Faculty Bibliography

Background: Mucinous adenocarcinoma is a special type of colorectal cancer (CRC) that has poor response to the treatment, more aggressive behavior and poorer outcome than non-mucinous CRC. Its biological and clinical behavior is largely determined by its molecular genetics. However, the genetics of this group of CRC is yet to be defined. Design: 152 cases of resected CRC with sequencing data generated by Ion AmpliSeq Cancer Hotspot Panel (or 50 genes) in the past two years were retrospectively retrieved from the departmental databases. No neoadjuvant therapy was performed before surgery. CRCs were divided into two groups: 1). Mucinous CRC (MCRC) group (13 mucinous CRC and 19 CRC with at least 20% of mucinous component (n=32) and 2). Non-mucinous CRC (NMCRC) group without mucinous component (n=120). The type and frequency of gene mutations and microsatellite instability (MSI) status defined by immunohistochemistry for mismatch repair proteins were analyzed. Fisher exact test was employed for statistical analysis. Results: In MCRC group, 31 of 32 (97%) were positive for the mutation of either KRAS (15/32), BRAF (15/32) or double mutations (1/32). Only one case showed no mutation for KRAS or BRAF, but TP53. The highest frequent mutations in MCRC group were KRAS (16/32) and BRAF (16/32), PIK3CA (10/32), followed by APC (9/32) and TP53 (8/32). In NMCRC group, 64 of 120 (53%) cases had either KRAS (50/120, 42%) or BRAF (14/120, 12%) mutation, and no double mutations. TP53 mutation (65/120, 54%) is most frequent mutation in this group, followed by KRAS (50/120, 42%), APC (39/120, 33%), PIK3CA (26/120, 22%) and BRAF (14/120, 12%). MSI-high status is more frequently seen in BRAF mutated CRCs in MCRC group (12/15, 80%) than in BRAF mutated NMCRC group (50%) (p<0.05), suggesting that MSI-high status is more commonly related with epigenetic effect in MCRCs. Conclusions: The vast majority of mucinous CRC or CRC with mucinous component have the mutations either in KRAS or BRAF in EGFR signaling pathway, suggesting that dysregulation of EGFR pathway plays a critical role in the development of mucinous CRC or CRC with mucinous component. Poor response to the treatment of mucinous adenocarcinoma may be partially attributable to the unique genetics of this group of CRCs

Background: CRC is a heterogeneous and complex disease, harboring numerous genetic and epigenetic alterations acquired during cancer development. The genetics and epigenetics of CRCs may dictate their histology, biology, and clinical outcome. We reviewed the sequencing data generated from the next generation sequencing technology to analyze the relationship between the quantity of gene mutations and the biology of CRCs Design: 152 cases of resected CRCs without neoadjuvant therapy that have sequencing data generated by Ion AmpliSeq Cancer Hotspot Panel (or 50 genes panel) were retrospectively identified from the department database. These 152 cases also had immunostaining results for mismatch repair proteins (surrogate markers for Microsatellite instability status, or MSI). The CRCs were divided into two groups: hypermutated (3 or more gene mutations) and hypomutated (2 or less gene mutations). Tumor grade, T stage, lymph node metastasis, and MSI status in the two groups were compared and the data analyzed using Fisher's exact test. Results: Of the 152 cases, 93 (61.2%) were classified into the hypomutation group and 59 (38.8%) into the hypermutation groups. In the hypomutation group, 80 (86.0%) were low (well and moderately differentiated) and 13 (14.0%) were high grade (poorly differentiated) CRCs. In the hypermutation group, 37 (62.7%) were diagnosed as low and 22 (37.3%) as high grade CRCs. The hypermutation status is strongly associated with high tumor grade (P=0.0014). High T stages (stage 4) does not correlate with mutation status (25/93 in hypomutation group and 19/59 in hypermutation group, p>0.05). In addition, no correlation between hypermutation and positive lymph nodes or MSI-High was found (54/93 or 20/90 in hypomutation group and 29/59 or 18/57 in hypermutation group, p>0.05). Conclusions: CRCs with hypermutation detected by Ion AmpliSeq Cancer Hotspot Panel are more likely to have high grade of histology, suggesting accumulation of gene mutations leading to worse biological behavior

Copy number alterations(CNAs) are the most common genetic changes observed in many cancers, reflecting the innate chromosomal instability of this disorder. Yet, how these alterations affect gene function to promote metastases across different tumor types has not been established. In this study, we developed a pan-cancer metastasis potential score (panMPS) based on observed CNAs. panMPS predicts metastasis and metastasis-free survival in cohorts of patients with prostate cancer, triple negative breast cancer and lung adenocarcinoma, and overall survival in the Metabric breast cancer cohort and three cohorts from The Cancer Genome Atlas (TCGA), including prostate, breast and lung adenocarcinoma. These CNAs are present in cell lines of metastatic tumors from eight different origins, reflected by an elevated panMPS for all cell lines. Many copy number alterations involve large chromosomal segments that encompass multiple genes ("clumps"). We show that harnessing this structural information to select only one gene per clump captures the contributions of other genes within the clump, resulting in a robust predictor of metastasis outcome. These sets of selected genes are distinct from cancer drivers that undergo mutation, and in fact, metastasis-related functions have been published for over half of them.

Infections caused by foodborne enteric pathogens including typhoidal and non-typhoidal Salmonella species can mimic symptoms of acute appendicitis. The association between such bacterial pathogens and pathology-proven acute appendicitis has been described, but this link is poorly understood. Here we describe a case of a young man with typhoid fever presenting with histology-proven acute appendicitis requiring urgent appendectomy, and provide a brief review of relevant literature to prompt more widespread recognition of this rare cause of a common surgical emergency.