bims-pimaco 2022-12-25 papers

on PI3K and MAPK signalling in colorectal cancer

Issue of 2022–12–25
twelve papers selected by
Lucas B. Zeiger, CRUK Scotland Institute, Beatson Institute for Cancer Research

Ras-mediated activation of mTORC2 promotes breast epithelial cell migration and invasion.
mTORC1 regulates a lysosome-dependent adaptive shift in intracellular lipid species.
Exploring the state- and allele-specific conformational landscapes of Ras: understanding their respective druggabilities.
Functional analysis of PTEN variants of unknown significance from PHTS patients unveils complex patterns of PTEN biological activity in disease.
Nuclear S6K1 Enhances Oncogenic Wnt Signaling by Inducing Wnt/β-Catenin Transcriptional Complex Formation.
Discovery of RMC-5552, a Selective Bi-Steric Inhibitor of mTORC1, for the Treatment of mTORC1-Activated Tumors.
Adagrasib with or without Cetuximab in Colorectal Cancer with Mutated KRAS G12C.
Long-term Survival Update and Extended RAS Mutational Analysis of the CAIRO2 Trial: Addition of Cetuximab to CAPOX/Bevacizumab in Metastatic Colorectal Cancer.
Ring domains are essential for GATOR2-dependent mTORC1 activation.
Metabolic Rewiring toward Oxidative Phosphorylation Disrupts Intrinsic Resistance to Ferroptosis of the Colon Adenocarcinoma Cells.
mTORC1 takes control of lysosomal lipid breakdown.
Deciphering colorectal cancer genetics through multi-omic analysis of 100,204 cases and 154,587 controls of European and east Asian ancestries.

Mol Biol Cell. 2022 Dec 21. mbcE22060236

Ras-mediated activation of mTORC2 promotes breast epithelial cell migration and invasion.

Shannon E Collins, Mollie E Wiegand, Alyssa N Werner, Isabella N Brown, Mary I Mundo, Douglas J Swango, Ghassan Mouneimne, Pascale G Charest.

We previously identified the mechanistic Target of Rapamycin Complex 2 (mTORC2) as an effector of Ras for the control of directed cell migration in Dictyostelium. Recently, the Ras-mediated regulation of mTORC2 was found to be conserved in mammalian cells, and mTORC2 was shown to be an effector of oncogenic Ras. Interestingly, mTORC2 has been linked to cancer cell migration, and particularly in breast cancer. Here, we investigated the role of Ras in promoting the migration and invasion of breast cancer cells through mTORC2. We observed that both Ras and mTORC2 promote the migration of different breast cancer cells and breast cancer cell models. Using HER2 and oncogenic Ras-transformed breast epithelial MCF10A cells, we found that both wild-type Ras and oncogenic Ras promote mTORC2 activation and an mTORC2-dependent migration and invasion in these breast cancer models. We further observed that, whereas oncogenic Ras-transformed MCF10A cells display uncontrolled cell proliferation and invasion, disruption of mTORC2 leads to loss of invasiveness only. Together, our findings suggest that, whereas the Ras-mediated activation of mTORC2 is expected to play a minor role in breast tumor formation, the Ras-mTORC2 pathway plays an important role in promoting the migration and invasion of breast cancer cells.

DOI: https://doi.org/10.1091/mbc.E22-06-0236
Nat Metab. 2022 Dec;4(12): 1792-1811

mTORC1 regulates a lysosome-dependent adaptive shift in intracellular lipid species.

Aaron M Hosios, Meghan E Wilkinson, Molly C McNamara, Krystle C Kalafut, Margaret E Torrence, John M Asara, Brendan D Manning.

