Primary Colorectal Cancer Research Articles

Analysis of clinicopathological features and prognosis of sporadic synchronous multiple primary colorectal cancers

Analysis of clinicopathological features and prognosis of sporadic synchronous multiple primary colorectal cancers

Prolonged preoperative sedentary time is a risk factor for postoperative ileus in patients with colorectal cancer: a propensity score-matched retrospective study.

This study aimed to investigate the association between prolonged preoperative sedentary time (ST) and postoperative ileus (POI) after adjusting for confounders in patients with colorectal cancer (CRC). This single-center retrospective study enrolled 155 consecutive patients who underwent surgery for primary CRC. A diagnosis of POI was made by the surgeons if the Clavien-Dindo classification (CD) grade is ≥ 2 within 30days after surgery. Preoperative ST was assessed using the International Physical Activity Questionnaire usual week short version (Japanese version). Patients were classified into two groups (ST < 6h/day and ST ≥ 6h/day) based on results from the questionnaire, and data were analyzed using a propensity score-matching strategy to adjust for confounders. In addition, receiver operating characteristic (ROC) curve analysis was performed to identify the optimal cutoff value of preoperative ST for predicting POI. Of the 155 patients, 134 were included in the analysis. POI occurred in 16 (11.9%) patients of overall patients and 11 (12.5%) of the 88 matched patients. The logistic regression analysis after propensity score-matching showed that prolonged preoperative ST (ST ≥ 6h/day) was associated with POI (odds ratio 5.40 (95% confidence interval: 1.09 - 26.60), p = 0.038). The ROC curve analysis indicated that the optimal cutoff value of preoperative ST for predicting POI was 6h/day. Prolonged preoperative ST is a risk factor for POI in patients with CRC. Therefore, reducing preoperative ST may play an important role in preventing POI.

Multilevel Heterogeneity of Colorectal Cancer Liver Metastasis.

Colorectal cancer liver metastasis (CRLM) is a highly heterogeneous disease. Therapies that target both primary foci and liver metastasis are severely lacking. Therefore, understanding the features of metastatic tumor cells in the liver is valuable for the overall control of CRLM patients. In this review, we summarize the heterogeneity exhibited in CRLM from five aspects (gene, transcriptome, protein, metabolism, and immunity). In addition to genetic heterogeneity, the other four aspects exhibit significant heterogeneity. Compared to primary CRC, the dysregulation of epithelial-mesenchymal transition (EMT)-related proteins, the enhanced metabolic activity, and the increased infiltration of immunosuppressive cells are detected in CRLM. Preclinical evidence shows that targeting the EMT process or enhancing cellular metabolism may represent a novel approach to increasing the therapeutic efficacy of CRLM.

Association of radiotherapy for prostate cancer and second primary colorectal cancer: a US population-based analysis.

Radiotherapy (RT) is a common treatment for prostate cancer, yet the risk of second primary colorectal cancer (SPCRC) in patients with prostate cancer undergoing RT has not been adequately studied. This study employed a population-based cohort design using the US Surveillance, Epidemiology, and End Results (SEER) database to identify individuals diagnosed between January 1975 and December 2015. The cumulative incidence of SPCRC was estimated using Fine-Gray competing risk regression. Poisson regression analysis was used to estimate the risk associated with RT. Survival outcomes of patients with SPCRC were evaluated using the Kaplan-Meier method. A total of 287,607 patients diagnosed with prostate cancer were identified. The cumulative incidences were higher in patients who did not receive RT (2.00%) compared to those who underwent RT (2.47%) after 25years. After adjustment for multiple variables, RT was associated with an increased risk of developing combined SPCRC (adjusted HR 1.590). Additionally, the overall survival was significantly lower in patients who developed colorectal cancer after receiving RT as compared to those who did not receive RT. These findings underscore the need for diligent long-term monitoring and effective management strategies to detect SPCRC in patients treated with RT for prostate cancer.

