bluuebunny/crossref_metadata_2025_split huggingface dataset:
Use of distinct molecular signatures of appendiceal cancer subtypes to assess biomarker development.
Authors: Tan Wan Ying , Tian Melissa , Ruzgar Nensi , Hengartner Astrid , Sailo Bethsebie , Ang-Olson Olivia , Ubas Airol , John Nithyla , Yaghoobi Vesal , Tang Haoyu , Sharma Anup , Nalbantoglu ILKe , Ahuja Nita 
Published: January 2023

189 Background: Appendiceal Neoplasms are diverse entities which have a variety of clinical presentations, histologic subtypes, biologic behavior, and patient outcomes. Advanced disease at initial diagnosis is not uncommon and therapeutic options are limited. This study aims to identify potential targets to develop epigenetics-based therapeutics/biomarkers. Methods: Archival (FFPE) specimens were collected from 25 patients with histologically confirmed and subtyped appendiceal neoplasia and 16 age-matched non-neoplastic controls. Four appendiceal neoplastic processes identified: Low grade appendiceal neoplasm (LAMN), pseudomyxoma peritonei (intra-peritoneal spread of LAMN), conventional-type adenocarcinoma and goblet cell adenocarcinoma. Gene expression profiling was performed using the HTG EdgeSeq Oncology Biomarker panel. Differentially expressed genes (DEGs) were selected with cut-off threshold FDR<0.05 and analyzed using Qlucore Explorer and functional analyses via Ingenuity Pathway Analysis (IPA). Results: Four appendiceal neoplastic processes identified: pseudomyxoma peritonei (20%), low-grade appendiceal mucinous neoplasm (24%), adenocarcinoma (24%), and goblet cell adenocarcinoma (32%). Unsupervised hierarchical clustering identified 498 DEGs (424 up, 74 down) between all appendiceal cancer versus age-matched controls that showed enrichment in B-cell inflammatory signaling, senescence, cell cycle regulation, PI3K/AKT signaling, cell cycle checkpoint control pathways, and sets relating to NANOG in stem cell pluripotency (all p0.001). G1/S checkpoint, apoptosis, ATM, and PTEN signaling are downregulated (p0.001). TP53, E2F1, IL6, IFNG, TNF, and HGF (p0.001) regulated overlapping genes. Four-subgroups comparison found 67 DEGs involved in T-helper cell differentiation, immune-mediated apoptosis, T-cell fatigue, and PD1/PDL1 signaling to be dysregulated (p0.001). IFNG, FGF2, POU5F1, TNF, and MYC (p0.001) were upstream regulators. Conclusions: In this study, downregulated gene expressions in appendiceal cancers are related to cell proliferation and death control mechanisms, with a trend towards overexpression of inflammatory and cell cycle pathways. It is postulated that genes involved in these pathways are hypermethylated. More research is being undertaken on epigenetics-based biomarkers for diagnosis and prognosis. Given PI’s decades of experience in biomarker research, we aim to develop a "single blood test" to expand bedside monitoring alternatives that align with the National Cancer Moonshot Initiative to discover cancer early, when the likelihood of a cure is highest.
Genomic landscape of acquired resistance to targeted therapies in metastatic colorectal cancer (mCRC).