The mechanistic target of rapamycin complex 1 (mTORC1) senses and relays environmental signals from growth factors and nutrients to metabolic networks and adaptive cellular systems to control the synthesis and breakdown of macromolecules; however, beyond inducing de novo lipid synthesis, the role of mTORC1 in controlling cellular lipid content remains poorly understood. Here we show that inhibition of mTORC1 via small molecule inhibitors or nutrient deprivation leads to the accumulation of intracellular triglycerides in both cultured cells and a mouse tumor model. The elevated triglyceride pool following mTORC1 inhibition stems from the lysosome-dependent, but autophagy-independent, hydrolysis of phospholipid fatty acids. The liberated fatty acids are available for either triglyceride synthesis or β-oxidation. Distinct from the established role of mTORC1 activation in promoting de novo lipid synthesis, our data indicate that mTORC1 inhibition triggers membrane phospholipid trafficking to the lysosome for catabolism and an adaptive shift in the use of constituent fatty acids for storage or energy production.

DOI: https://doi.org/10.1038/s42255-022-00706-6
Phys Chem Chem Phys. 2022 Dec 20.

Exploring the state- and allele-specific conformational landscapes of Ras: understanding their respective druggabilities.

Hui Wang, Dan Liu, Yongkui Yu, Mengqi Fang, Xue Gu, Dong Long.

Recent advances in direct inhibition of Ras benefit from the protein's intrinsic dynamic nature that derives therapeutically vulnerable conformers bearing transiently formed cryptic pockets. Hotspot mutants of Ras are major tumor drivers and are hyperactivated in cells at variable levels, which may require allele-specific strategies for effective targeting. However, it remains unclear how the prevalent oncogenic mutations and activation states perturb the free energy landscape governing the protein dynamics and druggability. Here we characterized the nucleotide state- and allele-dependent alterations of Ras conformational dynamics using a combined NMR experimental and computational approach and constructed quantitative ensembles revealing the conservation of the cryptic SI/II-P and SII-P pockets in different states and alleles. Highly local but critical conformational reorganizations that undermine the SII-P accessibility to residue 12 have been identified as a common mechanism resulting in the low reactivities of Ras·GTP as well as Ras(G12D)·GDP with covalent SII-P inhibitors. Our results strongly support the conformational selection scenario for interactions between Ras and the previously reported binders and offer insights for the future development of state- and allele-specific, as well as pan-Ras, inhibitors.

DOI: https://doi.org/10.1039/d2cp04964c
Eur J Hum Genet. 2022 Dec 21.

Functional analysis of PTEN variants of unknown significance from PHTS patients unveils complex patterns of PTEN biological activity in disease.

Leire Torices, Janire Mingo, Isabel Rodríguez-Escudero, Teresa Fernández-Acero, Sandra Luna, Caroline E Nunes-Xavier, José I López, Fátima Mercadillo, María Currás, Miguel Urioste, María Molina, Víctor J Cid, Rafael Pulido.

Heterozygous germline mutations in PTEN gene predispose to hamartomas and tumors in different tissues, as well as to neurodevelopmental disorders, and define at genetic level the PTEN Hamartoma Tumor Syndrome (PHTS). The major physiologic role of PTEN protein is the dephosphorylation of phosphatidylinositol (3,4,5)-trisphosphate (PIP3), counteracting the pro-oncogenic function of phosphatidylinositol 3-kinase (PI3K), and PTEN mutations in PHTS patients frequently abrogate PTEN PIP3 catalytic activity. PTEN also displays non-canonical PIP3-independent functions, but their involvement in PHTS pathogeny is less understood. We have previously identified and described, at clinical and genetic level, novel PTEN variants of unknown functional significance in PHTS patients. Here, we have performed an extensive functional characterization of these PTEN variants (c.77 C > T, p.(Thr26Ile), T26I; c.284 C > G, p.(Pro95Arg), P95R; c.529 T > A, p.(Tyr177Asn), Y177N; c.781 C > G, p.(Gln261Glu), Q261E; c.829 A > G, p.(Thr277Ala), T277A; and c.929 A > G, p.(Asp310Gly), D310G), including cell expression levels and protein stability, PIP3-phosphatase activity, and subcellular localization. In addition, caspase-3 cleavage analysis in cells has been assessed using a C2-domain caspase-3 cleavage-specific anti-PTEN antibody. We have found complex patterns of functional activity on PTEN variants, ranging from loss of PIP3-phosphatase activity, diminished protein expression and stability, and altered nuclear/cytoplasmic localization, to intact functional properties, when compared with PTEN wild type. Furthermore, we have found that PTEN cleavage at the C2-domain by the pro-apoptotic protease caspase-3 is diminished in specific PTEN PHTS variants. Our findings illustrate the multifaceted molecular features of pathogenic PTEN protein variants, which could account for the complexity in the genotype/phenotype manifestations of PHTS patients.

