Right-sided Colorectal Cancer Research Articles

Clinicopathological Differences between Right and Left Colorectal Cancer by Sex

Background: Until now, studies on colorectal cancer (CRC) have focused on clinicopathological characteristics based on location without considering sex differences. However, as men and women have fundamentally different physiological characteristics, research results in the clinical field are limited. We aimed to elucidate the differences in the clinicopathological characteristics between right-sided CRC (RCC) and left-sided CRC (LCC) according to sex. Methods: We classified 1492 South Korean patients with no history of colon surgery between July 2005 and June 2015 based on tumor location and sex. For these patients, differences in the clinical characteristics according to sex were compared using univariate and multivariate analyses. Results: Of the 1269 patients, 951 (74.9%) had LCC, and 318 (25.1%) had RCC, making LCC approximately three times more common than RCC. When sex was not taken into account, patients with RCC had significantly higher rates of anemia and undifferentiated cancers than the rates in those with LCC. Even considering sex, anemia and undifferentiated cancer were more prevalent in RCC than in LCC in both men and women. In contrast, age over 65 years and abnormal white blood cell count differed between RCC and LCC only in women. Conclusions: The clinicopathologic characteristics of CRC vary according to the location and sex. Therefore, sex must be considered as a fundamental characteristic of personalized treatment.

Right-side shift of colorectal cancer in Trinidad and Tobago: A change in distribution

Background and Objectives: Previously published epidemiologic data from Trinidad and Tobago suggested that left-sided colorectal cancer (CRC) was more common, but accepted, standardized definitions for CRC laterality were not used. This study aims to collect data from patients with CRC in Trinidad & Tobago in order to determine anatomic site using standardized definitions. Methods: A retrospective audit of hospital records was carried out for all patients with CRC over a 10-year period from January 1, 2011 to January 30, 2021. Standardized definitions were used to classify CRC laterality: Right-sided CRC was defined as those that arose in the cecum, ascending colon, hepatic flexure and/or transverse colon. Left-sided primaries were defined as those that originated from the splenic flexure, descending colon and/or sigmoid colon. The following data were extracted: laterality, gender, age and ethnicity. Descriptive statistical analyses were generated with SPSS version 21. Results: The records of 326 patients with CRC were examined in this study. There was a predominance of right-sided (43%) over left sided primaries. There was a statistically significant relationship between right sided CRC and female (58.2% vs. 41.8%; P = 0.00168), black ethnicity (60.2% vs. 38.6%; P = 0.0076) and younger age (60.9 vs. 65.9 years; P = 0.00028). Conclusion: There is a predominance of right-sided CRC in this eastern Caribbean nation, significantly associated with younger, female and black population.

Single-cell transcriptomics and Mendelian randomization reveal LUCAT1's role in right-sided colorectal cancer risk.

Background: Colorectal cancer (CRC) is a malignancy with high incidence and mortality rates globally, categorized into left-sided and right-sided CRC, each exhibiting significant differences in molecular characteristics, clinical manifestations, and prognosis. Methods: This study employed single-cell transcriptomic data and various bioinformatics approaches, such as two-sample Mendelian randomization, reverse Mendelian randomization, colocalization analysis, directed filtering, pseudotime analysis, and intercellular communication analysis. It analyzed cellular-level disparities between left-sided and right-sided CRC, identifying distinct subpopulations with characteristic variations. For these cells, two-sample Mendelian randomization was utilized to explore gene-to-one-sided CRC causality. Results: LUCAT1 was enriched in high-abundance monocyte subpopulations in right-sided CRC and demonstrated potential risk factor status through Mendelian randomization analysis. The specific single-nucleotide polymorphism (SNP) rs10774624 was associated with an increased risk of CRC. Moreover, metabolic pathway analysis revealed that LUCAT1+ monocytes exhibit lower communication activity in the tumor microenvironment and heightened activity in metabolic functions like glycosaminoglycan degradation. Its biological functions are related to the positive regulation of interleukin-6 production and NF-kappa B signaling, among others. Conclusion: This study confirmed a potential causal relationship between LUCAT1 and right-sided CRC risk through Mendelian randomization analysis. These findings provide novel insights into the pathogenesis of right-sided CRC and may aid in developing early detection and treatment strategies for right-sided CRC.

Analysis of the characteristics of coexisting lesions in colorectal cancer patients in an international study: A subgroup analysis of the ATLAS trial.

