Colorectal Cancer-Associated Smad4 R361 Hotspot Mutations Boost Wnt/β-Catenin Signaling through Enhanced Smad4-LEF1 Binding
Open accessPublished version of a preprint
Abstract
About 10% to 30% of patients with colorectal cancer harbor either loss of or missense mutations in SMAD4, a critical component of the TGFβ signaling pathway. The pathophysiologic function of missense mutations in Smad4 is not fully understood. They usually map to the MH2 domain, specifically to residues that are involved in heterodimeric complex formation with regulatory Smads (such as Smad2/3) and ensuing transcriptional activation. These detrimental effects suggest that SMAD4 missense mutations can be categorized as loss-of-function. However, they tend to cluster in a few hotspots, which is more consistent with them acting by a gain-of-function mechanism. In this study, we investigated the functional role of Smad4 R361 mutants by re-expressing two R361 Smad4 variants in several Smad4-null colorectal cancer cell lines. As predicted, R361 mutations disrupted Smad2/3-Smad4 heteromeric complex formation and abolished canonical TGFβ signaling. In that, they were similar to SMAD4 loss. However, RNA sequencing and subsequent RT-PCR assays revealed that Smad4mut cells acquired a gene signature associated with enhanced Lef1 protein function and increased Wnt signaling. Mechanistically, Smad4 mutant proteins retained binding to Lef1 protein and drove a commensurate increase in downstream Wnt signaling as measured by TOP/FOP luciferase assay and Wnt-dependent cell motility. Consistent with these findings, human colorectal cancers with SMAD4 missense mutations were less likely to acquire activating mutations in the key Wnt pathway gene CTNNB1 (encoding β-catenin) than colorectal cancers with truncating SMAD4 nonsense mutations. Implications: Our studies suggest that in colorectal cancer hotspot mutations in Smad4 confer enhanced Wnt signaling and possibly heightened sensitivity to Wnt pathway inhibitors.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Paneth-like cells were readily induced by KRAS-EGFR inhibition in both SMAD4 wild-type models (LS174T and KRAS G12D PDOs) and SMAD4 mutant lines (SW1463 and RW7213) harboring the loss-of-function SMAD4 R361C mutation.
“Moreover, Paneth-like cells were readily induced by KRAS-EGFR inhibition in both SMAD4 wild-type models (LS174T and KRAS G12D PDOs) (Figures 1I–1N, S1J, and S1K) and SMAD4 mutant lines (SW1463 and RW7213) harboring the loss-of-function SMAD4 R361C mutation (Figures S1L–S1O).53”
From Paneth-like transition drives resistance to dual targeting of KRAS and EGFR in colorectal cancer (2026) · cites this paper as [53]
The Results section (‘Smad4 mutants do not support canonical TGFβ-induced transcriptional activity’; page unavailable) supports calling R361C loss-of-function for canonical TGFβ signaling. Our copy does not establish that SW1463 or RW7213 harbor R361C, or report Paneth-like cell induction after KRAS–EGFR inhibition; the citing sentence points to its own figures for the induction results. (LLM, conf=0.82)
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Subramanian, A., Tamayo, P., Mootha, V. K., Mukherjee, S., Ebert, B. L., Gillette, M. A., Paulovich, A., Pomeroy, S. L., Golub, T. R., Lander, E. S., et al. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0506580102 · Cited by 53,625 · see citing works
Comprehensive molecular characterization of human colon and rectal cancer