DOI: https://doi.org/10.1038/s41431-022-01265-w
Int J Mol Sci. 2022 Dec 18. pii: 16143. [Epub ahead of print]23(24):

Nuclear S6K1 Enhances Oncogenic Wnt Signaling by Inducing Wnt/β-Catenin Transcriptional Complex Formation.

Min Gyu Lee, Hwamok Oh, Jong Woo Park, Jueng Soo You, Jeung-Whan Han.

  Ribosomal protein S6 kinase 1 (S6K1), a key downstream effector of the mammalian target of rapamycin (mTOR), regulates diverse functions, such as cell proliferation, cell growth, and protein synthesis. Because S6K1 was previously known to be localized in the cytoplasm, its function has been mainly studied in the cytoplasm. However, the nuclear localization and function of S6K1 have recently been elucidated and other nuclear functions are expected to exist but remain elusive. Here, we show a novel nuclear role of S6K1 in regulating the expression of the Wnt target genes. Upon activation of the Wnt signaling, S6K1 translocated from the cytosol into the nucleus and subsequently bound to β-catenin and the cofactors of the Wnt/β-catenin transcriptional complex, leading to the upregulation of the Wnt target genes. The depletion or repression of S6K1 downregulated the Wnt target gene expression by inhibiting the formation of the Wnt/β-catenin transcriptional complex. The S6K1-depleted colon cancer cell lines showed lower transcription levels of the Wnt/β-catenin target genes and a decrease in the cell proliferation and invasion compared to the control cell lines. Taken together, these results indicate that nuclear S6K1 positively regulates the expression of the Wnt target genes by inducing the reciprocal interaction of the subunits of the transcriptional complex.

Keywords:  Wnt signaling; Wnt-transcriptional complex; mTOR; p70 S6K1; β-catenin

DOI:  https://doi.org/10.3390/ijms232416143
J Med Chem. 2022 Dec 19.

Discovery of RMC-5552, a Selective Bi-Steric Inhibitor of mTORC1, for the Treatment of mTORC1-Activated Tumors.

G Leslie Burnett, Yu C Yang, James B Aggen, Jennifer Pitzen, Micah K Gliedt, Chris M Semko, Abby Marquez, James W Evans, Gang Wang, Walter S Won, Aidan C A Tomlinson, Gert Kiss, Christos Tzitzilonis, Arun P Thottumkara, James Cregg, Kevin T Mellem, Jong S Choi, Julie C Lee, Yongyuan Zhao, Bianca J Lee, Justin G Meyerowitz, John E Knox, Jingjing Jiang, Zhican Wang, David Wildes, Zhengping Wang, Mallika Singh, Jacqueline A M Smith, Adrian L Gill.

Hyperactivation of mTOR kinase by mutations in the PI3K/mTOR pathway or by crosstalk with other mutant cancer drivers, such as RAS, is a feature of many tumors. Multiple allosteric inhibitors of mTORC1 and orthosteric dual inhibitors of mTORC1 and mTORC2 have been developed as anticancer drugs, but their clinical utility has been limited. To address these limitations, we have developed a novel class of "bi-steric inhibitors" that interact with both the orthosteric and the allosteric binding sites in order to deepen the inhibition of mTORC1 while also preserving selectivity for mTORC1 over mTORC2. In this report, we describe the discovery and preclinical profile of the development candidate RMC-5552 and the in vivo preclinical tool compound RMC-6272. We also present evidence that selective inhibition of mTORC1 in combination with covalent inhibition of KRASG12C shows increased antitumor activity in a preclinical model of KRASG12C mutant NSCLC that exhibits resistance to KRASG12C inhibitor monotherapy.