We investigated coexisting lesion types in patients with invasive colorectal cancer (CRC) in a multinational study for comprehending the adenoma-carcinoma and serrated pathway about the development of CRC. We retrospectively reviewed 3050 patients enrolled in the international randomized controlled trial (ATLAS study) to evaluate the colorectal polyp detection performance of image-enhanced endoscopy in 11 institutions in four Asian countries/regions. In the current study, as a subgroup analysis of the ATLAS study, 92 CRC patients were extracted and compared to 2958 patients without CRC to examine the effects of age, sex, and coexisting lesion types (high-grade adenoma [HGA], low-grade adenoma with villous component [LGAV], 10 adenomas, adenoma ≥10 mm, sessile serrated lesions [SSL], and SSL with dysplasia [SSLD]). Additional analyses of coexisting lesion types were performed according to sex and location of CRC (right- or left-sided). A multivariate analysis showed that HGA (odds ratio [95%confidence interval] 4.29 [2.16-8.18]; p<0.01), LGAV (3.02 [1.16-7.83], p=0.02) and age (1.04 [1.01-1.06], p=0.01) were independently associated with CRC. According to sex, the coexisting lesion types significantly associated with CRC were LGAV (5.58 [1.94-16.0], p<0.01) and HGA (4.46 [1.95-10.20], p<0.01) in males and HGA (4.82 [1.47-15.80], p<0.01) in females. Regarding the location of CRC, SSLD (21.9 [1.31-365.0], p=0.03) was significant for right-sided CRC, and HGA (5.22 [2.39-11.4], p<0.01) and LGAV (3.46 [1.13-10.6], p=0.02) were significant for left-sided CRC. The significant coexisting lesions in CRC differed according to sex and location. These findings may contribute to comprehending the pathogenesis of CRC.

Abstract LB251: Widespread epigenetic deregulation and its dependency on tumor sidedness in colorectal cancer

Abstract Clinical evidence suggests that right-sided colorectal cancer (CRC) tends to have a worse prognosis compared to left-sided CRC. The distinct functional mechanisms underlying this “sidedness” remain cryptic and poorly understood. Thus, molecular classification of CRC is of paramount in targeting specific subtypes and personalizing treatment for patients. To identify targetable molecular features to improve treatment regimens, we performed multi-faceted network analyses of a large number of CRC patients. In our network model, differential expression of transcript abundance, epigenetic features, and mutational frequency were used to identify widespread gene dysregulation and perturbed pathways to reveal disrupted networks distinct to right or left sided colorectal cancer. We discovered histone related genes and distinct epigenetic signals are at play in right-sided CRC. Additionally, our studies reveal “at risk” patient characteristics suggestive of survival differences, to improve diagnostic predictors based on CRC sidedness. Overall, our integrative approach serves to link molecular profiles distinct between left and right sided colorectal cancer, while paving the way towards identifying more effective treatment alternatives from a previously overlooked, readily characterized subtype of colorectal cancer. Citation Format: Brandon Burgman, Xingxin Pan, Anjali Agrawal, Nidhi Sahni, S. Stephen Yi. Widespread epigenetic deregulation and its dependency on tumor sidedness in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB251.

Abstract 6683: The abundance of Fusobacteria nucleatum in tumor tissue is a prognostic factor in patients of right-sided colorectal cancer

Abstract Background: A significant association between the gut microbiome and colorectal carcinogenesis, as well as cancer progression. It has been reported that Fusobacteria nucleatum (F. nucleatum) is one of the most famous bacteria associated with colorectal cancer (CRC). It has been reported that the abundance of F. nucleatum is associated with colorectal cancer-specific survival (CSS), however it remains unclear for association with F. nulceatum and relapse-free survival (RFS). If F. nucleatum has a significant involvement in tumor progression of colorectal cancer, the abundance of F. nucleatum should be associated with not only CSS but also RFS in colorectal cancer. In this study, we measured the bacterial mass of F. nucleatum in tumor tissue of CRC patients in Stage II-III to explore the differences in prognosis. Methods: We included patients with CRC in stage II-III who underwent surgical treatment at Nippon Medical School Hospital between January 2017 and December 2020 except patients who received preoperative chemoradiotherapy and had multiple cancers. We measured the absolute of F. nucleatum copy number of the DNA exacted tumor tissues using droplet digital PCR. Results: 253 patients with CRC were included. 128 patients had pathological stage II and 125 patients had pathological stage III. Among 253 patients, 104 patients had right-sided CRC, 89 patients had left-sided, and 60 patients had rectal cancer. F. nucleatum was detected in 166 patients (65.6%), and the median of F. nucleatum copy number was 1.08 (range; 0.00 -2791.3). F. nucleatum copy number was more abundant in right-sided CRC than in left-sided and rectal cancer (p= 0.02, p=0.01). There was no significant difference between stage II CRC and stage III. We categorized patients into two groups based on the median cut point of F. nucleatum copy number: the F. nucleatum-high group and the F. nucleatum-low group for comparison with clinicopathological features and prognosis. Patients with high abundance of F. nucleatum exhibited T4 of tumor depth (p=0.03), right-sided CRC (p=0.01), longer tumor circumference (p &amp;lt;0.001), longer tumor length (p &amp;lt;0.001), and no lymph node metastasis (p=0.024). There was no significant difference in relapse-free survival between the F. nucleatum-high group and F. nucleatum-low group among whole patients (p=0.53). Analyzing divided tumor location, in right-sided CRC high abundance of F. nucleatum was significantly associated with shorter relapse-free survival than low abundance (p=0.02), while in left-sided and rectal cancer there was no significant difference (p=0.61). Conclusion: F. nucleatum was more abundant in right-sided CRC and associated with relapse-free survival only in right-sided CRC. F. nucleatum may make a greater impact on right-sided CRC than on left-sided and rectal cancer. Citation Format: Toshimitsu Miyasaka, Takeshi Yamada, Sho Kuriyama, Akihisa Matsuda, Kay Uehara, Seiichi Shinji, Yasuyuki Yokoyama, Goro Takahashi, Takuma Iwai, Kohki Takeda, Shintaro Kanaka, Hiroshi Yoshida. The abundance of Fusobacteria nucleatum in tumor tissue is a prognostic factor in patients of right-sided colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6683.

