Gallbladder adenocarcinomas undergo subclonal diversification and selection from precancerous lesions to metastatic tumors
- Department of Internal Medicine, Seoul National University Bundang Hospital, Republic of Korea
- Department of Pathology, Seoul National University Bundang Hospital, Republic of Korea
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Republic of Korea
- Genealogy Inc, Republic of Korea
- Center for Precision Medicine, Seoul National University Bundang Hospital, Republic of Korea
- Medical Research Collaboration Center, Seoul National University Bundang Hospital, Republic of Korea
- Department of Data Science, Dana Farber Cancer Institute, Harvard T.H. Chan School of Public Health, United States
- Biomedical Research Institute, Seoul National University Bundang Hospital, Republic of Korea
- Department of Surgery, Seoul National University Bundang Hospital, Republic of Korea
Figures
Figure 1 with 2 supplements
Clinical history of patients, mutational landscape, and study workflow.
(A) Clinical history of 11 patients is summarized in the swimmer plot. (B) The mutational landscape of 11 primary tumors (GB) is visualized and compared with the two previous studies on gallbladder …
Figure 1—figure supplement 1
Inference of clonal structure by PyClone algorithm.
(A–K) The clonal population structure was statistically inferred for GB-A1 (A), GB-S1 (B), GB-S2 (C), GB-S3 (D), GB-A2 (E), GB-S4 (F), GB-S5 (G), GB-S6 (H), GB-S7 (I), GB-S8 (J), and GB-S9 (K) using …
Figure 1—figure supplement 2
BiIlN and primary gallbladder adenocarcinoma (GBAC) of the GB-S7 patient presumed to be derived from different origins.
(A) H&E staining of BiIlN. (B) H&E staining of GBAC. (C) Variant allele frequency of mutated genes in BilIN and primary GBAC. BilIN, biliary intraepithelial neoplasia; H&E, hematoxylin and eosin.
Figure 2
Spatial and temporal clonal evolution of four patients with gallbladder adenocarcinoma (GBAC) whose precancerous BilIN tissues were analyzed.
(A–D) The most probable phylogenetic trees and MapScape and TimeScape results are visualized for GB-A1 (A), GB-S1 (B), GB-S2 (C), and GB-S3 (D). In MapScape visualization (table), the numbers in the …
Figure 3
Spatial and temporal clonal evolution of additional seven patients with gallbladder adenocarcinoma (GBAC).
(A–G) The most probable phylogenetic trees and MapScape and TimeScape results are visualized for GB-A2 (A), GB-S4 (B), GB-S5 (C), GB-S6 (D), GB-S7 (E), GB-S8 (F), and GB-S9 (G). In MapScape …
Figure 4 with 3 supplements
Mutational signature analysis.
(A–B) The 100% stacked bar plots compare the proportions of known COSMIC Mutational Signatures v2 within our dataset and two public (MSKCC and Shanhai) datasets (A), and each category split …
Figure 4—figure supplement 1
Mutational signatures within each sample from 11 gallbladder adenocarcinoma (GBAC) patients.
The 100% stacked bar plots comparing the proportions of known COSMIC Mutational Signatures v2 within each sample from 11 GBAC patients. BilIN, biliary intraepithelial neoplasia; CBD, common bile …
Figure 4—figure supplement 2
Mutational signatures within each category split according to the type of sample.
The 100% stacked bar plots comparing the proportions of known COSMIC Mutational Signatures v2 within each category split according to the type of sample. The total number of mutations (N) and cosine …
Figure 4—figure supplement 3
Mutational signature analysis validated by two additional tools, Signal and MuSiCa.
The 100% stacked bar plots comparing the proportions of known COSMIC Mutational Signatures v2 within each category split according to the timing of development during clonal evolution. The total …
Figure 5
ERBB2 copy number variation during neoplastic transformation of BilIN in GB-A1.
(A–G) ERBB2 gene amplification (A and B), HER2 SISH (C and D), and HER2 IHC (F and G) were compared between BilIN (A, C) and (F) and primary GBAC (B), (D), and (G) samples and the mean ERBB2/CEP17 …
Tables
Table 1
Baseline characteristics of 11 patients with GBAC.
| Patient ID* | Sex | Age at diagnosis | ECOG PS at diagnosis | Stage at diagnosis | Differentiation |
|---|---|---|---|---|---|
| GB-A1 | F | 70 | 1 | IV | PD |
| GB-S1 | F | 66 | 1 | IV | MD |
| GB-S2 | F | 66 | 1 | IV | MD |
| GB-S3 | F | 75 | 1 | III | MD |
| GB-A2 | M | 61 | 1 | IV | MD |
| GB-S4 | M | 72 | 1 | IV | MD |
| GB-S5 | F | 70 | 1 | IV | PD |
| GB-S6 | M | 70 | 0 | IV | MD |
| GB-S7 | F | 74 | 1 | IV | PD |
| GB-S8 | M | 67 | 1 | III | WD |
| GB-S9 | M | 59 | 0 | IV | MD |
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*
In patient ID, ‘A’ indicates autopsy cases whereas ‘S’ indicates surgery cases.
