Colorectal carcinoma (CRC) exhibits metastatic organotropism, primarily targeting liver, lung, and rarely the brain. Here, we study chromosomal imbalances (CIs) in cohorts of primary CRCs and metastases. Brain metastases show the highest burden of CIs, including aneuploidies and focal CIs, with enrichment of +12p encoding KRAS. Compared to liver and lung metastases, brain metastases present with increased co-occurrence of KRAS mutation and amplification. CRCs with concurrent KRAS mutation and amplification display significant metabolic reprogramming with upregulation of glycolysis, alongside upregulation of cell cycle pathways, including copy number gains of MDM2 and CDK4. Evolutionary modeling suggests early acquisition of many organotropic CIs enriched in both liver and brain metastases, while brain-enriched CIs preferentially emerge later. Collectively, this study supports a model where cytogenetic events in CRCs favor site-specific metastatic colonization. These site-enriched CI patterns may serve as biomarkers for metastatic potential in precision oncology.

Supplementary Figure S1; Supplementary Table S1.

Supplementary Tables 1-5 from Gene Expression Profiling Reveals a Massive, Aneuploidy-Dependent Transcriptional Deregulation and Distinct Differences between Lymph Node–Negative and Lymph Node–Positive Colon Carcinomas

Supplementary Tables 1-9 from Aneuploidy-Dependent Massive Deregulation of the Cellular Transcriptome and Apparent Divergence of the Wnt/β-catenin Signaling Pathway in Human Rectal Carcinomas

162 Background: TNT, consisting of preoperative chemoradiation (CRT +5-FU) followed by 3 cycles FOLFOX chemotherapy (cCTX) and total mesorectal excison (TME), was performed in rectal cancer patients (stages UICC ≥ II) according to the TransValid-B-phase-I/II-protocol (WHO-UTN-U1111-1132-0235) at a single site. The aim was to evaluate safety, feasibility, and long-term survival. Furthermore, the impact of postsurgical surrogate-parameters was determined. Methods: 62 patients (15 f, 47 m; median age: 62 years) with resectable LARC of the lower (43.5%; < 6 cm from the anal verge) or mid rectal third (56.5%, ≥ 6 - 12 cm) were included. Staging procedures revealed a positive circumferential resection margin (CRM < 2 mm) in 85.5% and clinical stages II to IV in 3.2%, 88.7% and 8.1%, respectively. TNT was performed by radiation (28x 1.8 Gy; total 50.4 Gy), civ infusion of FU (250 mg/m2/d; d1 - d14 and d22 - d35) and OX (50 mg/m2 on d1, d8, d22 and d29). Four weeks later, 3 FOLFOX cycles were applied with OX (80-100 mg/m2), followed by FA (400 mg/m2) and 5-FU (civ, 2400 mg/m2 over 46h, on d1, d15 and d30). Five to six weeks after cCTx, TME was performed with peri-/postoperative control of the specimen (MERCURY-criteria, 7th TNM/UICC-classification). Acute toxicities were recorded according to NCI-CTC-AE criteria (v4.03). Progression-free (PFS), overall (OS) and cancer-specific survival (CSS) were calculated using Kaplan-Meier estimators, logrank tests and multiparametric Cox proportional-hazards models. Results: During CRT (n = 62) and cCTx (n = 60), CTC-AE grades ≥ 3 occurred in 25.8% and 8.5%, respectively. Complete irradiation, concomitant CTx and consolidation FOLFOX-CTx were administered in 98.4%, 95.2% and 83.3%, respectively. After TNT, preoperative re-assessment showed a shift from stages ≥ III to ≤ II in 65% and from positive to negative CRM in 48,3%. 58 patients (93.5%) underwent TME-surgery with R0, negative CRM and optimal quality of the specimen in 94.8%, 91.4%, and 89.7%, respectively. Postoperatively, stages 0 to IV and complete remission (pCR; T0 N0) were diagnosed in 15.5%, 19%, 31%, 24.1%, 10.3% and 17.2%, respectively. Nearly complete remission (nCR; T1-T2 N0 and TRG 2 or TRG 3) occurred in 17.2%. Median follow-up time was 63 months (mo; quartiles: 48-103 months). Mean PFS and CSS were significantly higher for ypUICC stage ≤ II compared to stage ≥ III (111 ± 7.2 mo vs. 67 ± 12.2 mo; p = 0.006 and 130 ± 3.5 mo vs. 94 ± 10.2 mo; p = 0.004). Mean OS was 117 ± 6.4 mo for stages ≤ II vs. 91 ± 10.1 mo for stages ≥ III (p = 0.087). OS and PFS for patients with good (pCR and nCR) vs. poor response were 125 ± 7.0 mo vs. 101.5 ± 7.8 mo (p = 0.043) and 114 ± 9.6 mo vs. 87.9 ± 9.2 mo (p = 0.083). Conclusions: TNT is a safe, highly feasible and well-tolerated regimen with a good response of the primary rectal cancer and locoregional lymph nodes. Good response (pCR, nCR) or stage ≤ II results in higher rates for PFS, OS, and CSS. Clinical trial information: 2011-004228-37 .

Supplementary Figure 1 from Gene Expression Profiling Reveals a Massive, Aneuploidy-Dependent Transcriptional Deregulation and Distinct Differences between Lymph Node–Negative and Lymph Node–Positive Colon Carcinomas

Colorectal carcinomas (CRCs) progress through heterogeneous pathways. The aim of this study was to analyse whether or not the cytogenetic evolution of CRC is linked to tumour site, level of chromosomal imbalance and metastasis.