Abstract 1150: Unveiling the spatial landscape of tumor and stroma heterogeneity in colorectal cancer with spatial transcriptomics

Abstract Heterogeneity in colorectal cancer (CRC) manifests in the diversity and interactions among tumor cells, support stroma, and immune components, critically impacting patient prognosis and therapeutic efficacy. In this study, spatial transcriptomics (ST, 10x Genomics Visium Spatial Gene Expression) was performed on 40 retrospectively collected CRC samples, along with detailed clinicopathological parameters and long-term clinical outcomes, with the goal of unraveling the molecular topography of the tumor and surrounding stromal compartments, and associating their spatial interactions to clinical outcomes. Five primary RNA groups were identified through unsupervised clustering on ST data, correlating with tissue classes detected in H&amp;E-stained images via a pre-trained deep learning model. Markers and pathways specific to these tissues were identified. Furthermore, immune cell infiltration in these regions was deconvoluted using reference single-cell RNA sequencing (scRNA-seq) data. Sub-clustering within the tumor groups revealed five major tumor subtypes, each characterized by a distinct set of differentially expressed marker genes. Enrichment analysis across these subtypes highlighted distinct activation and suppression in pathways including KRAS, p53, MAPK, and Integrin. Tumors exhibited intra- and inter-tumoral heterogeneity. Location-specific tumor subtypes were observed, with those in right-sided CRC displaying increased immune cell infiltration, linked to enriched pathways such as Type II Interferon Signaling and Cytokine Signaling. Conversely, left-sided CRC subtypes had reduced immune cell presence, and were characterized by enhanced pathways related to vascular development, Hypoxia, and p53 Signaling. Inferred clonal lineages from copy number variation (CNV) using ST suggested a spatially structured phylogenetic organization corresponding to transcriptional clusters. Additionally, the ST data unveiled distinct spatial distribution patterns across various cancer-associated fibroblast (CAF) phenotypes, such as matrix, inflammatory, vessel-associated, tumor-promoting, and antigen-presenting CAFs. Transcriptional patterns uncovered through scRNA-seq, including epithelial-mesenchymal transition (EMT) signatures and consensus molecular subtypes (CMS), displayed unique spatial layouts within the tumor microenvironment. To our knowledge, this is the most comprehensive study to date on spatial transcriptomic heterogeneity within CRC patients, revealing distinct tumor, stroma and immune compositions and spatial structures. This spatially detailed map provides novel insights into CRC heterogeneity, critical for advancing personalized treatment. Citation Format: Jie Zhou, Todd B. Sheridan, Sergii Domanskyi, Stephanie L. Cowles, Sunghee Park, Ilham Putra, Olga Anczukow, Jeffrey H. Chuang, Jill C. Rubinstein. Unveiling the spatial landscape of tumor and stroma heterogeneity in colorectal cancer with spatial transcriptomics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1150.

Laparoscopic right hemicolectomy with complete mesocolic excision and D3 lymphadenectomy using the open book approach: a video vignette.