Authors: Harrold Emily , Keane Fergus , Sinopoli Jenna Cohen , Diaz Luis A. , Cercek Andrea , Yaeger Rona 
Published: January 2023

190 Background: Therapies targeting oncogenic driver mutations have radically altered the treatment paradigm for mCRC and improved outcomes. New selective inhibitors aim to expand the portion of mCRC with targetable alterations. However, these drugs are limited by a relatively short duration of response before the emergence of acquired resistance. We hypothesized that both the putative resistance mechanism (mutations (MUT) versus copy number alterations (CNA)) and the clonality of the emergent mutations may influence time to resistance. Methods: We screened the MSKCC IMPACT dataset of 5,403 MSS (microsatellite stable) CRC patient samples (3,704 primary sequenced, 1669 metastatic site sequenced) for patients (pts) who had been treated with targeted therapies against EGFR, BRAF, KRAS G12C, or HER2 with tissue or liquid biopsy samples profiled at progression. Clinicopathological features and acquired genomic changes emerging at resistance were assessed. Results: 42 pts were identified with targeted oncogenic drivers consisting of BRAF V600E (17 pts), EGFR (12 pts), KRAS G12C (11 pts), and HER2 (2 pts). Progression specimens analyzed consisted of tissue biopsies in 17 pts (40%) and circulating free DNA (cfDNA) in 21 pts (50%), 4 pts had both tissue and cfDNA analyzed at progression. Median time on targeted therapy (TOT) was 7.1 months (95% CI: 5.6-8.5). Putative resistance alterations were identified in 33 pts (79%) (18 cfDNA, 11 tissue, 4 both cfDNA and tissue) and consisted of MUT alone in 30%, MUT+CNA or rearrangement 70%. Concurrent PIK3CA mutations in pre-treatment tissues were identified in 17 pts (40%) and did not associate with TOT (p=0.68); acquired PI3K pathway alterations were identified in 5 pts (12%), including 2 pts who had baseline tumor PIK3CA mutation. Number of putative resistance alterations ranged from 0-13, with multiple resistance alterations identified in 18 pts (15 ctDNA, 3 tissue), and these could be categorized into three groups: one alteration (15/33; 45%), 2-4 alterations (8/33; 24%), and ≥5 alterations (10/33; 30%). Evaluating TOT by type of alteration: MUT only: 9.8 months, MUT+ CNA+/- rearrangement: 6.6 months (p=0.0079). Evaluating TOT by number of alterations: >4 alterations: 6.1 months versus 1-4 alterations: 8.9 months (p=0.012), or 1 alteration: 8.0 months versus >1 alteration: 6.7months (p= 0.5). There was no significant difference in TOT when evaluating by clonality of mutations, where subclonal was defined as <5% of highest variant allelic fraction (clonal vs subclonal, 9.7 vs 6.7 months, p= 0.09). Fusions identified at time of resistance (involving BRAF in 2 pts, MET in 1 pt, RET in 1 pt) occurred with ≥5 alterations in 3 of 4 pts. Conclusions: Presence of CNA and ≥5 new alterations at resistance were associated with shorter TOT, and there was a trend for subclonal alterations and shorter TOT. New approaches that target underlying mechanisms for these changes may extend TOT.
Characterizing the genomic landscape of POLE/POLD1-mutated colorectal adenocarcinoma.
Authors: Coston Tucker , Mauer Elizabeth , Jones Jeremy Clifton , Hubbard Joleen M. , Bekaii-Saab Tanios S. , Stoppler Melissa Conrad , Starr Jason S. 
