SMAD4 is an essential mediator in the transforming growth factor-β pathway. Sporadic mutations of SMAD4 are present in 2.1–20.0% of colorectal cancers (CRCs) but data are limited. In this study, we aimed to evaluate clinicopathologic characteristics, prognosis, and clinical outcome associated with this mutation in CRC cases. Data for patients with metastatic or unresectable CRC who underwent genotyping for SMAD4 mutation and received treatment at The University of Texas MD Anderson Cancer Center from 2000 to 2014 were reviewed. Their tumors were sequenced using a hotspot panel predicted to cover 80% of the reported SMAD4 mutations, and further targeted resequencing that included full-length SMAD4 was performed on mutated tumors using a HiSeq sequencing system. Using The Cancer Genome Atlas data on CRC, the characteristics of SMAD4 and transforming growth factor-β pathway mutations were evaluated according to different consensus molecular subtypes of CRC. Among 734 patients with CRC, 90 (12%) had SMAD4 mutations according to hotspot testing. SMAD4 mutation was associated with colon cancer more so than with rectal cancer (odds ratio 2.85; p<0.001), female sex (odds ratio 1.71; p = 0.02), and shorter overall survival than in wild-type SMAD4 cases (median, 29 months versus 56 months; hazard ratio 2.08; p<0.001 [log-rank test]). SMAD4 mutation was not associated with age, stage at presentation, colonic location, distant metastasis, or tumor grade. A subset of patients with metastatic CRC (n = 44) wild-type for KRAS, NRAS, and BRAF who received anti-epidermal growth factor receptor therapy with mutated SMAD4 (n = 13) had shorter progression-free survival duration than did patients wild-type for SMAD4 (n = 31) (median, 111 days versus 180 days; p = 0.003 [log-rank test]). Full-length sequencing confirmed that missense mutations at R361 and P356 in the MH2 domain were the most common SMAD4 alterations. In The Cancer Genome Atlas data, SMAD4 mutation frequently occurred with KRAS, NRAS, and BRAF mutations and was more common in patients with the consensus molecular subtype 3 of CRC than in those with the other 3 subtypes. This is one of the largest retrospective studies to date characterizing SMAD4 mutations in CRC patients and demonstrates the prognostic role and lack of response of CRC to anti-epidermal growth factor receptor therapy. Further studies are required to validate these findings and the role of SMAD4 mutation in CRC.

Background Colorectal high-grade neuroendocrine carcinomas (HGNEC) are a rare but aggressive group of malignancies without standard management recommendations. Methods We retrospectively reviewed the records of 100 consecutive patients with histologically confirmed colorectal HGNEC diagnosed at MD Anderson Cancer Center between 1991 and 2013. Results In our cohort, most tumors (89 %) were small cell carcinoma, and most (60 %) involved the sigmoid or the anorectal regions. Sixty-four patients (64 %) presented with metastatic disease at diagnosis. Striking epidemiological and clinical differences between those established in small cell lung cancer (SCLC) and our cohort were noted, including significantly lower rates of smoking and lower risk of bone, brain metastases. Over 30% of the tumors were found associated with an adenoma. Median overall survival (OS) of the cohort was 14.7 months, with 2-year and 5-year OS rates of 23 % and 8 %, respectively. In patients with localized disease, multimodality therapy was associated with a trend toward improved median OS (20.4 versus 15.4 months, p = 0.08). Metastases at presentation (OS 20.63 vs 8.7 months; localized vs metastatic disease at presentation, p < 0.001) and elevated LDH were strongly associated with a worse outcome. Conclusion In comparison to SCLC, less than half patients with colorectal HGNEC have history of smoking; metastatic patterns are also different between the two cancers. Nevertheless, HGNEC also has a aggressive biology with the rectum being the most common site of origin. For localized disease, multimodality approach seems to be associated with better outcomes, while systemic chemotherapy is the mainstay of treatment for advanced disease.