According to the concept of total mesorectal excision for rectal cancer, Hohenberger translated this concept to colonic cancer by introducing complete mesocolic excision (CME). The concept of this surgical technique was further elucidated by Benz et al. in the form of an open book approach. This article presents and demonstrates in a video a case of laparoscopic right hemicolectomy with CME and D3 lymphadenectomy using open book approach in the treatment of a T3N1M0 distal ascending colonic adenocarcinoma. The final pathology report confirmed moderately differentiated adenocarcinoma with a maximum tumor size of 55 mm and 0/60 lymph nodes. The mesocolic fascia was intact and R0 was achieved. The final staging was pT3pN0pM0. However, D3 lymphadenectomy is not universally adopted due to concerns of higher morbidity we believe that with adequate training and supervision CME with D3 LDN is feasible and safe to be offered to all right-sided colorectal cancers with curative intent treatment.

Comparison of left- and right-sided colorectal cancer to explore prognostic signatures related to pyroptosis

BackgroundColorectal cancer (CRC) is one of the most common malignancies, and pyroptosis exerts an immunoregulatory role in CRC. Although the location of the primary tumor is a prognostic factor for patients with CRC, the mechanisms of pyroptosis in left- and right-sided CRC remain unclear. MethodsExpression and clinical data were collected from The Cancer Genome Atlas and Gene Expression Omnibus databases. Differences in clinical characteristics, immune cell infiltration, and somatic mutations between left- and right-sided CRC were then compared. After screening for differentially expressed genes, Pearson correlation analysis was performed to select pyroptosis-related genes, followed by a gene set enrichment analysis. Univariate and multivariate Cox regression analyses were used to construct and validate the prognostic model and nomogram for predicting prognosis. Collected left- and right-sided CRC samples were subjected to reverse transcription-quantitative polymerase chain reaction (RT-qPCR) to validate the expression of key pyroptosis-related genes. ResultsLeft- and right-sided CRC exhibited significant differences in clinical features and immune cell infiltration. Five prognostic signatures were identified from among 134 pyroptosis-related differentially expressed genes to construct a risk score-based prognostic model, and adverse outcomes for high-risk patients were further verified using an external cohort. A nomogram was also generated based on three independent prognostic factors to predict survival probabilities, while calibration curves confirmed the consistency between the predicted and actual survival. Experiment data confirmed the significant differential expression of five genes between left- and right-sided CRC. ConclusionThe five identified pyroptosis-related gene signatures may be potential biomarkers for predicting prognosis in left- and right-sided CRC and may help improve the clinical outcomes of patients with CRC.

The prediction of colorectal cancer: Perspective of smoking and socioeconomic influence of culture in East Java with SEM analysis

Purpose: Colorectal cancer (CRC) is a global malignancy with 10.2% of cases, ranking third in worldwide cancer cases. According to Indonesia Health Research, CRC's prevalence has risen significantly, reaching 1, 8 per mile in 2018, and reports rising cancer cases in the past 5 years. This study explores the relationship model between smoking, socioeconomics, and CRC, considering cultural moderation.&#x0D; Design/Methodology/Approach: Conducted as a retrospective study with 212 respondents, comprising 172 cases of left-sided colorectal cancer (left CRC ) and 40 cases of right-sided colorectal cancer (right CRC) from three cultural areas. Structural Equation Modeling (SEM) employing Warp-PLS was utilized for data analysis.&#x0D; Finding: A significant positive relationship was found between smoking and CRC prediction (β = 0,081, p-value = 0,040). This pattern also applies to socioeconomic status and CRC prediction (β = 0,311, p-value = &lt;0,001). The influence of culture on both relationships is not the same. The relationship between smoking and CRC prediction is not influenced by culture (p-value = 0,318). Conversely, the relationship between socioeconomic status and CRC prediction is influenced by culture (β = 0,078, p = 0,047).&#x0D; Conclusion: Poor smoking habits and weak economic conditions influence the prediction of CRC negatively in East Java Province. Unfavorable cultural practices further worsen the relationship between weak socioeconomic status and poor CRC prediction in East Java Province. Recommendations suggest that preventing adverse CRC outcomes can be achieved through smoking cessation and improving socioeconomic conditions. Preventive efforts to enhance socioeconomic conditions should consider local cultural nuances.&#x0D; Research limitation: This research is limited to a population group in East Java Province, Indonesia, divided into three cultural areas: Mataraman, Arek, and Pendalungan.

NOS2 Polymorphism in Aspect of Left and Right-Sided Colorectal Cancer.

