African American Colorectal Cancer Patients Research Articles

Abstract 6180: Tumor microenvironment phenotypes predict recurrence in African Americans diagnosed with colorectal cancer: A comparative study of manual grading with digital pathology

Abstract African Americans face a higher rate of colorectal cancer (CRC) incidence and mortality compared to other ethnicities. Identifying key prognostic factors is essential for better outcomes in this group. This study focused on the prognostic value of stromal grading in the tumor microenvironment (TME) of African American CRC patients, using both manual grading and digital pathology. A retrospective analysis of CRC cases in African Americans was conducted. Two cohorts were established: a control cohort (patients without recurrence) and a recurrence cohort (patients with recurrence). Stromal grading was performed manually, categorizing tumors into Grade 1 (low risk), Grade 2 (moderate risk), and Grade 3 (high risk), and we also quantified the TME percentages by digital pathology: myxoid, collagen, immune and tumor. In the control cohort (N=40), stromal grading identified 30 Grade 1, 7 Grade 2, and 3 Grade 3 cases. Conversely, the recurrence cohort (N=17) demonstrated a starkly different distribution, with 1 Grade 1, 3 Grade 2, and 13 Grade 3 cases. The Chi-square statistic was notably significant (p<0.0001), indicating a strong association between higher stromal grades and the likelihood of recurrence. By unpaired t-test, high myxoid stroma (p<0.0001), low collagen (p<0.0001), and low tumor (p=0.0002) by digital pathology were associated with recurrence. TME phenotypes are a significant prognostic and recurrence indicator in African American patients with CRC. The marked difference in stromal grades and digital pathology features between the control and recurrence cohorts suggests that higher stromal grades, along with higher myxoid, lower collagen and lower tumor percentages are associated with an increased risk of recurrence. These findings underscore the need for tailored therapeutic strategies and more vigilant surveillance in African American patients exhibiting high-risk TME phenotypes. The efficacy of manual and digital pathology evaluation of the TME also warrants further exploration to enhance prognostic accuracy and treatment personalization. Citation Format: Dongling Wu, Rong Xia, Mouyed Alawad, Lili Lee, Tamas Gonda, Wenqing Cao, Sean Hacking. Tumor microenvironment phenotypes predict recurrence in African Americans diagnosed with colorectal cancer: A comparative study of manual grading with digital pathology [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 6180.

Abstract 1907: Unique and novel deleterious MSH6 mutation among African American patients with colorectal cancer

Abstract Background: Colorectal cancer (CRC) incidence and mortality in African Americans (AA) is higher compared to Caucasians (CAU). It has also been reported that the disparity is due to differences in the mutation spectrum particularly germline mutations in the DNA mismatch repair (MMR) genes (such as hMSH6). Aim: We aimed to determine MSH6 mutation profile in AAs with CRC. Methods: We performed RNA sequencing in 8 paired CRC samples (AA, n=4 and CAU, n=4) to identify the unique transcript and novel pathogenic mutation in AA compared to CAU by comparing CRC matched to corresponding normal epithelia. In silico analysis of TCGA COAD RNA sequencing data was performed. Results: We found non-synonymous germline mutations (p.G1139S) in exon 5 of MSH6 gene (one of the MMR genes) in AA CRC samples. Interestingly, this mutation is present in the active site of ATP binding (1135 to 11442 residue) motif of MSH6 protein. In silico analysis was used to determine the novelty and pathogenicity of this mutation by comparison to various publicly available databases. Also, the deleterious effect of p.G1139S missense mutation on the structure of MSH6 protein revealed that p.G1139S is destabilizing MSH6 protein. Based on Ramachandran plot analysis, we found lot of clash and outliers in the mutant type compared to wild type MSH6 protein. Structural analysis revealed that serine substitution results in a wide ATP binding site compared to glycine present in wild-type MSH6. In addition, we found a loss of hydrogen bonding or gain of ionic interaction between wild-type and mutant MSH6 protein. Conclusion: Based on our in silico analysis, the deleterious effect of the detected missense mutation in the active site of ATP binding motif of MSH6 affects the structure and function of MSH6. This may result in the accumulation of mono-, or di-nucleotide repeats instability in the genome, leading to genomic alterations that associate with carcinogenesis in African American CRC patients. Citation Format: Mudasir Rashid, Rumaisa Rashid, Sudhir Varma, Zaki Sherif, John Carethers, Hassan Brim, Hassan Ashktorab. Unique and novel deleterious MSH6 mutation among African American patients with colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1907.