DOI: https://doi.org/10.1021/acs.jmedchem.2c01658
N Engl J Med. 2022 Dec 21.

Adagrasib with or without Cetuximab in Colorectal Cancer with Mutated KRAS G12C.

Rona Yaeger, Jared Weiss, Meredith S Pelster, Alexander I Spira, Minal Barve, Sai-Hong I Ou, Ticiana A Leal, Tanios S Bekaii-Saab, Cloud P Paweletz, Grace A Heavey, James G Christensen, Karen Velastegui, Thian Kheoh, Hirak Der-Torossian, Samuel J Klempner.

BACKGROUND: Adagrasib, an oral small-molecule inhibitor of mutant KRAS G12C protein, has shown clinical activity in pretreated patients with several tumor types, including colorectal cancer. Preclinical studies suggest that combining a KRAS G12C inhibitor with an epidermal growth factor receptor antibody could be an effective clinical strategy.
METHODS: In this phase 1-2, open-label, nonrandomized clinical trial, we assigned heavily pretreated patients with metastatic colorectal cancer with mutant KRAS G12C to receive adagrasib monotherapy (600 mg orally twice daily) or adagrasib (at the same dose) in combination with intravenous cetuximab once a week (with an initial loading dose of 400 mg per square meter of body-surface area, followed by a dose of 250 mg per square meter) or every 2 weeks (with a dose of 500 mg per square meter). The primary end points were objective response (complete or partial response) and safety.
RESULTS: As of June 16, 2022, a total of 44 patients had received adagrasib, and 32 had received combination therapy with adagrasib and cetuximab, with a median follow-up of 20.1 months and 17.5 months, respectively. In the monotherapy group (43 evaluable patients), a response was reported in 19% of the patients (95% confidence interval [CI], 8 to 33). The median response duration was 4.3 months (95% CI, 2.3 to 8.3), and the median progression-free survival was 5.6 months (95% CI, 4.1 to 8.3). In the combination-therapy group (28 evaluable patients), the response was 46% (95% CI, 28 to 66). The median response duration was 7.6 months (95% CI, 5.7 to not estimable), and the median progression-free survival was 6.9 months (95% CI, 5.4 to 8.1). The percentage of grade 3 or 4 treatment-related adverse events was 34% in the monotherapy group and 16% in the combination-therapy group. No grade 5 adverse events were observed.
CONCLUSIONS: Adagrasib had antitumor activity in heavily pretreated patients with metastatic colorectal cancer with mutant KRAS G12C, both as oral monotherapy and in combination with cetuximab. The median response duration was more than 6 months in the combination-therapy group. Reversible adverse events were common in the two groups. (Funded by Mirati Therapeutics; KRYSTAL-1 ClinicalTrials.gov number, NCT03785249.).

DOI: https://doi.org/10.1056/NEJMoa2212419
Clin Colorectal Cancer. 2022 Dec 05. pii: S1533-0028(22)00132-3. [Epub ahead of print]

Long-term Survival Update and Extended RAS Mutational Analysis of the CAIRO2 Trial: Addition of Cetuximab to CAPOX/Bevacizumab in Metastatic Colorectal Cancer.

Sanne Ten Hoorn, Linda Mol, Dirkje W Sommeijer, Lisanne Nijman, Tom van den Bosch, Tim R de Back, Bauke Ylstra, Erik van Dijk, Carel J M van Noesel, Roy J Reinten, Iris D Nagtegaal, Miriam Koopman, Cornelis J A Punt, Louis Vermeulen.