Background: The NOS2 gene polymorphism rs2297518 is associated with an increased level of NO, which could contribute to colorectal cancer (CRC) development. We hypothesized that the potential influence of the NOS2 gene polymorphism on cancer development may vary between right-sided and left-sided colon cancers, and rectal cancers. The aim of this study was to determine the rs2297518 polymorphism influence on colorectal cancer development with regard to tumor localization. Methods: This case-control study included 199 patients with CRC and 120 controls. The qPCR endpoint genotyping was conducted using the TaqMan® genotyping assay. Results: This study revealed significant differences in tumor characteristic and in the minor alelle A frequency in the NOS2 genotype between colorectal cancers with different localizations. The mucinous adenocarcinoma was diagnosed significantly more often in right-sided cancers than in left-sided (30.6% vs. 10.9%, p = 0.009) and rectal cancers (30.6% vs. 7.1%, p = 0.0003). The minor allele A of the NOS2 genotype was observed more frequently in right-sided cancers than in left-sided cancers (44.9% vs. 23.1%, p = 0.0137) and more frequently in rectal cancers than in left-sided cancers (40.0% vs. 23.1%, p = 0.0285). Conclusions: In conclusion, the results support the hypothesis that the SNP rs2297518 of the NOS2 gene influences colorectal cancer development with regard to tumor localization.

MiR-27a-3p exacerbates cell migration and invasion in right-sided/left-sided colorectal cancer by targeting TGFBR2/TCF7L2.

Left-sided colorectal cancer (LSCC) and right-sided colorectal cancer (RSCC) belong to colorectal cancer happening at different positions, which exhibit different pathogenesis. MicroRNA (miRNA)s are widely known regulators in diverse carcinomas. This research aims to identify a differentially expressed miRNA that simultaneously regulates genes associated with LSCC and RSCC and reveal their regulatory relation in cell migration and invasion. Bioinformatics analyses were conducted to uncover the dysregulated functional genes in LSCC/RSCC and obtain their common targeted miRNAs. The expression pattern of miR-27a-3p, TCF7L2, and TGFBR2 in cancerous and adjacent tissues from LSCC/RSCC patients was assessed through qRT-PCR, followed by Pearson's correlation coefficients analysis. The interaction of miR-27a-3p with TCF7L2 or TGFBR2 was thereafter confirmed through luciferase reporter assay. TCF7L2 and TGFBR2 protein levels were assessed by western blotting after overexpressing level of miR-27a-3p. Cell migration and invasion were routinely examined by wound healing and transwell experiments, respectively. TCF7L2 and TGFBR2 were respectively identified and verified to be lowly expressed in LSCC and RSCC, both of them were predicted and confirmed as targets of miR-27a-3p. MiR-27a-3p elevation exacerbated migration and invasion of both LSCC and RSCC cells. The impacts of miR-27a-3p on migration and invasion could be blocked by overexpressing TCF7L2 in LSCC cells and also reversed by up-regulating TGFBR2 in RSCC cells. In general, miR-27a-3p accelerated the migration and invasion capabilities of LSCC and RSCC cells through negatively regulating TCF7L2 and TGFBR2, respectively, which might be an effective molecular target for the treatment of LSCC/RSCC.

APC as a high-utility mutational biomarker that may identify subpopulations of patients with mutant RAS/BRAF and right-sided colorectal cancer (CRC) who derive benefit from EGFR inhibitors (EGFRi).

56 Background: Although, EGFRi including Cetuximab (CTX) and Panitumumab (PMB) is restricted to KRAS wild-type ( KRASWT) tumors, ~50% of patients still fail to respond to therapy. Using a transcriptional signature as a surrogate for cetuximab response, we previously reported that mutations in APC ( APCMUT) and TP53( TP53MUT) might predict cetuximab sensitivity, particularly in RASWT tumors (Yang M. et al., 2019). The current study aimed to use real world EGFRi treatment and survival data to independently validate these mutations as predictive, high-utility biomarkers of benefit to specific subpopulations of CRC. Methods: CTX/PMB-treated CRC specimens (n=1846) with clinical outcomes and NextGen Sequencing of DNA (592-gene panel or whole exome sequencing) were tested at Caris Life Sciences (Phoenix, AZ). All analyses were performed in MSS tumors, determined by immunohistochemistry of MMR proteins and/or NGS. Tumors with likely pathogenic mutations in KRAS, NRAS or BRAF were considered as RASMUT /BRAFMUT, or RASWT /BRAFWT if no mutation was detected for each gene. Survival on EGFRi was calculated from the initiation of EGFRi to last contact (E-OS) or last dose of EGFRi (E-TOT) using Kaplan-Meir method. Results: While concurrent TP53MUT/ APCMUT were associated with improved E-OS compared to TP53MUT alone (hazard ratio [HR]=0.565, p&lt;0.00001), APCMUT tumors were associated with improved E-OS independent of TP53 mutation status. Compared to APCWT, APCMUT were associated with longer E-OS in RAS/BRAF mutant as well as wild-type subpopulations and in left- and right- sided tumors. Furthermore, APCMUT were associated with improved E-TOT in PMB treated tumors independent of RAS/BRAF mutation status and tumor sidedness (HR range:0.59-0.75, all p&lt;0.05). Conclusions: Our data suggests that the simple application of a high-utility mutational biomarker ( APC), may increase the eligibility for successful EGFRi therapy in a substantial subpopulation of RAS/BRAF mt patients as well as right-sided CRC, potentially altering the standard of care. Further validation of this biomarker in a prospective clinical trial is warranted. [Table: see text]

Circulating tumor DNA (ctDNA) positivity and its association with clinicopathological characteristics by novel blood-based test for colorectal cancer (CRC) screening from a multi-center large cohort: COSMOS-CRC-01.

