Whole Exome Sequencing of Biliary Tubulopapillary Neoplasms Reveals Common Mutations in Chromatin Remodeling Genes
Abstract
:Simple Summary
Abstract
1. Introduction
2. Materials and Methods
2.1. Study Cohort
2.2. Clinical Information and Statistical Analyses
2.3. Tumor Samples
2.4. SNV Calling
2.5. CNV Analysis
2.6. Fluorescence In Situ Hybridization (FISH) Analysis of Chromosome 1
3. Results
3.1. Single Nucleotide Variants (SNVs)
3.2. Mutational Signature Pattern
3.3. Recurrently Mutated Genes and Corresponding Pathways
3.4. Identified Potential Therapeutic Targets
3.5. Genes Classically Associated with Pancreato-Biliary Carcinogenesis Are Rarely Altered in ITPN Carcinogenesis
3.6. CNV Detects Recurrent Gains and Losses on Chromosome 1
3.7. Genetic Losses
3.8. Genetic Gains
4. Discussion
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Appendix A
Case ID # | Age at Diagnosis | Gender | Diagnosis | Invasive Tumor | Tumor Size (cm) | pT | pN | Survival (Months) | Status |
---|---|---|---|---|---|---|---|---|---|
1 | 75 | w | ITPN of the bile duct | no | 7.5 | n.a. | n.a | 31 | death |
2 | 59 | w | ITPN of the bile duct | yes | 6.0 | pT1 | pN0 (0/20) | 33 | alive at last follow-up |
3 | 48 | m | ITPN of the bile duct | yes (minimal invasive) | 15.0 | n.a. | n.a | 83 | alive at last follow-up |
4 | 72 | w | ITPN of the bile duct | yes | 6.7 | n.a. | pN0 (0/4) | 52 | alive at last follow-up |
5 | 68 | w | ITPN of the bile duct | yes | 5.5 | n.a. | pN0 (0/1) | 124 | alive at last follow-up |
6 | 64 | m | ITPN of the bile duct | yes | 9.0 | n.a. | n.a | 1 | perioperative death |
7 | 57 | w | ITPN of the bile duct | yes | 7.0 | pT2b | pN1 (1/24) | 39 | alive at last follow-up |
8 | 65 | w | ITPN of the bile duct | yes | 5.0 | n.a. | pN0 (0/4) | 55 | alive at last follow-up |
9 | 55 | w | ITPN of the bile duct | yes | 7.0 | n.a. | pN0 (0/5) | 1 | perioperative death |
10 | 58 | m | ITPN of the bile duct | yes | 5.0 | n.a. | n.a | 11 | alive at last follow-up |
11 | 78 | w | ITPN of the bile duct | yes | n.a. | n.a. | n.a | 150 | alive at last follow-up |
12 | 53 | m | ITPN of the pancreas | suspicious for invasion | 3.5 | pTis | pN0 (0/21) | 27 | alive at last follow-up |
13 | 87 | w | ITPN of the pancreas | no | 15.0 | pTis | pN0 | 33 | alive at last follow-up |
14 | 66 | w | ITPN of the pancreas | yes | 10.5 | pT2 | pN0 (0/24) | 3 | alive at last follow-up |
15 | 63 | m | ITPN of the pancreas | yes | 6.0 | pT3 | pN1 (1/17) | 70 | alive at last follow-up |
16 | 76 | m | ITPN of the pancreas | yes | 4.0 | pT3 | pN1 | 54 | alive at last follow-up |
17 | 63 | w | ITPN of the pancreas | yes | 1.8 | pT1c | pN1 (1/17) | 0 | perioperative death |
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Bile Duct | Pancreas | ||||
---|---|---|---|---|---|
Gene | Reported Mutation Rates in CCA [18] | Observed Frequency (SNV) in ITPN of the Bile Duct | Gene | Reported mutation Rates in PDAC [19] | Observed Frequency (SNV) in ITPN of the Pancreas |