Published: January 2023

199 Background: The progression of neoplasia in colorectal cancer (CRC) has been well characterized, with the evolution typically involving mutations in APC, KRAS, and p53, among others. POLE/POLD1 genes encode for proteins essential in enzymatic DNA polymerase function, yet POLE/POLD1 mutations in tumors are poorly characterized. Pathogenic mutations in POLE/POLD1 lead to decreased fidelity of DNA replication, resulting in a high tumor mutational burden (TMB-H) independent of deficient mismatch repair (dMMR) and high microsatellite instability (MSI-H). Studies have shown associations between this hypermutated phenotype and susceptibility to immune checkpoint inhibition, which may be attributable to neoantigen creation. As such, these tumors are a clinically relevant phenotype requiring further investigation. Here, we characterized POLE/POLD1 alterations in a large, real-world cohort of patients with CRC. Methods: We retrospectively analyzed de-identified records of 9,136 primary CRC patients profiled with the Tempus xT assay. The assay includes DNA-seq of 595-648 genes at 500x to evaluate single-nucleotide variants, insertions/deletions, and copy number changes. Immunological markers analyzed included tumor mutational burden (TMB), MSI, and dMMR. MSI-H was determined by the assay through assessment of 239 loci. dMMR was determined by immunohistochemistry. Results: A total of 217 patient tumors harbored somatic POLE/POLD1 mutations (n = 203 POLE, n = 13 POLD1, and n = 1 POLE and POLD1; none germline), with no differences noted in baseline demographics including gender and age. Among the POLE/POLD1-mutant cohort, POLE copy number losses accounted for most mutations (n = 127, 59%), with short variants and copy number amplifications accounting for 35% (n = 76). The remainder of tumors exhibited POLD1 copy number changes (n = 14), including one with both POLE and POLD1 copy number loss. POLE/POLD1-mutated tumors presented with a lower frequency of MSI-H compared to wild-type (1.8% vs 6.1%, P= 0.018). Conversely, there was a higher frequency of TMB-high cases ( > 10 mut/Mb) for POLE/POLD1-mutated compared to wild-type tumors (22% vs 9.9%, P< 0.001). Differences between POLE/POLD1-mutated and wild-type tumors were also observed among many co-mutated genes, including APC (80% vs 65%, P< 0.001), ALK (31% vs 11%, P< 0.001), ATM (12% vs 3.6%, P< 0.001), BRCA2 (12% vs. 3.2%), and RET (24% vs 8.9%, P< 0.001). Conclusions: Patients with POLE/POLD1 mutations exhibited significant differences across immunological markers and molecular co-alterations. POLE/POLD1 mutations in CRC have been previously described to present with a hypermutated phenotype; however, 78% of tumors exhibited low TMB despite POLE/POLD1 mutations. Thus, these results have identified POLE/POLD1-mutated tumors as a unique genomic subpopulation, and further studies are needed to better characterize POLE/POLD1 mutations in CRC.
Disparate outcomes for Black patients following neoadjuvant chemoradiation for rectal cancer are multifactorial in origin.
Authors: Shulman Rebecca Maria , Lynch Shannon M. , Deng Mengying , Handorf Elizabeth A. , Meyer Joshua E. , Arora Sanjeevani 
Published: January 2023

21 Background: Studies have shown that Black patients receiving chemoradiation (CRT) for locally advanced rectal cancer (LARC) have achieved clinical outcomes less satisfactory than those achieved by other racial groups, but the source of this disparity is poorly understood. This study investigated the demographic, geographic, socioeconomic, and clinical factors that underlie this disparity. Methods: We interrogated the National Cancer Database from 2004-2017 to identify patients with T3-T4 or N > 0 LARC treated with CRT prior to surgery. Response to CRT was determined by the rates of pathologic complete response (pCR) and tumor downstaging after treatment. Univariate analysis (UVA) was performed with chi-square and Fisher’s exact tests. Multivariate analysis (MVA) was then used to identify independent factors associated with improved pCR. Results: A total of 37,783 patient records were reviewed for the study (7.8% Black, 86.0% White, 6.1% Other). Black patients were younger (p < 0.0001), more often female (p < 0.0001), and more likely to live in metropolitan areas (p < 0.0001). LARC in Black patients was diagnosed at a higher clinical stage (p = 0.0007) and was more often treated with abdominoperineal resection in preference to low anterior resection (p < 0.0001). Black patients were more often uninsured or covered by Medicaid (p < 0.0001) and less often covered by commercial insurance (p < .0001). UVA demonstrated that Black patients achieved pCR and tumor downstaging at lower rates than White patients (11.6% vs 14.5%; 46.9% vs 51.8%, both p < 0.0001). On MVA, Black race (OR 0.8015, 95%CI 0.7101-0.9047), a rural location (OR 0.8211, 95% CI 0.7082-0.952), absence of commercial medical insurance (Medicaid OR 0.8394 95% CI 0.7456-0.9449; Medicare OR 0.8989 95% CI 0.8226-0.9823; No Insurance OR 0.6107 95% CI 0.5103-0.7309), and higher tumor grade and stage remained independent risk factors for a lower pCR. Additional significant unfavorable prognostic factors for pCR included younger age, male sex, lower hospital treatment volume, and higher tumor grade or stage. Similarly, Black race, lower hospital treatment volume, absence of commercial medical insurance, and higher grade or stage were significant unfavorable prognostic factors for downstaging. Neither lower income nor fewer years of education was associated with pCR or tumor downstaging. Conclusions: The results confirm a lower rate of response to CRT in Black patients with LARC. The identification of race as an independent risk factor after adjustment for sociodemographic, geographic, and clinical factors suggests that other unknown variables–including genetic differences unaddressed in this study–must be pursued comprehensively in future studies. The more advanced stage of rectal cancers in Black patients suggests that critical evaluation of current cancer screening methods may play a role in this effort.