Downregulation of osteoprotegerin in colorectal cancer cells promotes liver metastasis via activating tumor-associated macrophage

Osteoprotegerin (OPG) is a secreted cytokine that functions as a decoy receptor for receptor activator of nuclear factor kappa-B (RANK) ligand (RANKL). Anti-RANKL treatment for bone metastasis has been widely accepted for solid tumors. However, the mechanism of OPG-RANKL-RANK signaling in systemic colorectal cancer (CRC) metastasis remains unclear. In this study, we investigated the relevance and function of OPG expression in CRC liver metastasis. First, we performed in silico analysis using The Cancer Genome Atlas public database and found that lower OPG expression in CRC was associated with poor overall survival. Immunohistochemistry analyses using resected specimen from patients with CRC in our institute confirmed the result. Patient-matched primary CRC and liver metastases showed a significant downregulation of OPG expression in metastatic lesions. In CRC cell lines, OPG expression did not suppress cell proliferation and migration. However, OPG expression inhibited macrophage migration by suppressing the RANKL-RANK pathway. Moreover, in vivo mouse liver metastasis models showed that OPG expression in CRC cells suppressed liver metastases. In addition, treatment with an anti-RANKL neutralizing antibody also suppressed liver metastases. These results showed that downregulation of OPG expression in CRC cells promotes liver metastasis by activating tumor-associated macrophage, which can become a candidate for targeted therapy with anti-RANKL neutralizing antibody for CRC liver metastasis.

Plasma Assay of Cell-Free Methylated DNA Markers of Colorectal Cancer: A Tumor-Agnostic Approach to Monitor Recurrence and Response to Anticancer Therapies.

Radiographic surveillance of colorectal cancer (CRC) after curative-intent therapy is costly and unreliable. Methylated DNA markers (MDMs) detected primary CRC and metastatic recurrence with high sensitivity and specificity in cross-sectional studies. This study evaluated using serial MDMs to detect recurrence and monitor the treatment response to anti-cancer therapies. A nested case-control study was drawn from a prospective cohort of patients with CRC who completed curative-intent therapy for CRC of all stages. Plasma MDMs were assayed vis target enrichment long-probe quantitative-amplified signal assays, normalized to B3GALT6, and analyzed in combination with serum carcinoembryonic antigen to yield an MDM score. Clinical information, including treatment and radiographic measurements of the tumor burden, were longitudinally collected. Of the 35 patients, 18 had recurrence and 17 had no evidence of disease during the study period. The MDM score was positive in 16 out of 18 patients who recurred and only 2 of the 17 patients without recurrence. The MDM score detected recurrence in 12 patients preceding clinical or radiographic detection of recurrent CRC by a median of 106 days (range 90-232 days). Plasma MDMs can detect recurrent CRC prior to radiographic detection; this tumor-agnostic liquid biopsy approach may assist cancer surveillance and monitoring.

GIPC1 regulates MACC1-driven metastasis.

Identification of cancer metastasis-relevant molecular networks is desired to provide the basis for understanding and developing intervention strategies. Here we address the role of GIPC1 in the process of MACC1-driven metastasis. MACC1 is a prognostic indicator for patient metastasis formation and metastasis-free survival. MACC1 controls gene transcription, promotes motility, invasion and proliferation of colon cancer cells in vitro, and causes tumor growth and metastasis in mice. By using yeast-two-hybrid assay, mass spectrometry, co-immunoprecipitation and peptide array we analyzed GIPC1 protein binding partners, by using the MACC1 gene promoter and chromatin immunoprecipitation and electrophoretic mobility shift assay we probed for GIPC1 as transcription factor. We employed GIPC1/MACC1-manipulated cell lines for in vitro and in vivo analyses, and we probed the GIPC1/MACC1 impact using human primary colorectal cancer (CRC) tissue. We identified MACC1 and its paralogue SH3BP4 as protein binding partners of the protein GIPC1, and we also demonstrated the binding of GIPC1 as transcription factor to the MACC1 promoter (TSS to -60 bp). GIPC1 knockdown reduced endogenous, but not CMV promoter-driven MACC1 expression, and diminished MACC1-induced cell migration and invasion. GIPC1 suppression reduced tumor growth and metastasis in mice intrasplenically transplanted with MACC1-overexpressing CRC cells. In human primary CRC specimens, GIPC1 correlates with MACC1 expression and is of prognostic value for metastasis formation and metastasis-free survival. Combination of MACC1 and GIPC1 expression improved patient survival prognosis, whereas SH3BP4 expression did not show any prognostic value. We identified an important, dual function of GIPC1 - as protein interaction partner and as transcription factor of MACC1 - for tumor progression and cancer metastasis.