Abstract 647: Identification of novel and known hotspot variants in African Americans with colorectal cancer

Abstract Background: The recent introduction of the cancer hotspot panel can help enhance targeted cancer therapy, but requires further refinement to identify which genes have significant clinical value for the population of interest. We aim to determine such genes by identifying somatic alterations in the 48 cancer gene panel in African Americans. Methods: Tumor matched normal tissues (n=16) from African American colorectal cancer patients were analyzed using a 48 hotspot cancer panel by Ion Torrent sequencing. Variants of the genes found in TruSeq Amplicon - Cancer Panel (TSACP) were identified and validated. The type of variant was determined using bioinformatic pipelines including Ensembl's Variant Effect Predictor. The genes with relevant clinical value were determined based on frequency of somatic variants and results from previous studies. Results: Somatic variants were detected in 39/48 (82%) genes. Of the 39 genes, the 7 with the most clinical value were selected for further analysis. Overall, 46 novel and known hotspot somatic variants were determined in the following 7 genes: KRAS (7/46 [15%]), NRAS (2/46 [4%]), MLH1 (1/46 [2%]), PIK3CA (8/46 [18%]), SMAD4 (6/46 [13%]), RET (9/46 [20%]), and TP53 (13/46 [28%]). Of the KRAS variants, 57% (4/7) were found in codons 12 and 13 while the other 43% (3/7) were found in codons 117 and 146. Out of the 46 somatic variants, 30% (14/46) were in hotspot regions. Of the KRAS hotspot variants, 100% (4/4) were in codons 12 and 13. The 2 NRAS variants were in codons 59 and 61. Lastly, the 9 genes without variants in our population are CDKN2A, SMARCB1, AKT1, ALK, FGFR2, IDH2, CSF1R, HNF1A and MPL. Conclusion: We have identified novel and known hotspot somatic variants in African Americans with colorectal lesions. Patients with significant hotspot variants, primarily missense alterations, had a worse prognosis. As a result, cancer gene panel hotspot profile should be taken into consideration when treating African American CRC patients. Citation Format: Hassan Brim, Payaam Tavakoli, Mohammad Reza Daremipouran, Babak Shokrani, Edward Lee, Mehdi Nouraie, Adeinko O. Laiyemo, Hassan Ashktorab. Identification of novel and known hotspot variants in African Americans with colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 647.

Genomics of Colorectal Cancer in African Americans.

Genome-wide studies are increasingly becoming a must, especially for complex diseases such as cancer where multiple genes and diverse molecular mechanisms are known to be involved in genes' function alteration. In this review, we report our latest genomic and epigenomic findings in African-American colorectal cancer patients. This population suffers a higher burden of the disease and most investigators in this field are looking for the underlying genetic and epigenetic targets that might be responsible for this disparity. We here report genome-wide copy number variations, single nucleotide mutations and DNA methylation findings that might be specific to this population.

Lymph nodes' evaluation in relation to colorectal cancer staging among African Americans.

BackgroundLymph nodes’ examination in colorectal cancer (CRC) resection specimens is an important determinant that aids in the accuracy of CRC staging and treatment outcomes. Current guidelines call for the examination of at least 12 lymph nodes (LN) in resected specimens in order to establish accurate staging.AimTo investigate lymph nodes’ examination protocol as it relates to accurate CRC staging.MethodsWe reviewed 216 African American CRC patients from 1996–2013 who underwent CRC resection and met inclusion criteria for this study. The number of retrieved LNs, length of resected specimens, tumor grade, stage, location, size and histology were examined.ResultsThe cohort study was made of 49 % males, median age was 63 years and 45 % of patients were at stage III and IV. The median (IQR) number of examined LNs was 15 (10–22) and the rate of patients with more than 12 examined LNs was 64 %. There was a gradual increase in the percentage of patients with adequate number (>12) of examined LNs during the study period (from 60 % in 1996–2000 to 84 % in 2010–2013 period, P = 0.014). Adequate LNs resection was neither associated with shift of stage from II to III (P = 0.3) nor with the changes from stage IIIa to IIIc (P = 0.9). Metastatic LNs were observed in 8 % of samples with LNs (>12) vs. 13 % of samples with <12 examined LNs (P = 0.1). Patients that had pre-surgical treatment (chemotherapy and radiotherapy) before surgery had <12 LNs examined. There was also a trend of having more examined lymph nodes in large tumors.ConclusionsOur study shows that there has been an increase in the number of lymph nodes examined in CRC resections since the advent of the current quality initiative. However this increase does not seem to affect the stage or percentage of metastatic lymph nodes’ detection in CRC patients.