Mutation status of full RAS and BRAF in 169 Moroccan patients with colorectal cancer.
Authors: El zaitouni Sara , Laraqui Abdelilah , Ghaouti Meriem , Benzekri Asmae , Kettani Fouad , El Annaz Hicham , Abi Rachid , Tagajdid Mohamed Rida , El Kochri Safae , Lahlou Idriss Amine , Ameziane El Hassani Rabii , Ennibi Khalid 
Published: January 2023

216 Background: Morocco has the highest cancer mortality rate in MENA Countries. Colorectal cancer (CRC) is classified as the first digestive cancer and remains a burden in Morocco. According to the data on GLOBOCAN 2020, there were 4324 new CRC patients and 2374 deaths, accounting for 7.3% and 2.8% of all cancers, respectively. Our study aimed to investigate the frequency of the full RAS ( KRAS, NRAS) and BRAF genes in CRC patients from Morocco and their possible associations with clinico-pathological features. Methods: Archived FFPE of 169 CRC patients were screened for KRAS, NRAS and BRAF mutations by Idylla technology. Results: Full RAS mutations were identified in 46.1% (42% in KRAS, 4.1% in NRAS). In KRAS gene, exon 2 mutations accounted for 84.5% (69% in codon 12, 15.5 % in codon 13). Within codon 12, KRAS G12D and G12C were more frequently detected (29.5% and 16.9%, respectively). Detection of KRAS mutations, and particularly G12D and G12C subtypes, are of large significance for CRC patients, have possible therapeutic implications. Within codon 13, the most frequently observed mutation was G13D (15.5 %). Outside exon 2, the mutation rate was 35.1% (8.4% in exon 3 and 26.7% in exon 4). Concurrent KRAS mutations were identified in 8 cases, which suggests that multiple mutations can occur in the same or different codons. In NRAS gene, the mutation rates of exon 2 and 3 were 71.4% and 57.1% respectively. G13V and Q61K were the most common mutations, accounting for 28.6 % of each. Concurrent KRAS mutations were identified in 2 cases. Of the 169 samples, mutations in the BRAF gene at V600E were detected in 3.5%. Combined mutational analysis of KRAS, NRAS and BRAF was able to identify 49.6% of patients with CRC as likely non-responders to anti-EGFR therapy. There was an association between KRAS mutations and age, which were higher in the age group>50 years old (p=0.022). Tumors in the left colon (36.61%) are more likely to harbor mutations in KRAS than the rectum (19.7%) in both sexes. The adenocarcinoma well-differentiated was the most frequent for patients with KRAS mutations (54.9%). No significant clinicopathologic correlations with NRAS and BRAF mutations were identified. Conclusions: Beside established anti-CRC treatment, better understanding of the causality of CRC can be established by combining epidemiology and genetic/epigenetic on CRC etiology in Morocco. This approach may be able to significantly reduce the burden of disease in the country. Moreover, the Moroccan government should develop policy on CRC prevention and public health programs which may serve as a feasible setting to increase public awareness on lifestyle risk factors.