Correlation between second and first primary cancer: systematic review and meta-analysis of 9 million cancer patients.

Many survivors of a first primary cancer (FPCs) are at risk of developing a second primary cancer (SPC), with effects on patient prognosis. Primary cancers have different frequencies of specific SPC development and the development of SPCs may be closely related to the FPC. The aim of this study was to explore possible correlations between SPCs and FPCs. Relevant literature on SPCs was retrospectively searched and screened from four databases, namely, PubMed, EMBASE, Web of Science, and PMC. Data on the number of patients with SPC in 28 different organ sites were also collected from The Surveillance, Epidemiology, and End Results (SEER) 8 Registry and NHANES database. A total of 9 617 643 patients with an FPC and 677 430 patients with an SPC were included in the meta-analysis. Patients with a first primary gynaecological cancer and thyroid cancer frequently developed a second primary breast cancer and colorectal cancer. Moreover, those with a first primary head and neck cancer, anal cancer and oesophageal cancer developed a second primary lung cancer more frequently. A second primary lung cancer and prostate cancer was also common among patients with first primary bladder cancer and penile cancer. Patients with second primary bladder cancer accounted for 56% of first primary ureteral cancer patients with SPCs. This study recommends close clinical follow-up, monitoring and appropriate interventions in patients with relevant FPCs for better screening and early diagnosis of SPCs.

Changing patterns and surgical outcomes of small bowel obstruction in the era of minimally invasive surgery for colorectal cancer.

This study aimed to investigate whether the incidence, patterns, and surgical outcomes of small bowel obstruction (SBO) have changed in the era of minimally invasive surgery (MIS) for primary colorectal cancer (CRC). Consecutive patients who underwent laparotomy for SBO were divided into MIS and traditional open surgery (TOS) groups based on the previous colorectal cancer operation technique used. The MIS group was selected from 1544 consecutive patients who underwent MIS as a treatment for primary CRCs between 2014 and 2022, while the TOS group was selected from 1604 consecutive patients who underwent TOS as a treatment for primary CRCs between 2004 and 2013. The demographics, clinicopathological features, and surgical outcomes were compared between the two groups. The SBO incidence in patients who underwent MIS for primary CRC was significantly lower than that in patients who underwent TOS (4.4%, n =68/1544 vs. 9.7%, n =156/1604, P <0.0001). Compared with the TOS group, the MIS group had significantly different ( P <0.0001) SBO patterns: adhesion (48.5 vs. 91.7%), internal herniation (23.5 vs. 2.6%), external herniation (11.8 vs. 1.9%), twisted bowel limbs (4.4 vs. 0.6%), ileal volvulus with pelvic floor adhesion (5.9 vs. 1.9%), and nonspecific external compression (5.9 vs. 1.3%). A subset analysis of patients with adhesive SBO (ASBO) showed that the MIS group tended to ( P <0.0001) have bands or simple adhesions (75.8%), whereas the TOS group predominantly had matted-type adhesions (59.4%). Furthermore, SBO in the MIS group had an acute (<3 months) or early (3-12 months) onset (64.7%), while that in the TOS group ( P <0.0001) had an intermediate or a late onset. When the surgical outcomes of SBO were evaluated, the TOS group had significantly more ( P <0.0001) blood loss and longer operation time; however, no significant difference was observed in the surgical morbidity/mortality (Clavien-Dindo classification ≧3, 11.8 vs. 14.1%, P =0.6367), hospitalization, and readmission rates between the two groups. Postoperative follow-up showed that the estimated 3-year (11.37 vs. 18.8%) and 6-year (25.54 vs. 67.4%) recurrence rates of SBO were significantly lower ( P =0.016) in the MIS group than in the TOS group. The wide adoption of MIS to treat primary CRC has led to a lower incidence, altered patterns, and reduced recurrence rates of SBO. Awareness of this new trend will help develop surgical techniques to prevent incomplete restoration of anatomical defects and bowel malalignments specifically associated with MIS for CRC, as well as facilitate timely and appropriate management of SBO complications whenever they occur.