The Cancer Genome Atlas Network (2012) · Nature · doi:10.1038/nature11252 · Cited by 8,499 · see citing works
Mechanisms of TGF-β Signaling from Cell Membrane to the Nucleus
Shi, Y., & Massagué, J. (2003) · Cell · doi:10.1016/s0092-8674(03)00432-x · Cited by 5,860 · see citing works
Smad-dependent and Smad-independent pathways in TGF-β family signalling
Derynck, R., & Zhang, Y. E. (2003) · Nature · doi:10.1038/nature02006 · Cited by 5,370 · see citing works
The consensus molecular subtypes of colorectal cancer
Guinney, J., Dienstmann, R., Wang, X., de Reyniès, A., Schlicker, A., Soneson, C., Marisa, L., Roepman, P., Nyamundanda, G., Angelino, P., et al. (2015) · Nature Medicine · doi:10.1038/nm.3967 · Cited by 5,170 · see citing works
Massagué, J. (2012) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3434 · Cited by 3,130 · see citing works
Zhan, T., Rindtorff, N., & Boutros, M. (2017) · Oncogene · doi:10.1038/onc.2016.304 · Cited by 2,626 · see citing works
Molecular Genetics of Colorectal Cancer
Fearon, E. R. (2011) · Annual Review of Pathology: Mechanisms of Disease · doi:10.1146/annurev-pathol-011110-130235 · Cited by 1,805 · see citing works
Dennler, S., Itoh, S., Vivien, D., ten Dijke, P., Huet, S., & Gauthier, J. (1998) · The EMBO Journal · doi:10.1093/emboj/17.11.3091 · Cited by 1,793 · see citing works
Consensus molecular subtypes and the evolution of precision medicine in colorectal cancer
Dienstmann, R., Vermeulen, L., Guinney, J., Kopetz, S., Tejpar, S., & Tabernero, J. M. (2017) · Nature reviews. Cancer · doi:10.1038/nrc.2016.126 · Cited by 1,038 · see citing works
Zebrafish Prickle, a Modulator of Noncanonical Wnt/Fz Signaling, Regulates Gastrulation Movements
Veeman, M. T., Slusarski, D. C., Kaykas, A., Louie, S. H., & Moon, R. T. (2003) · Current Biology · doi:10.1016/s0960-9822(03)00240-9 · Cited by 945 · see citing works
Human Smad3 and Smad4 Are Sequence-Specific Transcription Activators
Zawel, L. S., Dai, J. L., Buckhaults, P., Zhou, S., Kinzler, K. W., Vogelstein, B., & Kern, S. E. (1998) · Molecular Cell · doi:10.1016/s1097-2765(00)80061-1 · Cited by 940 · see citing works
Epigenetic and genetic features of 24 colon cancer cell lines
Ahmed, D., Eide, P. W., Eilertsen, I. A., Danielsen, S. A., Eknæs, M., Hektoen, M., Lind, G. E., & Lothe, R. A. (2013) · Oncogenesis · doi:10.1038/oncsis.2013.35 · Cited by 913 · see citing works
Clinical Sequencing Defines the Genomic Landscape of Metastatic Colorectal Cancer
Yaeger, R., Chatila, W. K., Lipsyc, M. D., Hechtman, J. F., Cercek, A., Sanchez-Vega, F., Jayakumaran, G., Middha, S., Zehir, A., Donoghue, M. T. A., et al. (2018) · Cancer Cell · doi:10.1016/j.ccell.2017.12.004 · Cited by 858 · see citing works
The role of TGF-β/SMAD4 signaling in cancer
Zhao, M., Mishra, L., & Deng, C.-X. (2018) · International Journal of Biological Sciences · doi:10.7150/ijbs.23230 · Cited by 631 · see citing works
Koi, M., Umar, A., Chauhan, D. P., Cherian, S. P., Carethers, J. M., Kunkel, T. A., & Boland, C. R. (1994) · PubMed · Cited by 515 · see citing works
TGF-β Family Signaling in Tumor Suppression and Cancer ProgressionPreprint
Seoane, J., & Gomis, R. R. (2017) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a022277 · Cited by 512 · see citing works
A structural basis for mutational inactivation of the tumour suppressor Smad4
Shi, Y., Hata, A., Lo, R. S., Massagué, J., & Pavletich, N. P. (1997) · Nature · doi:10.1038/40431 · Cited by 461 · see citing works