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GBAC, gallbladder adenocarcinoma; ECOG PS, Eastern Cooperative Oncology Group performance status; M, male; F, female; PD, poorly differentiated; MD, moderately differentiated; WD, well-differentiated.
Table 2
List of subclones expanding during metastasis.
| Patient ID | Subclone | No. of mutations | Putative driver mutations | Clonal prevalence in primary tumor | Clonal prevalence in metastasis | Metastatic organ |
|---|---|---|---|---|---|---|
| GB-A1 | E | 121 | JARID2 p.K603Q (LOH) | 0.2% | 20.5% | CBD |
| F | 54 | SMAD4 p.L414fs (LOH) | 0.4% | 49.8% | Omentum 1 | |
| 27.0% | Omentum 2 | |||||
| GB-S1 | E | 6 | ROBO1 p.P1360Q | 0.0% | 59.2% | Distant LN |
| GB-S2 | H | 6 | – | 1.2% | 28.1% | Regional LN |
| GB-A2 | F | 14 | PRKCD p.I153L | 0.3% | 73.1% | Liver |
| 68.3% | Mesentery | |||||
| G | 3 | DICER1 p.T519A | 2.8% | 39.9% | Lung | |
| 61.5% | Chest wall | |||||
| GB-S4 | F | 32 | FBXW2 p.W450C | 0.0% | 34.1% | Colon wall |
| H | 36 | – | 0.0% | 34.9% | Distant LN | |
| GB-S5 | B | 28 | KIAA0100 p.F5S | 1.2% | 54.4% | Liver |
| CSMD2 p.E411K | ||||||
| GB-S6 | B | 7 | OSCP1 p.R351X | 1.1% | 60.2% | Lung |
| GB-S7 | C | 5 | – | 3.3% | 24.7% | Regional LN |
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Putative driver mutations are indicated, and a full list of mutated genes is specified in Supplementary file 2.
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GB, gallbladder; LN, lymph node; CBD, common bile duct.
Author response table 1
Proportion of mutations satisfying the conditions: (1) C:G > T:A variants, and (2) VAF < 5% in sample-specific clusters.
| Patient ID | Sample | Type of sample | Sample specific clusters* | Number of mutations in sample-specific clusters† | Number of filtered mutations in sample-specific clusters | Percentage (%) |
|---|---|---|---|---|---|---|
| GB-A1 | BilIN | FFPE | 2 | 34 | 3 | 8.8 |
| CBD | FFPE | 3 | 121 | 13 | 10.7 | |
| GB-S1 | BilIN | FFPE | 2 | 9 | 3 | 33.3 |
| GB | FFPE | 4 | 18 | 7 | 38.9 | |
| Distant LN | FFPE | 7 | 6 | 0 | 0.0 | |
| GB-S2 | BilIN | FFPE | 6 | 8 | 3 | 37.5 |
| GB | FFPE | 0 | 7 | 2 | 28.6 | |
| GB-S3 | BilIN | FFPE | 3 | 7 | 1 | 14.3 |
| GB | FFPE | 2 | 3 | 0 | 0.0 | |
| GB-A2 | GB | Fresh-frozen | 2 | 40 | 0 | 0.0 |
| Lung (old) | FFPE | 10 | 17 | 1 | 5.9 | |
| Lung | Fresh-frozen | 5 | 15 | 0 | 0.0 | |
| Chest wall | Fresh-frozen | 3 | 23 | 0 | 0.0 | |
| Liver | Fresh-frozen | 4 | 31 | 0 | 0.0 | |
| Mesentery | Fresh-frozen | 6 | 8 | 2 | 25.0 | |
| GB-S4 | Colon wall | FFPE | 3 | 36 | 0 | 0.0 |
| Distant LN | FFPE | 1 | 9 | 2 | 22.2 | |
| GB-S5 | GB | FFPE | 3 | 13 | 0 | 0.0 |
| GB-S6 | GB | FFPE | 1 | 5 | 0 | 0.0 |
| Lung | FFPE | 2 | 7 | 0 | 0.0 | |
| GB-S7 | GB | FFPE | 0 | 11 | 0 | 0.0 |
| Regional LN | FFPE | 3 | 5 | 0 | 0.0 | |
| GB-S8 | GB | FFPE | 2 | 35 | 4 | 11.4 |
| Regional LN | FFPE | 0 | 81 | 3 | 3.7 |
Additional files
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Supplementary file 1
Tables.
(A) Baseline characteristics of samples are summarized. (B) Mutational signatures of our dataset are analyzed by three different tools, Mutalisk, Signal, and MuSiCa.
- https://cdn.elifesciences.org/articles/78636/elife-78636-supp1-v3.docx
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Supplementary file 2
Detected somatic alternations in 11 patients with gallbladder adenocarcinoma (GBAC).
Full list of mutations called in our cohort.
- https://cdn.elifesciences.org/articles/78636/elife-78636-supp2-v3.xlsx
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MDAR checklist
- https://cdn.elifesciences.org/articles/78636/elife-78636-mdarchecklist1-v3.docx