A prospective, single-centre, randomized, double-blind controlled study protocol to study whether long-term oral metronidazole can effectively reduce the incidence of postoperative liver metastasis in patients with colorectal cancer

IntroductionFifteen to 25% of patients with colorectal cancer have combined liver metastases at the time of diagnosis, whereas an additional 15 to 25% will develop liver metastases after curative resection of primary colorectal cancer, with the vast majority (80–90%) of liver metastases unresponsive to curative resection at first. Colorectal cancer liver metastasis is also the leading cause of death in patients with colorectal cancer. In recent years, several studies have demonstrated that intestinal flora, especially Fusobacterium nucleatum, plays a crucial role in the development of colorectal cancer liver metastasis, so we hypothesized that long-term metronidazole use could effectively reduce the incidence of postoperative liver metastasis in colorectal cancer patients.Methods/designThis study is a prospective, single-centre, randomized, double-blind controlled study in which 300 patients will be randomly assigned to the test group or the control group in a 1:1 allocation ratio. The aim of this trial is to demonstrate that long-term oral antibiotics can effectively reduce the incidence of postoperative liver metastasis in patients with colorectal cancer.Ethics and disseminationEthics approval was obtained from the Ethics Committee at the Chinese Ethics Committee of Registering Clinical Trials (ChiECRCT20210229). The results of this study will be disseminated at several research conferences and as published articles in peer-reviewed journals.Trial registrationChinese Clinical Trial Registry ChiCTR2100046201. Registered on July 05, 2021.

Stromal localization of inactive CD8+ T cells in metastatic mismatch repair deficient colorectal cancer.

The determinants of metastasis in mismatch repair deficiency with high levels of microsatellite instability (MSI-H) in colorectal cancer (CRC) are poorly understood. Here, we hypothesized that distinct immune and stromal microenvironments in primary tumors may discriminate between non-metastatic MSI-H CRC and metastatic MSI-H CRC. We profiled 46,727 single cells using high-plex imaging mass cytometry and analyzed both differential cell type abundance, and spatial distribution of fibroblasts and immune cells in primary CRC tumors with or without metastatic capacity. We validated our findings in a second independent cohort using immunohistochemistry. High-plex imaging mass cytometry and hierarchical clustering based on microenvironmental markers separated primary MSI-H CRC tumors with and without metastatic capacity. Primary tumors with metastatic capacity displayed a high stromal content and low influx of CD8+ T cells, which expressed significantly lower levels of markers reflecting proliferation (Ki67) and antigen-experience (CD45RO) compared to CD8+ T cells in non-metastatic tumors. CD8+ T cells showed intra-epithelial localization in non-metastatic tumors, but stromal localization in metastatic tumors, which was validated in a second cohort. We conclude that localization of phenotypically distinct CD8+ T cells within stroma may predict metastasis formation in MSI-H CRC.

Abstract B039: T cell recruitment dynamics at different stages of primary and metastatic colorectal cancer

Abstract Colorectal cancer (CRC) is the fourth deadliest cancer worldwide, primarily due to metastasis. The current standard therapy for patients with CRC includes neoadjuvant therapies combined with surgery, often resulting in severe complications that affect patients’ lifestyles. Hence, there is a critical need to improve our understanding of the tumor microenvironment to improve the current therapeutics for metastatic CRC. We characterized T cell dynamics in response to tumors at early (1-2 weeks) versus late stages (6-7 weeks) of CRC development in different colon compartments (tumor, epithelium, lamina propria), as well as in colon-draining lymph nodes and the liver as potential metastasis sites. To achieve this, we injected by colonoscopy tumor AKP mouse organoids (mutations in APC, Kras, and P53 genes) or metastatic AKP mouse organoids in the colon walls of a novel fate-mapping strain (iSell-tomato). This model allows for the labelling of peripheral T cells that are recruited to the tissue or tumor sites. Our initial data showed an enhanced recruitment of CD4 and CD8ab T cells to the colon epithelium in early stage AKP (non-metastatic) tumor models compared to late-stage AKP and metastatic-AKP models at both stages. These recruited cells exhibited an enhanced anti-tumorigenic profile characterized by the production of IFNg and reduced frequency of FoxP3+ CD4 regulatory T cells (Tregs). In contrast, T cells recruited to early stage metastatic-AKP tumors and late-stage tumors of the colon and liver exhibited enhanced exhaustion characterized by an increased frequency of PD1+ CD4 and CD8ab T cells. These data suggest a time- and aggressiveness-dependent effect of tumors on immune cell infiltrates that, in turn, affect tumor progression and metastasis. Citation Format: Marwa A Saad, Angelina Bilate, Daniel Mucida. T cell recruitment dynamics at different stages of primary and metastatic colorectal cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2023 Oct 1-4; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Immunol Res 2023;11(12 Suppl):Abstract nr B039.