Labbé, E., Letamendı́a, A., & Attisano, L. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.150152697 · Cited by 442 · see citing works
Higher frequency of Smad4 gene mutation in human colorectal cancer with distant metastasis
Miyaki, M., Iijima, T., Konishi, M., Sakai, K., Ishii, A., Yasuno, M., Hishima, T., Koike, M., Shitara, N., Iwama∥, T., et al. (1999) · Oncogene · doi:10.1038/sj.onc.1202642 · Cited by 438 · see citing works
Pardali, K., Kurisaki, A., Morén, A., ten Dijke, P., Kardassis, D., & Moustakas, A. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m909467199 · Cited by 392 · see citing works
Brannon, A. R., Vakiani, E., Sylvester, B. E., Scott, S. N., McDermott, G. C., Shah, R. H., Kania, K., Viale, A. J., Oschwald, D. M., Vacic, V., et al. (2014) · Genome biology · doi:10.1186/s13059-014-0454-7 · Cited by 369 · see citing works
Willis, A. C., Jung, E. J., Wakefield, T., & Chen, X. (2004) · Oncogene · doi:10.1038/sj.onc.1207396 · Cited by 334 · see citing works
SMAD2 , SMAD3 and SMAD4 Mutations in Colorectal Cancer
Fleming, N. I., Jorissen, R. N., Mouradov, D., Christie, M., Sakthianandeswaren, A., Palmieri, M., Day, F. L., Li, S., Tsui, C., Lipton, L. R., et al. (2012) · Cancer Research · doi:10.1158/0008-5472.can-12-2706 · Cited by 327 · see citing works
The canonical Wnt signalling pathway and its APC partner in colon cancer development
Schneikert, J., & Behrens, J. (2006) · Gut · doi:10.1136/gut.2006.093310 · Cited by 289 · see citing works
Transforming Growth Factor β-Independent Shuttling of Smad4 between the Cytoplasm and Nucleus
Pierreux, C. E., Nicolás, F. J., & Hill, C. S. (2000) · Molecular and Cellular Biology · doi:10.1128/mcb.20.23.9041-9054.2000 · Cited by 274 · see citing works
Smad4/DPC4-mediated tumor suppression through suppression of angiogenesis
Schwarte‐Waldhoff, I., Volpert, O. V., Bouck, N., Sipos, B., Hahn, S. A., Klein‐Scory, S., Lüttges, J., Klöppel, G., Graeven, U., Eilert-Micus, C., et al. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.97.17.9624 · Cited by 266 · see citing works
The Molecular Hallmarks of the Serrated Pathway in Colorectal Cancer
Palma, F. D. E. D., D’Argenio, V., Pol, J. G., Kroemer, G., Maiuri, M. C., & Salvatore, F. (2019) · Cancers · doi:10.3390/cancers11071017 · Cited by 212 · see citing works
Smad4 Inactivation Promotes Malignancy and Drug Resistance of Colon Cancer
Papageorgis, P., Cheng, K., Ozturk, S., Gong, Y., Lambert, A. W., Abdolmaleky, H. M., Zhou, J., & Thiagalingam, S. (2011) · Cancer Research · doi:10.1158/0008-5472.can-09-3269 · Cited by 211 · see citing works
SMAD4 as a Prognostic Marker in Colorectal Cancer
Alazzouzi, H., Alhopuro, P., Salovaara, R., Sammalkorpi, H., Järvinen, H., Mecklin, J., Hemminki, A., Schwartz, S., Aaltonen, L. A., & Arango, D. (2005) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-04-1458 · Cited by 202 · see citing works
Woodford-Richens, K., Rowan, A., Gorman, P., Halford, S. E. R., Bicknell, D. C., Wasan, H. S., Roylance, R. R., Bodmer, W. F., & Tomlinson, I. P. M. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.171321498 · Cited by 199 · see citing works
Payne, S. R., & Kemp, C. J. (2005) · Carcinogenesis · doi:10.1093/carcin/bgi223 · Cited by 186 · see citing works
Smad4-Mediated Signaling Inhibits Intestinal Neoplasia by Inhibiting Expression of β-Catenin
Freeman, T. J., Smith, J. J., Chen, X., Washington, M. K., Roland, J. T., Means, A. L., Eschrich, S. A., Yeatman, T. J., Deane, N. G., & Beauchamp, R. D. (2011) · Gastroenterology · doi:10.1053/j.gastro.2011.11.026 · Cited by 182 · see citing works