Abstract 3853: Predictive and prognostic analysis of KRAS and MSI markers in treatment of urban African American colorectal cancer patients

Abstract Background: Advancement of molecular analytic techniques has led to the discovery of a number of genetic biomarkers thought to be associated with prognosis and treatment outcomes in colorectal cancer (CRC). Aim: To analyze response to treatment in a group of CRC patients as a function of their genetic background. Method: A retrospective chart review of patients diagnosed with CRC from 2010- 2012 at Howard University Hospital was undertaken. African American (AA) patients diagnosed with CRC, the majority of whom received 5-Fluorouracil based chemotherapy, were selected. Data was collected from in-patient and out-patient records. Response to treatment was determined by Response Evaluation Criteria In Solid Tumors (RECIST) criteria from prior radiological investigations. The data was analyzed using Kaplan-Meier survival estimate and log rank test to compare the disease free survival (DFS) in correlation with clinical and genetic markers. Results: There were 30 AA patients with CRC who received chemotherapy. The average age of the cohort was 59 years, 53 % (n=16) were females and 80% (n=24) of the CRCs were distal. There were 10% (n=3), 23% (n=7), 37% (n=11), and 30% (n=9) patients at stage I, II, III, and IV, respectively. After three years of follow-up, disease free survival was 0.37 (95%CI: 0.14-0.60). Patients with MSI-H (n=3) had worse DFS. Patients with wild-type (WT) KRAS (n=16) had better DFS than mutant KRAS (n=10). The type of chemotherapy received did not affect response. Conclusions: DFS was worse in patients with a higher stage at the time of diagnosis, as well as, in patients with MSI-H versus MSS. Further study is warranted in AA since CRC patients with MSI-H historically have a better prognosis. DFS was found to be better in patients with WT KRAS, independent of chemotherapeutic regimen. These findings confirm that KRAS mutations negatively affected the prognosis in our study population. Table 1Characteristics of Responders vs Non-respondersCharacteristicsResponderNon-responderP-valueGenderMale770.4Female106Age&amp;lt; 60 years750.9≥60 years108StageI300.026II52III74IV27LocationLeft1590.3Right24MSIMSS157&amp;lt;0.0001(n=25)MSI-H03KRASmutant280.022(n=26)WT1245FUyes7120.1no101Oxaliplatinyes990.4no84Cetuximabyes100.6no1613Irinotectanyes020.05no1711 Citation Format: Priya Gopie, Maryam Yazdy, Bashira Giwa, Sanjeev Solomon, Gladys Onojobi, Seyed-Mehdi Nouraie, Bonnie Davis, Kamyar Sartip, Shokrani Babak, Lee Edward, Hassan Brim, Hassan Ashktorab. Predictive and prognostic analysis of KRAS and MSI markers in treatment of urban African American colorectal cancer patients. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3853. doi:10.1158/1538-7445.AM2014-3853

Identification of novel mutations by exome sequencing in African American colorectal cancer patients.

The purpose of this study was to identify genome-wide single nucleotide variants and mutations in African American patients with colorectal cancer (CRC). There is a need of such studies in African Americans, because they display a higher incidence of aggressive CRC tumors. We performed whole exome sequencing (WES) on DNA from 12 normal/tumor pairs of African American CRC patient tissues. Data analysis was performed using the software package GATK (Genome Analysis Tool Kit). Normative population databases (eg, 1000 Genomes SNP database, dbSNP, and HapMap) were used for comparison. Variants were annotated using analysis of variance and were validated via Sanger sequencing. We identified somatic mutations in genes that are known targets in CRC such as APC, BRAF, KRAS, and PIK3CA. We detected novel alterations in the Wnt pathway gene, APC, within its exon 15, of which mutations are highly associated with CRC. This WES study in African American patients with CRC provides insight into the identification of novel somatic mutations in APC. Our data suggest an association between specific mutations in the Wnt signaling pathway and an increased risk of CRC. The analysis of the pathogenicity of these novel variants may shed light on the aggressive nature of CRC in African Americans.