69 Background: Blood-based CRC screening has yielded performance comparable to stool-based screening tests and may be a modality that addresses the adherence gap in CRC screening. To investigate the diagnostic performance and its clinical relevance, we evaluated the test performance of a blood-based CRC screening test in a large cohort of individuals enriched for advanced colorectal neoplasia and early CRCs. Methods: 501 individuals presenting to ten institutions in Japan from 2020 to 2021 for treatment of advanced adenomas (AAs) or CRCs were consented and provided a pre-treatment blood sample (40mL whole blood in Streck cfDNA blood collection tubes). All eligible individuals underwent surgery or endoscopic resection within 30 days after sample collection and the pathological specimens were reviewed to determine cancer histology and stage, as well as AA histology. Pre-treatment blood samples were analyzed with a multi-modal (genomic and epigenomic) cfDNA CRC detection assay (Shield, Guardant Health, USA). Final cfDNA results were correlated with clinical data to determine the association of clinicopathological characteristics with test sensitivity. This study is registered as a clinical trial under UMIN000037765. Results: 451/501 (90%) individuals met inclusion/exclusion criteria and provided adequate blood samples that passed testing quality control criteria. Median age at consent was 67.4 years (range 31 – 92). 44% were female. 214/451 (47%) had a prior positive fecal occult blood test (FOBT). Of individuals with a negative or unknown FOBT testing, 161/237 (68%) had GI symptoms (e.g. abdominal pain, bloody/narrowing stool, constipation/diarrhea). The test identified 88% (268/305) of CRCs, including 71% (79/111) Stage I, 98% (87/89) Stage II, 97% (90/93) Stage III, and 100% (12/12) Stage IV. Overall sensitivity in detecting Stage I-III was 87%. The test identified 37% (54/146) of AAs, including 49% (33/68) of carcinoma in situs and 24% (9/37) of AAs with high-grade dysplasia. Sensitivity for right-sided CRC was 84% (61/73), 87% (59/68) for left-sided CRC, and 90% (148/164) for rectal tumors. Stage I test sensitivity was significantly associated with tumor size (&gt;20mm; p&lt;0.01), left-sided or rectal tumor location (p&lt;0.05), and tumor depth (p&lt;0.01) in univariate analysis, whereas the tumor depth (T2) was the sole factor associated with test positivity (p&lt;0.05) in multivariate analysis. Specificity on this assay is 90% as determined in the ECLIPSE clinical study (NCT04136002). Conclusions: This study evaluates the performance of a blood-based test for CRC and its clinicopathological relevance in a large-scale cohort. In this population enriched for early colorectal neoplasia, the sensitivity was 88% for CRC and 37% for AAs. This performance is consistent with previous reports. Clinical trial information: UMIN000037765 .

Transverse Colon Primary Tumor Location as a Biomarker in Metastatic Colorectal Cancer: A Pooled Analysis of CCTG/AGITG CO.17 and CO.20 Randomized Clinical Trials.

Sidedness is prognostic and predictive of anti-EGFR efficacy in metastatic colorectal cancer (mCRC). Transverse colon has been historically excluded from several analyses of sidedness and the optimal division between left- and right-sided colorectal cancer is unclear. We investigated transverse colon primary tumor location as a biomarker in mCRC. Pooled analysis of CCTG/AGITG CO.17 and CO.20 trials of cetuximab in chemotherapy-refractory mCRC. Outcomes of patients with RAS/BRAF wild-type (WT) mCRC from CO.17 and KRAS WT mCRC from CO.20 were analyzed according to location. A total of 553 patients were analyzed, 32 (5.8%) with cancers from the transverse, 101 (18.3%) from right, and 420 from (75.9%) left colon. Transverse mCRC failed to reach significant benefit from cetuximab versus best supportive care (BSC) for overall survival [OS; median, 5.9 vs. 2.1 months; HR, 0.63; 95% confidence interval (CI), 0.28-1.42; P=0.26] and progression-free survival (PFS; median, 1.8 vs. 1.3 months; HR, 0.57; 95% CI, 0.26-1.28; P=0.16). Analyzing exclusively patients randomized to cetuximab, right-sided and transverse had comparable outcomes for OS (median, 5.6 vs. 5.9 months; HR, 0.82; 95% CI, 0.50-1.34; P=0.43) and PFS (median, 1.9 vs. 1.8 months; HR, 0.78; 95% CI, 0.49-1.26; P=0.31). Patients with left-sided mCRC had superior outcomes with cetuximab compared with transverse for OS (median, 9.7 vs. 5.9 months; HR, 0.42; 95% CI, 0.27-0.67; P=0.0002) and PFS (median, 3.8 vs. 1.8 months; HR, 0,49; 95% CI, 0.31-0.76; P=0.001). Location was not prognostic in patients treated with BSC alone. Transverse mCRC has comparable prognostic and predictive features with right-sided mCRC.