Systematic Functional Interrogation of Rare Cancer Variants Identifies Oncogenic Alleles
Kim, E., Ilić, N., Shrestha, Y., Zou, L., Kamburov, A., Zhu, C., Yang, X., Lubonja, R., Tran, N. H., Nguyen, C., et al. (2016) · Cancer Discovery · doi:10.1158/2159-8290.cd-16-0160 · Cited by 168 · see citing works
Allelic loss on chromosome 18q as a prognostic marker in stage II colorectal cancer
Martínez-López, E., Abad, A., Pous, A. F., Monzó, M., Ojanguren, I., Pifarré, À., Sánchez, J. J., Martín, C., & Rosell, R. (1998) · Gastroenterology · doi:10.1016/s0016-5085(98)70423-8 · Cited by 148 · see citing works
Zhang, B., Zhang, B., Chen, X., Bae, S., Singh, K. P., Washington, M. K., & Datta, P. K. (2014) · British Journal of Cancer · doi:10.1038/bjc.2013.789 · Cited by 113 · see citing works
Sakai, S., Ohhata, T., Kitagawa, K., Uchida, C., Aoshima, T., Niida, H., Suzuki, T., Inoue, Y., Miyazawa, K., & Kitagawa, M. (2019) · Cancer Research · doi:10.1158/0008-5472.can-18-3210 · Cited by 101 · see citing works
Differential Ubiquitination Defines the Functional Status of the Tumor Suppressor Smad4
Morén, A., Hellman, U., Inada, Y., Imamura, T., Heldin, C., & Moustakas, A. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m300159200 · Cited by 99 · see citing works
Loss of Smad4 Function in Pancreatic Tumors
Maurice, D., Pierreux, C. E., Howell, M. T., Wilentz, R. E., Owen, M. J., & Hill, C. S. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m105895200 · Cited by 94 · see citing works
Iacobuzio–Donahue, C. A., Song, J., Parmiagiani, G., Yeo, C. J., Hruban, R. H., & Kern, S. E. (2004) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-1121-3 · Cited by 93 · see citing works
Rab25 as a tumour suppressor in colon carcinogenesis
Goldenring, J. R., & Nam, K. T. (2010) · British Journal of Cancer · doi:10.1038/sj.bjc.6605983 · Cited by 88 · see citing works
Sarshekeh, A. M., Advani, S., Overman, M. J., Manyam, G. C., Kee, B. K., Fogelman, D. R., Dasari, A. N., Raghav, K. P. S., Vilar, E., Manuel, S., et al. (2017) · PLoS ONE · doi:10.1371/journal.pone.0173345 · Cited by 85 · see citing works
Voorneveld, P. W., Kodach, L. L., Jacobs, R. J., van Noesel, C. J. M., Peppelenbosch, M. P., Korkmaz, K., Molendijk, I., Dekker, E., Morreau, H., van Pelt, G. W., et al. (2014) · British Journal of Cancer · doi:10.1038/bjc.2014.560 · Cited by 80 · see citing works
Shiou, S., Singh, A. B., Krishnan, M., Datta, P. K., Washington, M. K., Beauchamp, R. D., & Dhawan, P. (2007) · Cancer Research · doi:10.1158/0008-5472.can-06-1680 · Cited by 79 · see citing works
Comprehensive Analysis of SMAD4 Mutations and Protein Expression in Juvenile Polyposis
Woodford-Richens, K., Rowan, A., Poulsom, R., Bevan, S., Salovaara, R., Aaltonen, L. A., Houlston, R. S., Wright, N. A., & Tomlinson, I. P. M. (2001) · American Journal Of Pathology · doi:10.1016/s0002-9440(10)62516-3 · Cited by 64 · see citing works
Tian, X., Zhang, J., Tan, T. K., Lyons, J. G., Zhao, H., Niu, B., Lee, S. R., Tsatralis, T., Zhao, Y., Wang, Y., et al. (2012) · Journal of Cell Science · doi:10.1242/jcs.103036 · Cited by 60 · see citing works
Liu, S., Fan, W., Gao, X., Huang, K., Ding, C., Ma, G., Yan, L., & Song, S. (2019) · Cellular Signalling · doi:10.1016/j.cellsig.2019.05.009 · Cited by 57 · see citing works
Loss of Smad4 expression predicts liver metastasis in human colorectal cancer
Losi, L., Bouzourène, H., & Benhattar, J. (2007) · Oncology Reports · doi:10.3892/or.17.5.1095 · Cited by 52 · see citing works