Sa1895 Identification of Novel APC Mutations by Exome Sequencing in African American Colorectal Cancer Patients

Sa1895 Identification of Novel APC Mutations by Exome Sequencing in African American Colorectal Cancer Patients

Abstract 1661: Fine-mapping of GWAS variants in BMP4, GREM1, CDH1, and RHPN2 in African American colorectal cancer patients

Abstract Background: Genome-wide association studies (GWAS) of colorectal cancer (CRC) have identified risk variants in candidate genes involved in TGF-ß signaling including BMP4, GREM1, CDH1, RHPN2 and SMAD7. We previously replicated the association with a 3′-UTR SNP in GREM1 (rs10318) in African Americans but did not find evidence of associations in the other genes. This finding could be explained by different genomic structure in African Americans. Therefore, we sought to fine-map these genes to identify CRC risk variants in African Americans who are at highest risk of CRC in the US. Methods: DNA from cases and controls was obtained from two US institutions. In total, we included DNA from 795 AA cases and 985 AA controls. TagSNPs with minor allele frequencies &amp;gt;5% and pairwise r2 &amp;gt;0.8 were identified in five genes using YRI Hapmap data. A total of 81 SNPs were genotyped in cases and controls using Sequenom MassARRAY. We calculated odds ratios and 95% confidence intervals using logistic regression controlling for ancestry, age, gender and multiple testing in PLINK. Results: Association analysis was completed for four genes: BMP4, GREM1, CDH1 and RHPN2. The top tagSNP associations for each gene are shown in the Table. None of the SNPs were significant after permutation testing. In GREM1, the strongest SNP associations were found at the 3′ end of the gene. In BMP4, we identified two SNPs (rs1957852 and rs7146040) that are in LD with rs4444235 previously identified in a European GWAS. In CDH1, rs12931189 is located in the same LD block as the strongest association signal (rs7199991) in a recent fine-mapping study in Europeans. Finally, we have no evidence for associations in RHPN2 in African Americans. Conclusion: These results provide preliminary evidence of associations in African American colorectal cancer patients in BMP4, GREM1 and CDH1 identified by GWAS in Europeans. Ongoing work is testing associations in SMAD7 and further fine-mapping by imputation and resequencing in these regions. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1661. doi:1538-7445.AM2012-1661

Molecular Analysis of Colorectal Tumors within a Diverse Patient Cohort at a Single Institution

African American colorectal cancer patients have worse survival outcomes than Caucasian patients. To determine whether differences exist in the molecular mechanisms driving colorectal cancer between African Americans and Caucasians, we characterized patient tumors from a single institution by assessing genetic alterations involved in colorectal cancer progression and response to treatment. We retrospectively examined 448 African Americans and Caucasians diagnosed with colorectal cancer at The University of Chicago Medical Center between 1992 and 2002. Microsatellite instability (MSI) status was determined by genotyping the BAT25, BAT26, BAT40, D5S346, and BAX loci. Mutations in KRAS codons 12 and 13 and BRAF codon 600 were identified by direct sequencing. MSI and detected mutations were correlated with clinicopathologic features. Overall, no difference existed in MSI or BRAF mutation frequencies between African Americans and Caucasians. However, African Americans with microsatellite stable (MSS)/MSI-low (MSI-L) tumors had a higher proportion of KRAS mutations than Caucasians (34% vs. 23%, P = 0.048) that was isolated to proximal colon cancers and primarily driven by mutations in codon 13. There was no racial difference in receipt of chemotherapy, but African Americans with MSS/MSI-L tumors had a 73% increased risk of death over Caucasians that could not be explained by known prognostic factors. The significantly higher risk of death among African Americans with MSS/MSI-L tumors may be related to differences in the distribution of factors influencing response to standard therapies. These data underscore the need for further research into the molecular mechanisms driving colorectal cancer progression in underserved and understudied populations.