra were observed in the distinct cancerous nodules of patients MPTC1 and 5, suggesting that these nodules originated from independent precursors. In another three cases (MPTC2, 6, and 8), the distinct MPTC foci of these patients had no other shared mutations except BRAF V600E, also indicating likely independent origins. Two patients (MPTC3 and 4) shared almost identical mutational spectra amongst their separate tumour nodules, suggesting a common clonal origin. MPTC patient 7 had seven cancer foci, of which two foci shared 66.7% of mutations, while the remaining cancer foci displayed no common non-synonymous mutations, indicating that MPTC7 has multiple independent origins accompanied by intraglandular disease dissemination. In this study, we found that 75% of MPTC cases arose as independent tumours, which supports the field cancerization hypothesis describing multiple malignant lesions. MPTC may also arise from intrathyroidal metastases from a single malignant clone, as well as multiple independent origins accompanied by intrathyroidal metastasis.

Keywords: clonal origin; exome sequencing; field cancerization; multifocality; papillary thyroid cancer; tumour evolution.

Conflict of interest statement

No conflicts of interest were declared.

Figures

Figure 1
Figure 1
Landscape of genomic alterations in eight multifocal papillary thyroid carcinomas. Top: mutation density (mutations/Mb) in coding regions according to mutation type (non-synonymous in blue; synonymous in green). Bottom: genetic profiles by exome DNA sequencing of eight MPTCs. Right: the frequency of mutation of each gene.
Figure 2
Figure 2
MPTC1 exhibits genetic and histological characteristics of clones of independent origin. (A) The sites of the two cancer foci (TR1, TR2) in the right thyroid lobe. Two metastases (LR1, LR2) emerged following radical thyroidectomy in the right cervical lymph nodes. (B) Somatic mutation profiles of distinct tumour foci (TR1, TR2) and two lymph node metastases (LR1, LR2). The colour bar indicates the mutant allele fraction. (C) Histopathological appearance of distinct tumour foci and different lymph node metastases are illustrated (H&E; original magnification 400×). (D) IHC staining for BRAF V600E in M1TR1 and M1TR2. M1TR1 had a BRAF V600E mutation detected by sequencing and showed moderate BRAF V600E mutant protein expression. The second focus from patient MPTC1, M1TR2, lacked a BRAF V600E gene mutation and BRAF V600E mutant protein expression. (E) The clonal origin model of MPTC1. The two lymph node metastases (LR1, LR2) are more likely to have originated from focus M1TR1.
Figure 3
Figure 3
MPTC2 is an example of MPTC foci developing from independent clonal origins. (A) The gross specimen of MPTC2 shows sites of two cancer foci (M2TL and M2TR) in the left and right thyroid lobe, respectively, and one adenoma (M2AR) in the right thyroid lobe. (B) Somatic mutation profile of distinct tumour foci (M2TL and M2TR) and adenoma (M2AR). The colour bar indicates the percentage of mutation alleles. (C) Histopathological appearance of the two distinct cancer foci (M2TL and M2TR) (H&E; original magnification 400×). Both cancer foci display obvious papillae and nuclear features consistent with PTC.
Figure 4
Figure 4
Cancer foci of MPTC4 exhibit characteristics of a common clonal origin. (A) The gross tumour specimens from patient MPTC4 show the sites of two cancer foci (M4TL and M4TR) in the left and right thyroid lobes, respectively. (B) Somatic mutation profile and RET/CCDC6 fusion gene of the distinct tumour foci (M4TL and M4TR). The colour bar indicates the mutant allele percentage. (C) Sanger sequencing verifies the RET/CCDC6 rearrangement identified by NGS. The corresponding fusion point is indicated by arrowheads. (D) Histological appearance of the two distinct cancer foci (M4TL and M4TR) (H&E; original magnification 400×). Both cancer foci showed follicular variant PTC and have similar nuclear features, consistent with PTC.
Figure 5
Figure 5
MPTC7 is an example of tumour foci of independent clonal origin accompanied by intrathyroidal dissemination. (A) Gross specimen shows sites of seven cancer foci analysed in the bilateral thyroid lobes: three in the left lobe (M7TL1, M7TL2, M7TL3), one in the thyroid isthmus (M7TI), and three in the right lobe (M7TR1, M7TR2, M7TR3) after radical thyroidectomy. (B) Somatic mutation profile of distinct tumour foci (M7TL1, M7TL2, M7TL3, M7TI, M7TR1, M7TR2, M7TR3). The colour bar indicates the mutant allele fraction of each alteration. (C) Histological appearance of distinct cancer foci (H&E; original magnification 400×).

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