Impact of RAS and BRAF heterogeneity on the efficacy of EGFR blockade in patients with metastatic colorectal cancer.
Authors: Yamada Takeshi , Matsuhashi Nobuhisa , Takahashi Takao , Hirata Keiji , Nagasaka Takeshi , Nakamura Yuki , Sakamoto Kazuhiro , Koda Keiji , Hiramatsu Kazuhiro , Matsuoka Hiroshi , Kuramochi Hidekazu , Ishida Hideyuki , Kataoka Kozo , Yokomizo Hajime , Kagawa Yoshinori , Suenaga Mitsukuni , Ohta Ryo , Matsuda Akihisa , Yoshida Hiroshi 
Published: January 2023

219 Background: Epidermal growth factor receptor (EGFR) blockade can effectively shrink tumors in metastatic colorectal cancer (CRC) patients without RAS nor BRAF mutations. However, some patients without RAS nor BRAF mutations in their primary tumors have them in metastatic tumors (heterogeneity). Circulating tumor DNA (ctDNA) can reflect these mutations in metastatic tumors. Here, we evaluated the efficacy of EGFR blockade in patients who had no RAS nor BRAF mutations in their primary tumors, but who had them in ctDNA. Methods: We prospectively enrolled 100 patients with confirmed metastatic CRC without RAS nor BRAF mutations in their primary tumors. Patients were treated with first-line systemic chemotherapy that included EGFR blockade. We obtained ctDNA from each patient before they started chemotherapy, and at the time they acquired resistance. We detected RAS, BRAF (V600E), and PIK3CA mutations using digital polymerase chain reaction. Results: In the ctDNA obtained before starting chemotherapy, RAS, BRAF, and PIK3CA mutations were detected in 10, 4, and 2 of the 100 patients, respectively. No patients had both RAS and BRAF mutations in their ctDNA; however, one patient had both BRAF and PIK3CA mutations. Eighty-nine patients had measurable tumor lesions. Of those, 3 experienced a complete response (CR), 72 had a partial response (PR), 12 had stable disease (SD), and 2 had progressive disease (PD). Of 14 patients who had measurable tumors and RAS or BRAF mutations in the ctDNA, 11 (79%) had a PR and 3 (21%) had SD. Of 75 patients who had measurable tumors and no RAS or BRAF mutations in the ctDNA, 3 (4%) experienced a CR, 61 (81%) had PR, 9 (12%) had SD, and 2 (3%) had PD. Patients with RAS or BRAF mutations and patients with neither mutation had response rates of 79% and 85%, respectively. There was no significant difference. Conclusions: As we previously reported, incidence of RAS and BRAF heterogeneity were 10% and 4%, respectively. Heterogeneity of RAS and BRAF mutations had no effect on the response rate of EGFR blockade as first line chemotherapy. Other possible causes of resistance could be MET or HER-2 amplification, PIK3CA mutation, or ALK fusion. The effect of heterogeneity on the duration of response is of great interest; however, one-third of patients are still undergoing treatment with EGFR blockade. Clinical trial information: 000031177 .
Unique microbial biomarkers identified in Nigerian patients with colorectal cancer.