Allogeneic NK cells induce monocyte-to-dendritic cell conversion, control tumor growth, and trigger a pro-inflammatory shift in patient-derived cultures of primary and metastatic colorectal cancer

IntroductionNatural killer (NK) cells are innate lymphocytes with a key role in the defense against tumors. Recently, allogeneic NK cell-based therapies have gained interest because of their ability to directly...

Trends and age, sex, and race disparities in time to second primary cancer from 1990 to 2019.

Despite the growth in primary cancer (PC) survivors, the trends and disparities in this population have yet to be comprehensively examined using competing risk analysis. The objective is to examine trends in time to second primary cancer (SPC) and to characterize age, sex, and racial disparities in time-to-SPC. A retrospective analysis was conducted based on Surveillance, Epidemiology, and End Results (SEER). Two datasets for this study are (1) the discovery dataset with patients from SEER-8 (1990-2019) and (2) the validation dataset with patients from SEER-17 (2000-2019), excluding those in the discovery dataset. Patients were survivors of lung, colorectal, breast (female only), and prostate PCs. The 5-year SPC cumulative incidences of lung PC increased from 1990 to 2019, with the cumulative incidence ratio being 1.73 (95% confidence intervals [CI], 1.64-1.82; p < 0.001). Age disparities among all PCs remained from 2010 to 2019, and the adjusted HRs (aHRs) of all PCs were above 1.43 when those below 65 were compared with those 65 and above. Sex disparity exists among colorectal and lung PC survivors. Racial disparities existed among non-Hispanic (NH) Black breast PC survivors (aHR: 1.11; 95% CI: 1.07-1.17; p < 0.001). The types of SPC vary according to PC and sex. Over the past three decades, there has been a noticeably shortened time-to-SPC among lung PC survivors. This is likely attributed to the reduced number of lung cancer deaths due to advancements in effective treatments. However, disparities in age, sex, and race still exist, indicating that further effort is needed to close the gap.

Abstract C001: Retrospective analysis of TROP2 expression in colorectal cancer (CRC) primary tumors and liver metastases (LM) and its correlation with clinical factors

Abstract Background: Trophoblast cell surface antigen 2 (TROP2) is a transmembrane glycoprotein which is upregulated in CRC, is associated with tumorigenesis, and may serve as a drug target. We aimed to measure TROP2 expression by immunohistochemistry in CRC LM and primary tumors, and to determine how TROP2 expression correlates with prognosis and baseline clinical factors. Methods: TROP2 immunohistochemistry was retrospectively performed by a pathologist (ab214488; Abcam, Cambridge, UK) in paraffin-embedded CRC LM and primary tumor specimens (biopsy or resection, stored at the University of Colorado Surgical Pathology Archive) from adult patients between January 2006 and June 2022. Baseline clinical and survival data was collected. Differences in TROP2 frequency (range: 0-4), intensity (range: 0-3), and frequency x intensity combined scores (range: 0-12) for paired CRC primary and LM specimens were analyzed using a paired t-test. Additional statistical analyses included nonparametric Spearman’s correlation test (correlation of scores between LM and primary tumor), Mann Whitney U test (effect of prior systemic cancer treatment on TROP2 expression), Kaplan-Meier method (survival rates based on TROP2 expression), and log-rank test (differences in survival). Results: TROP2 was expressed in 100% (60/60) of CRC primary and 93% (52/56) of LM specimens, including 50 CRC primary-LM pairs and additional unpaired specimens (10 primary and 6 LM). Among all specimens, primary and LM specimens both had a median intensity score of 2, whereas CRC specimens had a slightly higher frequency score than LM specimens (2 vs. 1, respectively). In paired samples, the TROP2 frequency, intensity, and combined score distribution varied slightly between primary and LM specimens. The median intensity was higher in primary vs LM specimens (3 vs 2, respectively), mean difference was 0.26 (p=0.08), and correlation was weak (Spearman r=0.29, p=0.04). Similarly, the median frequency was higher in primary vs LM specimens (2 vs 1, respectively), mean difference was 0.20 (p=0.21), with moderate correlation (Spearman r=0.55, p&amp;lt;0.0001). The median combined score was higher in primary vs LM specimens (4 vs 3, respectively), mean difference was 0.98 (p=0.04), with moderate correlation (Spearman r=0.51, p=0.0001). Prior systemic cancer therapy did not significantly affect TROP2 intensity, frequency, or combined score in primary or LM specimens (data to be presented). Overall survival was not significantly different between low (&amp;lt;5) or high (≥5) TROP2 combined score (stratified by the median value) for primary (log-rank p=0.67) or LM specimens (log-rank p=0.66). Similarly, there was no difference in overall survival stratified by TROP2 frequency or intensity in CRC primary or LM (data to be presented). Conclusions: TROP2 expression was observed in both primary CRC and LM specimens, and the frequency x intensity combined score was significantly higher in primary CRC specimens compared to paired LM. Higher TROP2 expression in either primary tumors or LM did not correlate with overall survival. Citation Format: Robert W Lentz, Miriam Barnett, Michele Gerber, Jeffrey Kaplan, Adrie van Bokhoven, Kathleen C Torkko. Retrospective analysis of TROP2 expression in colorectal cancer (CRC) primary tumors and liver metastases (LM) and its correlation with clinical factors [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C001.