TP53 | 26% | 9% | KRAS | 92% | 0% |
KRAS | 17% | 0% | TP53 | 45% | 0% |
SMAD4 | 8% | 0% | SMAD4 | 17% | 17% |
NF1 | 6% | 0% | FLG | 10% | 0% |
ARID1A | 6% | 9% | ATXN1 | 7% | 0% |
PBRM1 | 6% | 0% | COL14A1 | 6% | 0% |
KMT2D | 6% | 0% | ITGAE | 6% | 0% |
ATR | 6% | 0% | GLI3 | 6% | 0% |
PIK3CA | 5% | 0% | GNAS | 6% | 0% |
ERBB3 | 5% | 0% | SPTA1 | 6% | 0% |
KMT2C | 5% | 9% | ARID1A | 5% | 0% |
PIK3C2G | 4% | 0% | CDKN2A | 5% | 0% * |
APC | 4% | 0% | RP1L1 | 5% | 0% |
BAP1 | 4% | 9% | BCLAF1 | 5% | 0% |
POLQ | 4% | 0% | AXIN1 | 5% | 0% |
ARID2 | 4% | 9% | NIN | 5% | 0% |
IDH1 | 3% | 0% | RNF43 | 4% | 0% |
TET1 | 3% | 0% | RBM10 | 4% | 0% |
CTNNB1 | 3% | 0% | IRF2 | 4% | 0% |
BRAF | 3% | 9% | HDAC2 | 3% | 0% |
Identified Actionable Genes | Case ID | OncoKB Search | |||||
---|---|---|---|---|---|---|---|
Pathway | Gene | Alteration | Entity | Drugs | Level of Evidence | Level-assoc. Cancer Types | |
MAPK signaling | BRAF | p.Val600Glu | ITPN pancreas (1/6) | # 2 | Vemurafenib, Dabrafenib, Trametinib | 1 | Melanoma |
Encorafenib + Cetuximab | 1 | Colorectal cancer | |||||
NRAS | p.Gly12Asp | ITPN pancreas (1/6) | # 12 | Binimetinib, Combimetinib, Iodine I 131-6-Beta-Iodomethyl-19-Norcholesterol + Selumetinib | 3A | Melanoma, Histiocytosis, Thyroid cancer | |
Panitumumab, Cetuximab | R1 | Colorectal cancer | |||||
MTOR signaling | MTOR | p.Ser1863Leu* | ITPN pancreas (1/6) | # 14 | Everolimus, Temsirolimus | 4 | All solid tumors |
FGF signaling | FGFR2 | p.Ile355Arg* p.Ile643Arg* | ITPN bile duct (2/11) | # 7,# 9 | Erdafitinib, Debio 1347, AZD4547, BGJ398 | 4 | All solid tumors |
Chromatin remodeling | KDM6A | p.Ser440Leu* | ITPN bile duct (1/11) | # 8 | Tazemetostat | 4 | Bladder cancer |
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Gross, C.; Engleitner, T.; Lange, S.; Weber, J.; Jesinghaus, M.; Konukiewitz, B.; Muckenhuber, A.; Steiger, K.; Pfarr, N.; Goeppert, B.; et al. Whole Exome Sequencing of Biliary Tubulopapillary Neoplasms Reveals Common Mutations in Chromatin Remodeling Genes. Cancers 2021, 13, 2742. https://doi.org/10.3390/cancers13112742
Gross C, Engleitner T, Lange S, Weber J, Jesinghaus M, Konukiewitz B, Muckenhuber A, Steiger K, Pfarr N, Goeppert B, et al. Whole Exome Sequencing of Biliary Tubulopapillary Neoplasms Reveals Common Mutations in Chromatin Remodeling Genes. Cancers. 2021; 13(11):2742. https://doi.org/10.3390/cancers13112742
Chicago/Turabian StyleGross, Claudia, Thomas Engleitner, Sebastian Lange, Julia Weber, Moritz Jesinghaus, Björn Konukiewitz, Alexander Muckenhuber, Katja Steiger, Nicole Pfarr, Benjamin Goeppert, and et al. 2021. "Whole Exome Sequencing of Biliary Tubulopapillary Neoplasms Reveals Common Mutations in Chromatin Remodeling Genes" Cancers 13, no. 11: 2742. https://doi.org/10.3390/cancers13112742