Authors: Abate Miseker , Alatise Olusegun Isaac , Omisore Adeleye Dorcas , Komolafe Akinwunmi O. , Omoyiola Oluwatosin Zainab , Abdulkareem Fatimah Biade , Olatoke Samuel Adegboyega , Adeyeye Ademola Adetoyese , Agodirin Sulaiman Olayide , Lawal AbdulRazzaq Oluwagbemiga , Olasehinde Olalekan , Osinowo Adedapo Olumide , Owoade Israel Adeyemi , Njokanma Iloba Gabriel , Oludara Mobolaji A , Kingham T. Peter , Weiser Martin R. , Vanderbilt Chad 
Published: January 2023

222 Background: The microbiome is an important biomarker associated with the pathogenesis and progression of disease in colorectal cancer (CRC). Genetic, dietary and environmental factors have been implicated in CRC microbial dysbiosis, however geographical distinctions in the microbiome of CRC are largely unknown. In this study, we characterize distinctions in the microbial diversity and microbial enrichment of CRC specimen obtained from a Nigerian and U.S. population. Methods: A validated microbiome bioinformatics pipeline that is generalizable across multiple next generation sequencing platforms was utilized. Microbial profiles for alpha diversity and enrichment were generated for two large, geographically distinct cohorts: (1) U.S. (n=498) and (2) Nigerian (n=65) cohorts. CRC specimen from Nigeria were compared to CRC specimen from the U.S. using the same microbial bioinformatics pipeline and methodology for analysis. Microbial differences stratified based on CRC microsatellite-instability (MSI) status were identified. Results: 9 unique microbial species were significantly enriched in the CRC specimen from the Nigerian cohort when compared to the US cohort. Subset analysis based on MSI status revealed enrichment of Faecalibacterium and Veillonella in the Nigerian cohort for both MSI and microsatellite stable (MSS) CRC (Table). Prevotella was significantly enriched in MSS CRC in the Nigerian cohort (OR=53.35, CI=10.34,275.37, p<0.001). There were no significant differences in alpha diversity between the Nigerian and U.S. cohorts (p>0.05). Conclusions: Several unique species with taxonomic diversity are enriched in Nigerian CRC and can be independently validated based on stratification by MSI status. Given the varied accessibility of diagnostic and therapeutic tools for CRC in these distinct geographical settings, understanding unique microbial biomarkers will provide the landscape to explore key microbial targets for therapy specific to this population.[Table: see text]
Immunohistochemical assessment of COX2, P53, and beta-catenin expression to predict metachronous lesion development following polypectomy.
Authors: Johnstone Mark Scott , Al-Badran Sara SF , Stoops Reiss , Hay Jennifer , Jawny Jakub , Lynch Gerard , McSorley Stephen T , Edwards Joanne 
Published: January 2023

234 Background: Following colorectal polypectomy, 20-50% develop metachronous polyps, and some have increased colorectal cancer (CRC) risk. Surveillance colonoscopy is recommended to high-risk patients, based on index polyp number, histology and size. We aimed to assess if COX2, p53 and beta-catenin expression could predict metachronous polyp/ CRC risk. Methods: Tissue microarrays (TMA’s) were constructed for 339 patients from the INCISE study, a retrospective analysis of all patients undergoing screening polypectomy (Apr’09-Dec’16) followed by surveillance (6months-6years) in Glasgow, UK. Epithelial COX2, p53 and beta-catenin expression were assessed for each patient’s most advanced index polyp using immunohistochemistry, quantified by QuPath software. Kaplan-Meier analysis, log-rank tests and univariate/ multivariate cox regression assessed the association between marker expression and time to metachronous polyp/ CRC detection. Results: Low nuclear p53 expression was associated with shorter time to metachronous polyp/ CRC detection (p=0.024). Low nuclear (p=0.012) and membranous (p=0.046) beta-catenin expression was associated with shorter time to metachronous polyp/ CRC detection. There was no association between cytoplasmic COX2 expression and time to metachronous polyp/ CRC detection overall (p=0.309), but high cytoplasmic COX2 expression was associated with shorter time to detection of advanced metachronous lesions (advanced colorectal polyps/ CRC) (p=0.011). A combined score using the two most powerful biomarkers (nuclear p53 and nuclear beta-catenin – both high/ one low/ both low) was also associated with shorter time to metachronous polyp/ CRC detection (p=0.011). Univariate and multivariate cox regression are shown. Conclusions: Index polyp number and combined nuclear p53/beta-catenin expression independently predicted time to metachronous polyp/ CRC detection. [Table: see text]