The heterogeneous impact of targeted therapy on the prognosis of stage III/IV colorectal cancer patients with different subtypes of TP53 mutations.

The relationship between molecular characteristics and the prognosis of colorectal cancer (CRC) patients has not been fully understood. This study explored the impact of targeted therapy on the prognosis of CRC patients with different TP53 mutations, in the context of comprehensive treatment. This study included patients with stage III/IV primary CRC from the electronic medical record system. TP53 mutations were detected via next-generation sequencing (NGS) using formalin-fixed paraffin-embedded (FFPE) tissues. Applying two methods, we classified TP53 mutations as gain of function (GOF)/non-GOF mutations or known/likely loss of function (LOF) mutations. Kaplan-Meier plot and parametric survival analysis were performed to evaluate the prognosis of CRC patients and identify potential predictors. There were 286 patients included, of which 166 (58.04%) patients received targeted therapy and 120 (41.96%) did not. There were 286 patients in the TP53 GOF classification set and 247 in the TP53 LOF classification set. Parametric survival analysis, adjusted for sex, onset, KRAS mutation, sidedness, stage, and surgery, showed that receiving targeted therapy predicted better overall survival (OS) among patients who harbored TP53 GOF mutations (HR 0.40, 95% confidence interval (CI) [0.21, 0.76], p = 0.005) or known LOF mutations (HR 0.21, 95% CI [0.07, 0.60], p = 0.002). However, there was no significant impact of receiving targeted therapy on OS among patients harboring TP53 non-GOF mutations (HR 1.68, 95% CI [0.50, 5.63], p = 0.403) or likely LOF mutations (HR 0.90, 95% CI [0.34, 2.39], p = 0.837). Receiving targeted therapy had a heterogeneous impact on the prognosis of CRC patients harboring different TP53 mutations. These results provide promising value for future personalized treatment and precision medicine.

Single-cell transcriptomic analysis deciphers heterogenous cancer stem-like cells in colorectal cancer and their organ-specific metastasis

ObjectiveMetastasis is the major cause of cancer death. However, what types of heterogenous cancer cells in primary tumour and how they metastasise to the target organs remain largely undiscovered.DesignWe performed...

Risk factors for metachronous colorectal cancer and advanced neoplasia following primary colorectal cancer: a systematic review and meta-analysis