   BACKGROUND: Here we present updated survival of the CAIRO2 trial and assessed whether the addition of anti-EGFR to anti-VEGF therapy could still be an effective treatment option for patients with extended RAS/BRAF wildtype and left-sided metastatic colorectal cancer (mCRC).
MATERIALS AND METHODS: Retrospective updated survival and extended RAS and BRAF V600E mutational analysis were performed in the CAIRO2 trial, a multicenter, randomized phase III trial on the effect of adding cetuximab to a combination of capecitabine, oxaliplatin (CAPOX), and bevacizumab in mCRC.
RESULTS: Updated survival analysis confirmed that the addition of cetuximab did not provide a benefit on either progression free (PFS) or overall survival (OS) in the intention-to-treat population. With the extended mutational analyses 31 KRAS, 31 NRAS and 12 BRAF V600E additional mutations were found. No benefit of the addition of cetuximab was observed within the extended wildtype group, even when selecting only left-sided tumors (PFS HR 0.96, p = 0.7775). However, compared to the original trial an increase of 6.5 months was seen for patients with both extended wildtype and left-sided tumors (median OS 28.6 months).
CONCLUSION: Adding cetuximab to CAPOX and bevacizumab does not provide clinical benefit in patients with mCRC, even in the extended wildtype group with left-sided tumors. However, in the extended wildtype group we did observe clinically relevant higher survival compared to the initial trial report, indicating that it is important to analyze a broader panel of RAS and BRAF variants using more recent sequencing techniques when assessing survival benefit after anti-EGFR therapy.

Keywords:  Gastrointestinal cancer, Adjuvant chemotherapy, Anti-EGFR, Anti-VEGF; Molecular subtypes

DOI:  https://doi.org/10.1016/j.clcc.2022.11.006
Mol Cell. 2022 Dec 08. pii: S1097-2765(22)01134-0. [Epub ahead of print]

Ring domains are essential for GATOR2-dependent mTORC1 activation.

Cong Jiang, Xiaoming Dai, Shaohui He, Hongfei Zhou, Lan Fang, Jianping Guo, Songlei Liu, Tao Zhang, Weijuan Pan, Haihong Yu, Tianmin Fu, Dali Li, Hiroyuki Inuzuka, Ping Wang, Jianru Xiao, Wenyi Wei.

  The GATOR2-GATOR1 signaling axis is essential for amino-acid-dependent mTORC1 activation. However, the molecular function of the GATOR2 complex remains unknown. Here, we report that disruption of the Ring domains of Mios, WDR24, or WDR59 completely impedes amino-acid-mediated mTORC1 activation. Mechanistically, via interacting with Ring domains of WDR59 and WDR24, the Ring domain of Mios acts as a hub to maintain GATOR2 integrity, disruption of which leads to self-ubiquitination of WDR24. Physiologically, leucine stimulation dissociates Sestrin2 from the Ring domain of WDR24 and confers its availability to UBE2D3 and subsequent ubiquitination of NPRL2, contributing to GATOR2-mediated GATOR1 inactivation. As such, WDR24 ablation or Ring deletion prevents mTORC1 activation, leading to severe growth defects and embryonic lethality at E10.5 in mice. Hence, our findings demonstrate that Ring domains are essential for GATOR2 to transmit amino acid availability to mTORC1 and further reveal the essentiality of nutrient sensing during embryonic development.

Keywords:  Gator1; Gator2; NPRL2; Sestrin; WDR24; amino acid sensing; mTOR; ubiquitination

DOI:  https://doi.org/10.1016/j.molcel.2022.11.021
Antioxidants (Basel). 2022 Dec 06. pii: 2412. [Epub ahead of print]11(12):

Metabolic Rewiring toward Oxidative Phosphorylation Disrupts Intrinsic Resistance to Ferroptosis of the Colon Adenocarcinoma Cells.

Célia Gotorbe, Jérôme Durivault, Willian Meira, Shamir Cassim, Maša Ždralević, Jacques Pouysségur, Milica Vučetić.