Lim, S. K., & Hoffmann, F. M. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0604773103 · Cited by 50 · see citing works
Calvo-Sánchez, M. I., Fernández-Martos, S., Carrasco, E., Moreno‐Bueno, G., Bernabéu, C., Quintanilla, M., & Espada, J. (2018) · Journal of Molecular Cell Biology · doi:10.1093/jmcb/mjy051 · Cited by 43 · see citing works
Wu, C., Koay, T. S., Esfandiari, A., Ho, Y.-H., Lovat, P. E., & Lunec, J. (2018) · Cancers · doi:10.3390/cancers11010003 · Cited by 39 · see citing works
PRSS8 suppresses colorectal carcinogenesis and metastasis
Bao, Y., Guo, Y., Yang, Y., Wei, X., Zhang, S., Zhang, Y., Li, K., Yuan, M., Guo, D., Macias, V., et al. (2018) · Oncogene · doi:10.1038/s41388-018-0453-3 · Cited by 36 · see citing works
Allelotype analysis of early colorectal cancers with lymph node metastasis
Arai, T., Akiyama, Y., Yamamura, A., Hosoi, T., Shibata, T., Saitoh, K., Okabe, S., & Yuasa, Y. (1998) · International Journal of Cancer · doi:10.1002/(sici)1097-0215(19980821)79:4 · Cited by 26 · see citing works
Qu, H., Zheng, L., Jiao, W., Mei, H., Li, D., Song, H., Fang, E., Wang, X., Li, S., Huang, K., et al. (2016) · Scientific Reports · doi:10.1038/srep32628 · Cited by 22 · see citing works
Yoshioka, Y., Togashi, Y., Chikugo, T., Kogita, A., Taguri, M., Terashima, M., Mizukami, T., Hayashi, H., Sakai, K., Velasco, M. A. D., et al. (2015) · Cancer · doi:10.1002/cncr.29676 · Cited by 21 · see citing works
Dews, M., Tan, G. S., Hultine, S., Raman, P., Choi, J., Duperret, E. K., Lawler, J., Bass, A. J., & Thomas‐Tikhonenko, A. (2014) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/dju043 · Cited by 18 · see citing works
Self-citation
Flagged first, then by citations
3 of the 59 references couldn’t be matched to a known paper.
Cited by
Sorted by citations
Wnt signaling in cancer: from biomarkers to targeted therapies and clinical translation
Tufail, M., Jiang, C., & Li, N. (2025) · Molecular Cancer · doi:10.1186/s12943-025-02306-w · Cited by 82 · see citing works
Gharib, E., & Robichaud, G. A. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25179463 · Cited by 53 · see citing works
Zenbout, I., Bouramoul, A., Meshoul, S., & Amrane, M. (2023) · IEEE Access · doi:10.1109/access.2023.3234294 · Cited by 26 · see citing works
Paneth-like transition drives resistance to dual targeting of KRAS and EGFR in colorectal cancer
Zhang, Y., Chen, J., She, Y., Fang, Z., Zhang, Y., Ruan, D., Guo, W., Liao, J., Zhou, W., Lao, J., et al. (2026) · Cancer Cell · doi:10.1016/j.ccell.2025.10.010 · Cited by 23 · see citing works
Sehgal, P. D., Lanauze, C., Wang, X., Hayer, K. E., Torres-Diz, M., Leu, N. A., Sela, Y., Stanger, B. Z., Lengner, C. J., & Thomas-Tikhonenko, A. (2021) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-21-0666 · Cited by 20 · see citing works
Self-citationGenetic and microenvironmental evolution of colorectal liver metastases under chemotherapy
Shi, M., Yang, Y., Huang, N., Zeng, D., Mo, Z., Wang, J., Zhang, X., Liu, R., Wang, C., Rong, X., et al. (2024) · Cell Reports Medicine · doi:10.1016/j.xcrm.2024.101838 · Cited by 17 · see citing works
Exploring the molecular mechanisms and therapeutic potential of SMAD4 in colorectal cancer
Shan, H., Tian, G., Zhang, Y., & Qiu, Z. (2024) · Cancer Biology & Therapy · doi:10.1080/15384047.2024.2392341 · Cited by 14 · see citing works
Loss of function SMAD4 nonstop mutations in human cancer
