Dickson, Paxton V
Mayo Clinic
Department of Surgery, University of Tennessee Health Science Center, Memphis, Tennessee.
Citations 2
Convergent Genetic Adaptation in Human Tumors Developed Under Systemic Hypoxia and in Populations Living at High Altitudes
Arenillas, Carlota , Celada, Lucía , Ruiz-Cantador, José , Calsina, Bruna , Datta, Debayan , García‐Galea, Eduardo , Fasani, Roberta , Moreno-Cárdenas, Ana Belén , Alba‐Linares, Juan José , Miranda, Berta , Martínez‐Montes, Ángel M. , Álvarez-Escolá, Cristina , Lecumberri, Beatriz , García, Ana González , Flores, Shahida K., Esquivel, Emmanuel , Ding, Yanli , Peitzsch, Mirko , Robles-Guirado, José-Ángel , Zapata, Rita Maria Regojo , Iglesias, Carmela , Dwight, Trisha , Oleaga, Amelia , Garrido‐Lestache, Elvira , Marín, María Jesús del Cerro , Martínez-Bendayán, Isaac , Álvarez-González, Enol , Cubiella, Tamara, Lourenço, Delmar Muniz , Pereira, Maria Adelaide Albergaria, Burnichon, Nelly , Broberg, Craig S. , Dickson, Paxton V. , Soriano, Joaquín Rueda , Dienstmann, Rodrigo , Villanueva, Josep , Capdevila, Jaume , Gimenez‐Roqueplo, Anne‐Paule , Bechmann, Nicole , Vaidya, Anand , Weghorn, Donate , Casteràs, Anna , Adameyko, Igor , Miranda-Barrio, Berta , González García, Ana , K Flores, Shahida , Regojo Zapata, Rita Maria , Pozo-Kreilinger, José Juan , Iglesias, Carmela , Dwight, Trisha , Muir, Christopher A , Oleaga, Amelia , Garrido-Lestache Rodríguez-Monte, Maria Elvira , Del Cerro, Maria Jesús , Martínez-Bendayán, Isaac , Álvarez-González, Enol , Cubiella, Tamara , Lourenço, Delmar Muniz , A Pereira, Maria Adelaide , Burnichon, Nelly , Buffet, Alexandre , Broberg, Craig , Dickson, Paxton V , Fraga, Mario F , Llorente Pendás, José Luis , Rueda Soriano, Joaquín , Buendía Fuentes, Francisco , Toledo, Sergio P A , Clifton-Bligh, Roderick , Dienstmann, Rodrigo , Villanueva, Josep , Capdevila, Jaume , Gimenez-Roqueplo, Anne-Paule , Favier, Judith , Nuciforo, Paolo , Young, W F , Bechmann, Nicole , Opotowsky, Alexander R , Vaidya, Anand , Bancos, Irina , Weghorn, Donate , Robledo, Mercedes , Casteràs, Anna , Dos-Subirà, Laura , Adameyko, Igor , Chiara, María-Dolores , Dahia, Patricia L M , Toledo, Rodrigo A , Fraga, Mario F. , Nucíforo, Paolo , Young, William F. , Bancos, Irina , Chiara, María‐Dolores , Dahia, Patricia L. M.
Cancer Discovery | April 8, 2025 | Volume: 15 | Issue: 5 | Pages: 1037-1062
Abstract This study explores parallels between systemic hypoxia adaptation in high-altitude populations and tumorigenesis. We identified EPAS1, a gene critical for hypoxia adaptation in populations such as Tibetans and Sherpas, as playing a similar adaptive role in tumors arising under hypoxic conditions. Tumors from patients with chronic hypoxia displayed impaired DNA repair and frequent emergence of EPAS1 variants, with frequencies reaching up to 90%, echoing the positive selection seen in high-altitude dwellers. Mechanistically, EPAS1 gain-of-function mutations promote COX4I2 expression, reducing cellular oxygen consumption and supporting tumor proliferation in hypoxia. Analysis of clinical data from patients with hypoxia revealed tissue-specific and time-sensitive tumorigenic effects, particularly impacting oxygen-sensitive cells in the postnatal period. Our findings suggest that EPAS1-driven adaptation mechanisms in high-altitude populations provide a model for understanding tumor evolution under hypoxic stress, highlighting how genetic adaptations to diverse stressors in natural populations may yield insights into tumorigenesis and cancer progression. Significance: This study reveals a broad convergence in genetic adaptation to hypoxia between natural populations and tumors, suggesting that insights from natural populations could enhance our understanding of cancer biology and identify novel therapeutic targets. See related commentary by Lee, p. 875
Peritoneal metastases from primary appendiceal and colorectal carcinomas demonstrate distinct molecular identities on comprehensive tumor analysis
Fleming, Andrew M. , Deschner, Benjamin W. , Williard, Forrest W., Xiu, Joanne , Somer, Bradley G. , Yakoub, Danny , Tsao, Miriam , Glazer, Evan S. , Dickson, Paxton V. , Shibata, David , Hwang, Jimmy J., Shields, Anthony F. , Lenz, Heinz‐Josef , Deneve, Jeremiah L. , Glazer, Evan S , Dickson, Paxton V , Deneve, Jeremiah L , Reiter, Audra , Drake, Justin A. , Vanderwalde, Ari M. , Philip, Philip A. , Marshall, John L , Korn, Wolfgang Michael
Journal of Surgical Oncology | January 11, 2023 | Volume: 127 | Issue: 5 | Pages: 815-822
AbstractBackground and ObjectivesPublished data comparing peritoneal metastases from appendiceal cancers (pAC) and colorectal cancers (pCRC) remain sparse. We compared pAC and pCRC using comprehensive tumor profiling (CTP).MethodsCTP was performed, including next‐generation sequencing and analysis of copy number variation (CNV), microsatellite instability (MSI) and tumor mutational burden (TMB).ResultsOne hundred thirty‐six pAC and 348 pCRC samples underwent CTP. The cohorts' age and gender were similar. pCRC demonstrated increased pathogenic variants (PATHs) in APC (48% vs. 3%, p < 0.01), ARID1A (12% vs. 2%, p < 0.01), BRAF (12% vs. 2%, p < 0.01), FBXW7 (7% vs. 2%, p < 0.01), KRAS (52% vs. 41%, p < 0.05), PIK3CA (15% vs. 2%, p < 0.01), and TP53 (53% vs. 23%, p < 0.01), and decreased PATHs in GNAS (8% vs. 31%, p < 0.01). There was no difference in CNV, fusion rate, or MSI. Median TMB was higher in pCRC (5.8 vs. 5.0 mutations per megabase, p = 0.0007). Rates of TMB‐high tumors were similar (pAC 2.1% vs. pCRC 9.0%, p = 0.1957). pCRC had significantly more TMB‐high tumors at lower thresholds.ConclusionsDespite a reduced overall TMB, pAC demonstrated mutations distinct from those seen in pCRC. These may serve as discrete biomarkers for future study.