  Glutathione peroxidase 4 (GPX4) has been reported as one of the major targets for ferroptosis induction, due to its pivotal role in lipid hydroperoxide removal. However, recent studies pointed toward alternative antioxidant systems in this context, such as the Coenzyme Q-FSP1 pathway. To investigate how effective these alternative pathways are in different cellular contexts, we used human colon adenocarcinoma (CRC) cells, highly resistant to GPX4 inhibition. Data obtained in the study showed that simultaneous pharmacological inhibition of GPX4 and FSP1 strongly compromised the survival of the CRC cells, which was prevented by the ferroptosis inhibitor, ferrostatin-1. Nonetheless, this could not be phenocopied by genetic deletion of FSP1, suggesting the development of resistance to ferroptosis in FSP1-KO CRC cells. Considering that CRC cells are highly glycolytic, we used CRC Warburg-incompetent cells, to investigate the role metabolism plays in this phenomenon. Indeed, the sensitivity to inhibition of both anti-ferroptotic axes (GPx4 and FSP1) was fully revealed in these cells, showing typical features of ferroptosis. Collectively, data indicate that two independent anti-ferroptotic pathways (GPX4-GSH and CoQ10-FSP1) operate within the overall physiological context of cancer cells and in some instances, their inhibition should be coupled with other metabolic modulators, such as inhibitors of glycolysis/Warburg effect.

Keywords:  OXPHOS; Warburg effect; colorectal adenocarcinoma; ferroptosis; ferroptosis suppressor protein 1; glutathione peroxidase 4

DOI:  https://doi.org/10.3390/antiox11122412
Nat Metab. 2022 Dec;4(12): 1620-1622

mTORC1 takes control of lysosomal lipid breakdown.

Laura Tribouillard, Mathieu Laplante.

DOI: https://doi.org/10.1038/s42255-022-00702-w
Nat Genet. 2022 Dec 20.

Deciphering colorectal cancer genetics through multi-omic analysis of 100,204 cases and 154,587 controls of European and east Asian ancestries.