BACKGROUND: CpG island methylator phenotype (CIMP) tumors, comprising 20% of colorectal cancers, are associated with female sex, age, right-sided location, and BRAF mutations. However, other factors potentially associated with CIMP have not been robustly examined. This meta-analysis provides a comprehensive assessment of the clinical, pathologic, and molecular characteristics that define CIMP tumors. METHODS: We conducted a comprehensive search of the literature from January 1999 through April 2018 and identified 122 articles, on which comprehensive data abstraction was performed on the clinical, pathologic, molecular, and mutational characteristics of CIMP subgroups, classified based on the extent of DNA methylation of tumor suppressor genes assessed using a variety of laboratory methods. Associations of CIMP with outcome parameters were estimated using pooled odds ratio or standardized mean differences using random-effects model. RESULTS: We confirmed prior associations including female sex, older age, right-sided tumor location, poor differentiation, and microsatellite instability. In addition to the recognized association with BRAF mutations, CIMP was also associated with PIK3CA mutations and lack of mutations in KRAS and TP53. Evidence of an activated immune response was seen with high rates of tumor-infiltrating lymphocytes (but not peritumoral lymphocytes), Crohn-like infiltrates, and infiltration with Fusobacterium nucleatum bacteria. Additionally, CIMP tumors were associated with advance T-stage and presence of perineural and lymphovascular invasion. CONCLUSION: The meta-analysis highlights key features distinguishing CIMP in colorectal cancer, including molecular characteristics of an active immune response. Improved understanding of this unique molecular subtype of colorectal cancer may provide insights into prevention and treatment.

BackgroundAppendiceal neuroendocrine neoplasms are most often diagnosed incidentally during appendectomy. The need for subsequent right hemicolectomy (RHC) is determined based on the risk of regional lymph node (LN) involvement. Tumor size has historically been used as an indicator of this risk, but controversy remains regarding its cut off. Furthermore, the impact of RHC on survival is unclear.MethodsWe used the SEER database to identify patients diagnosed with appendiceal neuroendocrine tumors.ResultsOf 1731 patients, 38.0% had well-differentiated neuroendocrine tumors (WDNETs), 60.8% had mixed histology tumors (MHTs), and 1.2% had poorly differentiated neuroendocrine carcinomas (PDNECs). In patients with WDNETs and MHTs who had adequate lymphadenectomy, higher rates of LN involvement were noted for tumors size 11–20 mm than ≤10 mm (56.8% vs. 11.6%, p <0.001; 32.9% vs. 10.4%, p=0.004, respectively). The type of surgery did not affect OS in cases with MHTs with LN involvement (HR 1.00; 95% CI, 0.53–1.89; p =0.99). Patients with regionally advanced WDNET showed excellent survival and only 3 patients (out of 118) died from cancer within 10 years.Conclusions10 mm appears to be a more appropriate cutoff than 20 mm for predicting LN metastasis in appendiceal NETs. Cases with WDNETs and nodal involvement demonstrate overall excellent prognosis irrespective of type of surgery (i.e. RHC may not improve outcome). In MHTs with LN metastases, survival is markedly worse in spite of RHC. The role of adjuvant therapy should be evaluated in this subset.

Introduction: ARID1A is commonly mutated in colorectal cancer (CRC), frequently resulting in truncation and loss of protein expression. ARID1A recruits MSH2 for mismatch-repair during DNA replication. ARID1A deficiency promotes hypermutability and immune activation in preclinical models but its role in CRC patients is being explored. Methods:The DNA sequencing and gene expression profiling of CRC patients were extracted from TCGA and MD Anderson Cancer Center databases, with validation utilizing external databases, and correlation between ARID1A and immunologic features. Immunohistochemistry for T-cell markers was performed on a separate cohort of patients.Results: 28/417 MSS CRC patients (6.7%) had ARID1A mutation. Among 58 genes most commonly mutated in CRC, ARID1A mutation had the highest increase with frameshift mutation rates in MSS cases (8-fold, p<0.001). In MSS, ARID1A mutation was enriched in immune subtype (CMS1) and had a strong correlation with IFN-γ expression (Δz score +1.91, p<0.001). Compared with ARID1A wild-type, statistically significant higher expression for key checkpoint genes (e.g., PD-L1, CTLA4, and PDCD1) and genes sets (e.g., antigen presentation, cytotoxic T cell function, and immune checkpoints) was observed in mutant cases. This was validated by unsupervised differential expression of genes related to immune response and further, confirmed by higher infiltration of T-cells in IHC of tumors with ARID1A mutation (p=0.01). Conclusion:The immunogenicity of ARID1A mutant cases is likely due to increased level of neoantigens resulting from increased TMB and frameshift mutations. Tumors with ARID1A mutation may be more susceptible to immune therapy-based treatment strategies and should be recognized as a unique molecular subgroup in future immune therapy trials.