BackgroundIdentifying risk factors for metachronous colorectal cancer (CRC) and metachronous advanced neoplasia could be useful for guiding surveillance. We conducted a systematic review and meta-analysis to investigate risk factors for metachronous CRC and advanced neoplasia.MethodsSearches were conducted in MEDLINE, Embase, Web of Science and Cochrane Central Registry of Controlled Trials for articles (searching period: 1945 to Feburary, 2021) that reported the results of an association between any factor and metachronous advanced neoplasia or metachronous CRC. There were no restrictions on the publication date or language. Random effects models were fitted to estimate the combined association between the risk factors and metachronous CRC or advanced neoplasia. The Risk of Bias In Non-Randomised Studies of Interventions tool (ROBINS-I) was used to assess the risk of bias of included studies.ResultsIn total, 22 observational studies with 625,208 participants were included in the systematic review and meta-analysis. Of these, 13 studies investigated risk factors for metachronous CRC and 9 for advanced neoplasia. The risks of metachronous CRC or advanced neoplasia were higher if the first CRC was diagnosed in the presence of a synchronous advanced lesion (pooled risk ratio (RR) from 3 studies: 3.61, 95% confidence interval (CI): 1.44–9.05; and pooled RR from 8 studies: 2.77, 95% CI: 2.23–3.43, respectively). The risk of metachronous CRC was lower, but the risk of metachronous advanced neoplasia was higher if the first CRC was distal (compared with proximal) (pooled RR from 3 studies: 0.48, 95% CI: 0.23–0.98; and pooled RR from 2 studies: 2.99, 95% CI: 1.60–5.58 respectively). The risk of metachronous advanced neoplasia increased with age (pooled RR from 3 studies: 1.07 per year of age, 95% CI: 1.03–1.11). There was no evidence that any lifestyle risk factors studied were associated with the risk of metachronous CRC or advanced neoplasia.ConclusionsThe identified risk factors for metachronous CRC and advanced neoplasia might be useful to tailor the existing surveillance guidelines after the first CRC. There were potential limitations due to possible misclassification of the outcome, confounding and risk of bias, and the findings cannot be generalised to high-risk genetic syndrome cases.

SNP array genomic analysis of matched pairs of brain and liver metastases in primary colorectal cancer

PurposeBrain metastasis formation is a rare and late event in colorectal cancer (CRC) patients and associated with poor survival. In contrast to other metastatic sites, the knowledge on chromosomal aberrations in brain metastases is very limited.MethodsTherefore, we carried out single nucleotide polymorphism (SNP) array analyses on matched primary CRC and brain metastases of four patients as well as on liver metastases of three patients.ResultsBrain metastases showed more chromosomal aberrations than primary tumors or liver metastases. Commonly occurring aberrations were gain of 8q11.1-q24.3 (primary CRC), gain of 13q12.13-q12.3 (liver metastases), and gain of 20q11.1-q13.33 (brain metastases). Furthermore, we found one copy-neutral loss of heterozygosity (cn-LOH) region on chromosome 3 in primary CRC, three cn-LOH regions in liver metastases and 23 cn-LOH regions in brain metastases, comprising 26 previously undescribed sites.ConclusionThe more frequent occurrence of cn-LOHs and subsequently affected genes in brain metastases shed light on the pathophysiology of brain metastasis formation. Further pairwise genetic analyses between primary tumors and their metastases will help to define the role of affected genes in cn-LOH regions.

Transcriptomic and genomic profiling of multiple primary colorectal cancers reveals intratumor heterogeneity and a distinct immune microenvironment

This study reported on the intratumor genomic and immunological heterogeneity of different tumor lesions from a single patient with multiple primary colorectal cancer (MPCC). The goal of this study was to explore the molecular and microenvironment characteristics of tumor lesions from different primary sites in a patient with MPCC.A total of three tumor lesions located in the hepatic flexure of the transverse colon, sigmoid colon, and rectum were collected from a 72-year-old male patient with MPCC. All three tumor samples were examined by using whole-exome sequencing (WES) and single-cell RNA sequencing (scRNA-seq). The transcriptome data of The Cancer Genome Atlas (TCGA) colon cancer (COAD) dataset were explored to characterize the biological impacts of certain immune cells. Only three nonsynonymous mutations were shared by all of the tumor lesions, whereas a number of single nucleotide variant (SNV) and copy number variation (CNV) mutations were shared by tumor samples from the sigmoid colon and rectum. Transcriptomic analysis showed that tumor lesions derived from the transverse colon had decreased levels of RTK, ERK, and AKT pathway activity, thus suggesting lower oncogenic properties in the transverse lesion compared to the other two samples. Further immune landscape evaluation by using single-cell transcriptomic analysis displayed significant intratumor heterogeneity in MPCC. Specifically, more abundant mucosal-associated invariant T (MAIT) cell infiltration was found in transverse colon tumor lesions. Afterwards, we found that higher MAIT cell infiltration may correlate with a better prognosis of patients with colon cancer (immunohistochemical status was MSI-L/pMMR) by using a publicly available TCGA dataset.