Prevalence of PIK3CA Mutation Based on Tumour Locations Among Colorectal Cancer Patients in Bali

Colorectal tumour location is important in determining therapeutic strategies because the location of the tumour will affect the histological and molecular characteristics of the cancer. Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) is a gene known to be associated with colorectal cancer location. The prevalence of PIK3CA mutations in colorectal cancer (CRC) ranges from 10-20%. Although the prevalence is small, this gene has a potential as a predictive and prognostic biomarker in the management of CRC. 80% of PIK3CA mutations occur in exon 9 (codon 542 and 545) and exon 20 (codon 1047). This study aimed to determine the prevalence of PIK3CA gene mutations based on tumour location among colorectal cancer patients in Bali, especially in Prof. dr. I G.N.G. Ngoerah Hospital, Denpasar, Bali. DNA was isolated from formalin-fixed-paraffin embedded (FFPE) blocks of colorectal cancer samples which were stored in the Department of Pathology of Prof. dr. I G.N.G. Ngoerah Hospital. Mutation was detected using polymerase chain reaction (PCR) and direct sequencing. Data on age, gender, and tumour location were recorded from patient medical records. Our findings on 31 colorectal cancer samples showed 26 samples (96.3%) were found with heterozygous mutation in exon 9 with AC genotype, but no mutation was found on exon 20. Based on tumor location, among 26 samples with mutation, 16 samples (61.5%) were left colorectal cancer and 10 samples (38.5%) were right colorectal cancer. Further studies are needed to identify the association of this mutation with colorectal cancer location and the other clinicopathological aspects of CRC. Keywords: Colorectal cancer, PIK3CA gene mutation, PIK3CA exon 9, PIK3CA exon 20, colorectal cancer location, left-sided colorectal cancer, right-sided colorectal cancer

Gut microbiota profiles in feces and paired tumor and non-tumor tissues from Colorectal Cancer patients. Relationship to the Body Mass Index.

Colorectal Cancer (CRC) and Obesity constitute two of the most common malignancies in the western world, and previously have been associated with intestinal microbial composition alterations. Our main aim in this study is to provide molecular data on intestinal microbiota patterns in subjects with CRC, as well as to establish possible associations with their Body Mass Index (BMI). A total of 113 samples from 45 subjects were collected and submitted to metagenomics analysis for gut microbiota. This study was performed by 16S ribosomal RNA bacterial gene amplification and sequencing using the Ion Torrent™ technology. The same dominant phyla were observed in feces and colorectal tissues, although a greater proportion of Fusobacteriota was found in tumor samples. Moreover, at the genus level, LEfSe analysis allowed us to detect a significant increase in Fusobacterium and Streptococcus in colorectal tissues with respect to fecal samples, with a significant preponderance of Fusobacterium in tumor tissues. Also, our data revealed relevant associations between gut microbiota composition and tumor location. When comparing bacterial profiles between right and left colon cancers, those from the left-sided colon showed a significant preponderance, among others, of the order Staphylococcales. Moreover, phyla Firmicutes and Spirochaetota were more abundant in the group of right-sided CRCs and phylum Proteobacteria was increased in rectal cancers. In relation to BMI of patients, we detected significant differences in beta diversity between the normal weight and the obese groups of cases. Microbiota from obese patients was significantly enriched, among others, in Bacteroidales. Therefore, our results are useful in the molecular characterization of CRC in obese and non-obese patients, with a clear impact on the establishment of diagnostic and prognosis of CRC.