Bauer, A. H., Basta, D. W., Hornick, J. L., & Dong, F. (2023) · Histopathology · doi:10.1111/his.14880 · Cited by 12 · see citing works
Lum, M. A., Jonas, K. A., Parmar, S., Black, A. R., O’Connor, C. M., Dobersch, S., Yamamoto, N., Robertson, T. M., Schutter, A., Giambi, M., et al. (2025) · Journal of Clinical Investigation · doi:10.1172/jci176093 · Cited by 7 · see citing works
Fu, J., Wang, D., Liu, W., Yu, Q., Zhang, C., Li, H., Jin-Shun, C. A. I., Ji, S., Zhang, L., & Sun, F. (2025) · Cells · doi:10.3390/cells14100714 · Cited by 5 · see citing works
Cao, X., Geng, X., Zhang, C., & Li, L. (2025) · International Journal of Oncology · doi:10.3892/ijo.2025.5767 · Cited by 4 · see citing works
Xue, X., Zhou, Y., Liu, H., Gao, Y., Ma, X., Xiao, Z., Zhang, W., Li, P., Tian, Z., Luan, Y., et al. (2025) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2025.117899 · Cited by 3 · see citing works
Dai, C., Zhao, Y., Zhang, H., Sultan, M. H., Huang, B., Tian, X., Jia, X., Li, H., Huang, F., & Wang, Y. (2025) · Cancer Gene Therapy · doi:10.1038/s41417-025-00976-8 · Cited by 2 · see citing works
Wang, Y., Zhang, S., Bai, J., Li, X., Han, Y., Ji, M., Jiang, C., Ge, X., Yu, T., Hou, Y., et al. (2026) · Advanced Science · doi:10.1002/advs.202519791 · Cited by 2 · see citing works
Global patterns of mutational profiles in biliary tract cancer
Zhu, Y., Wu, J. A., Zhang, D., Chowdhury, S., Wang, H., Lee, S. S., Meric‐Bernstam, F., Hu, Z. I., Javle, M. M., & Kwong, L. N. (2026) · Journal of Hepatology · doi:10.1016/j.jhep.2026.03.029 · Cited by 2 · see citing works
Lu, Q., Guo, Q., Zhou, Y., Tao, Q., Chen, R., Xu, Q., Zhao, Z., & Jiang, P. (2026) · International Journal of Molecular Sciences · doi:10.3390/ijms27177554 · Cited by 2 · see citing works
Chen, M., Wang, T., Feng, X., Gao, Y., Wei, X., Han, Z., & An, H. (2025) · Research Square · doi:10.21203/rs.3.rs-7066314/v1
Dysregulácia dráhy TGF-β v karcinóme pankreasu a kolorektálnom karcinóme: Porovnávacia analýza
Večurkovská, I., Mašlanková, J., Stupák, M., & Hubková, B. (2025) · Zdravotnícke štúdie · doi:10.54937/zs.2025.17.2.30-35
Genomic and Evolutionary Determinants of Two-hit Frequencies in Tumor Suppressor GenesPreprint
Mukherjee, N., & Sabarinathan, R. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.02.17.706175
Xian, L., Lu, J. Z., Zhou, L., & Xin, W. (2026) · Diagnostics · doi:10.3390/diagnostics16121804
- Authors
- Lanauze, C. B., Sehgal, P., Hayer, K., Torres-Diz, M., Pippin, J. A., Grant, S. F. A., & Thomas-Tikhonenko, A.
- Affiliations
- Children's Hospital of Philadelphia (US)
- 1Division of Pathobiology, Children’s Hospital of Philadelphia, Pennsylvania.
- ORCID
- Venue
- Molecular Cancer Research
- Published
- 2021-02-19
- Volume
- 19
- Issue
- 5
- Pages
- 823-833
- ISSN
- 1541-7786 (ISSN-L)
- 1557-3125
- PMC
- PMC8137583
- OpenAlex
- W3129236693
- Cited by
- 17
- References
- 59
- Citations by year
- 2026: 4 · 2025: 7 · 2024: 3 · 2023: 2 · 2021: 1
- FWCI
- 0.47
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Molecular Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NIH (R01 CA196299, 5T32 CA009140)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
- Keywords
- SMAD4, colorectal cancer, Wnt/β-catenin signaling, LEF1, TGF-beta signaling, gain-of-function mutations, CTNNB1 mutation, Wnt pathway inhibitors, cell motility
- MeSH terms
- Humans, Mutation, Transfection, Colorectal Neoplasms, Lymphoid Enhancer-Binding Factor 1, Smad4 Protein, Wnt Signaling Pathway
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