Ceres Fernandez-Rozadilla, Maria Timofeeva, Zhishan Chen, Philip Law, Minta Thomas, Stephanie Schmit, Virginia Díez-Obrero, Li Hsu, Juan Fernandez-Tajes, Claire Palles, Kitty Sherwood, Sarah Briggs, Victoria Svinti, Kevin Donnelly, Susan Farrington, James Blackmur, Peter Vaughan-Shaw, Xiao-Ou Shu, Jirong Long, Qiuyin Cai, Xingyi Guo, Yingchang Lu, Peter Broderick, James Studd, Jeroen Huyghe, Tabitha Harrison, David Conti, Christopher Dampier, Mathew Devall, Fredrick Schumacher, Marilena Melas, Gad Rennert, Mireia Obón-Santacana, Vicente Martín-Sánchez, Ferran Moratalla-Navarro, Jae Hwan Oh, Jeongseon Kim, Sun Ha Jee, Keum Ji Jung, Sun-Seog Kweon, Min-Ho Shin, Aesun Shin, Yoon-Ok Ahn, Dong-Hyun Kim, Isao Oze, Wanqing Wen, Keitaro Matsuo, Koichi Matsuda, Chizu Tanikawa, Zefang Ren, Yu-Tang Gao, Wei-Hua Jia, John Hopper, Mark Jenkins, Aung Ko Win, Rish Pai, Jane Figueiredo, Robert Haile, Steven Gallinger, Michael Woods, Polly Newcomb, David Duggan, Jeremy Cheadle, Richard Kaplan, Timothy Maughan, Rachel Kerr, David Kerr, Iva Kirac, Jan Böhm, Lukka-Pekka Mecklin, Pekka Jousilahti, Paul Knekt, Lauri Aaltonen, Harri Rissanen, Eero Pukkala, Johan Eriksson, Tatiana Cajuso, Ulrika Hänninen, Johanna Kondelin, Kimmo Palin, Tomas Tanskanen, Laura Renkonen-Sinisalo, Brent Zanke, Satu Männistö, Demetrius Albanes, Stephanie Weinstein, Edward Ruiz-Narvaez, Julie Palmer, Daniel Buchanan, Elizabeth Platz, Kala Visvanathan, Cornelia Ulrich, Erin Siegel, Stefanie Brezina, Andrea Gsur, Peter Campbell, Jenny Chang-Claude, Michael Hoffmeister, Hermann Brenner, Martha Slattery, John Potter, Konstantinos Tsilidis, Matthias Schulze, Marc Gunter, Neil Murphy, Antoni Castells, Sergi Castellví-Bel, Leticia Moreira, Volker Arndt, Anna Shcherbina, Mariana Stern, Bens Pardamean, Timothy Bishop, Graham Giles, Melissa Southey, Gregory Idos, Kevin McDonnell, Zomoroda Abu-Ful, Joel Greenson, Katerina Shulman, Flavio Lejbkowicz, Kenneth Offit, Yu-Ru Su, Robert Steinfelder, Temitope Keku, Bethany van Guelpen, Thomas Hudson, Heather Hampel, Rachel Pearlman, Sonja Berndt, Richard Hayes, Marie Elena Martinez, Sushma Thomas, Douglas Corley, Paul Pharoah, Susanna Larsson, Yun Yen, Heinz-Josef Lenz, Emily White, Li Li, Kimberly Doheny, Elizabeth Pugh, Tameka Shelford, Andrew Chan, Marcia Cruz-Correa, Annika Lindblom, David Hunter, Amit Joshi, Clemens Schafmayer, Peter Scacheri, Anshul Kundaje, Deborah Nickerson, Robert Schoen, Jochen Hampe, Zsofia Stadler, Pavel Vodicka, Ludmila Vodickova, Veronika Vymetalkova, Nickolas Papadopoulos, Chistopher Edlund, William Gauderman, Duncan Thomas, David Shibata, Amanda Toland, Sanford Markowitz, Andre Kim, Stephen Chanock, Franzel van Duijnhoven, Edith Feskens, Lori Sakoda, Manuela Gago-Dominguez, Alicja Wolk, Alessio Naccarati, Barbara Pardini, Liesel FitzGerald, Soo Chin Lee, Shuji Ogino, Stephanie Bien, Charles Kooperberg, Christopher Li, Yi Lin, Ross Prentice, Conghui Qu, Stéphane Bézieau, Catherine Tangen, Elaine Mardis, Taiki Yamaji, Norie Sawada, Motoki Iwasaki, Christopher Haiman, Loic Le Marchand, Anna Wu, Chenxu Qu, Caroline McNeil, Gerhard Coetzee, Caroline Hayward, Ian Deary, Sarah Harris, Evropi Theodoratou, Stuart Reid, Marion Walker, Li Yin Ooi, Victor Moreno, Graham Casey, Stephen Gruber, Ian Tomlinson, Wei Zheng, Malcolm Dunlop, Richard Houlston, Ulrike Peters.

Colorectal cancer (CRC) is a leading cause of mortality worldwide. We conducted a genome-wide association study meta-analysis of 100,204 CRC cases and 154,587 controls of European and east Asian ancestry, identifying 205 independent risk associations, of which 50 were unreported. We performed integrative genomic, transcriptomic and methylomic analyses across large bowel mucosa and other tissues. Transcriptome- and methylome-wide association studies revealed an additional 53 risk associations. We identified 155 high-confidence effector genes functionally linked to CRC risk, many of which had no previously established role in CRC. These have multiple different functions and specifically indicate that variation in normal colorectal homeostasis, proliferation, cell adhesion, migration, immunity and microbial interactions determines CRC risk. Crosstissue analyses indicated that over a third of effector genes most probably act outside the colonic mucosa. Our findings provide insights into colorectal oncogenesis and highlight potential targets across tissues for new CRC treatment and chemoprevention strategies.

DOI: https://doi.org/10.1038/s41588-022-01222-9