Loss of HES1 expression is associated with extracellular matrix remodeling and tumor immune suppression in KRAS mutant colon adenocarcinomas

The loss of HES1, a canonical Notch signaling target, may cooperate with KRAS mutations to remodel the extracellular matrix and to suppress the anti-tumor immune response. While HES1 expression is normal in benign hyperplastic polyps and normal colon tissue, HES1 expression is often lost in sessile serrated adenomas/polyps (SSAs/SSPs) and colorectal cancers (CRCs) such as those right-sided CRCs that commonly harbor BRAF or KRAS mutations. To develop a deeper understanding of interaction between KRAS and HES1 in colorectal carcinogenesis, we selected microsatellite stable (MSS) and KRAS mutant or KRAS wild type CRCs that show aberrant expression of HES1 by immunohistochemistry. By comparing the transcriptional landscapes of microsatellite stable (MSS) CRCs with or without nuclear HES1 expression, we investigated differentially expressed genes and activated pathways. We identified pathways and markers in the extracellular matrix and immune microenvironment that are associated with mutations in KRAS. We found that loss of HES1 expression positively correlated with matrix remodeling and epithelial-mesenchymal transition but negatively correlated with tumor cell proliferation. Furthermore, loss of HES1 expression in KRAS mutant CRCs correlates with a higher M2 macrophage polarization and activation of IL6 and IL10 immunosuppressive signature. Identifying these HES1-related markers may be useful for prognosis stratification and developing treatment for KRAS-mutant CRCs.

Identifying important microbial and genomic biomarkers for differentiating right- versus left-sided colorectal cancer using random forest models

BackgroundColorectal cancer (CRC) is a heterogeneous disease, with subtypes that have different clinical behaviours and subsequent prognoses. There is a growing body of evidence suggesting that right-sided colorectal cancer (RCC) and left-sided colorectal cancer (LCC) also differ in treatment success and patient outcomes. Biomarkers that differentiate between RCC and LCC are not well-established. Here, we apply random forest (RF) machine learning methods to identify genomic or microbial biomarkers that differentiate RCC and LCC.MethodsRNA-seq expression data for 58,677 coding and non-coding human genes and count data for 28,557 human unmapped reads were obtained from 308 patient CRC tumour samples. We created three RF models for datasets of human genes-only, microbes-only, and genes-and-microbes combined. We used a permutation test to identify features of significant importance. Finally, we used differential expression (DE) and paired Wilcoxon-rank sum tests to associate features with a particular side.ResultsRF model accuracy scores were 90%, 70%, and 87% with area under curve (AUC) of 0.9, 0.76, and 0.89 for the human genomic, microbial, and combined feature sets, respectively. 15 features were identified as significant in the model of genes-only, 54 microbes in the model of microbes-only, and 28 genes and 18 microbes in the model with genes-and-microbes combined. PRAC1 expression was the most important feature for differentiating RCC and LCC in the genes-only model, with HOXB13, SPAG16, HOXC4, and RNLS also playing a role. Ruminococcus gnavus and Clostridium acetireducens were the most important in the microbial-only model. MYOM3, HOXC4, Coprococcus eutactus, PRAC1, lncRNA AC012531.25, Ruminococcus gnavus, RNLS, HOXC6, SPAG16 and Fusobacterium nucleatum were most important in the combined model.ConclusionsMany of the identified genes and microbes among all models have previously established associations with CRC. However, the ability of RF models to account for inter-feature relationships within the underlying decision trees may yield a more sensitive and biologically interconnected set of genomic and microbial biomarkers.

Expression Pattern of DAB Adaptor Protein 2 in Left- and Right-Side Colorectal Carcinoma.

Left-sided and right-sided colorectal cancer (L-CRC and R-CRC) have relatively different clinical pictures and pathophysiological backgrounds. The aim of this study was to investigate the presence of DAB adapter protein 2 (DAB2) as a potential molecular mechanism that contributes to this diversity in terms of malignancy and responses to therapy. The expression of the suppressor gene DAB2 in colon cancer has already been analyzed, but its significance has not been fully elucidated. Archived samples from 34 patients who underwent colon cancer surgery were included in this study, with 13 patients with low-grade CRC and 21 with high-grade CRC. Twenty of the tumors were R-CRC, while 14 were L-CRC. DAB2 expression was analyzed immunohistochemically in the tumor tissue and the colon resection margin was used as a control. Tumors were divided into L-CRC and R-CRC, with splenic flexure as the cutoff point for each side. The results showed that R-CRC had lower DAB2 protein expression compared to L-CRC (p = 0.01). High-grade tumors had reduced DAB2 expression compared to low-grade tumors (p = 0.02). These results are consistent with the analysis of DAB2 gene expression data that we exported from the TCGA Colon and Rectal Cancer Study (COADREAD). In 736 samples of colon cancer, lower DAB2 gene expression was found in R-CRC compared to L-CRC (p < 0.0001). DAB2 gene expression was significantly higher in the sigmoid colon than in the cecum and ascending colon (p < 0.01). The analysis confirmed a lower expression of the DAB2 in tumors with positive microsatellite instability (p < 0.001). In conclusion, DAB2 has a role in the biological differences between R-CRC and L-CRC and its therapeutic and diagnostic potential needs to be further examined.