NEW YORK (GenomeWeb) – A team of researchers from the University of California, San Diego and Foundation Medicine has identified a set of genetic biomarkers that distinguish appendiceal neoplasms from similar acting colorectal cancer (CRC) cases.
In a study published this week in JCO Precision Oncology, corresponding author and UCSD researcher John Paul Shen and his colleagues genomically profiled 703 appendiceal neoplasms — the largest such cohort to date — to compare the mutation profiles of appendiceal cancer subtypes to CRC and other cancers.
Appendiceal neoplasms are rare, and therefore difficult to study, the authors wrote. The small number of appendiceal tumors that are detected are found in many cases as an incidental finding in about 1 percent of appendectomy specimens. They usually comprise multiple histopathologic subtypes.
Early-stage cancers can be treated with surgery, but there is no standard of care for the systemic treatment of advanced, unresectable disease, the researchers said. As there is an absence of randomized phase III data, medical oncologists tend to use CRC chemotherapy regimens to treat unresectable epithelial appendiceal neoplasms. In fact, the National Comprehensive Cancer Network guidelines currently recommend such treatment.
However, the authors found, "there is also a growing body of data showing that there are clear molecular differences between appendiceal and colorectal cancers."
The team submitted the 703 specimens to Foundation Medicine' CLIA-based lab in Boston, where researchers performed hybrid-capture-based sequencing on 3,769 exons from 315 cancer-related genes and 47 introns of 28 genes commonly modified in cancer. They then analyzed interactions between genotype, histological subtype, treatment, and overall survival in a clinical subset of 76 cases at UCSD.
The investigators confirmed that genetic mutations in appendiceal cancer do indeed differ from those found in colon cancer. In addition, they saw that mutations in the TP53 and GNAS genes act as strong predictors of survival among individuals with appendiceal neoplasms, especially in low-grade tumors.
Shen and his team also discovered that appendiceal neoplasms consist of five distinct histopathologic subtypes: mucinous adenocarcinomas, adenocarcinomas, goblet cell carcinoids, pseudomyxoma peritonei, and single ringlet cell carcinomas (SRCCs). In addition, they noticed significant differences in KRAS, GNAS, and FAT3 mutation prevalence among the subtypes.
Because clinicians typically treat metastatic appendiceal cancers with CRC regimens, the team then compared genomic alteration profiles in appendiceal subtypes with those of 10,000 CRCs profiled by the same laboratory.
Mutation in the GNAS gene appeared much more frequently in appendiceal cancers than CRC tumors, especially in mucinous adenocarcinomas and pseudomyxoma peritonei. In contrast, APC and TP53 mutations occurred less frequently in appendiceal cancers relative to CRC.
In order to figure out the impact of histologic and molecular features on clinical outcomes, the team performed a retrospective review of a series of cases at UCSD. Determining overall survival from the time of initial diagnosis, the researchers saw a trend toward better overall survival for low-grade appendiceal mucinous neoplasms and worse overall survival for SRCCs.
Patients with tumors containing a GNAS mutation had a median survival of almost 10 years, while individuals with TP53 mutations had a median survival rate of three years. In comparison, patients lacking either of the mutation had an average six-year survival rate.
The authors acknowledged the study's retrospective design as one of its major limitations. In terms of the larger cohort examined at the Foundation Medicine lab, the researchers lacked clinical information such as the precise stage of cancer that they collected from patients. While pathologists independently reviewed the samples before they underwent sequencing, the authors noted that the subtype definitions were "subject to overlap and variability," since there was "no classification system until recently."
In addition, the authors mentioned that other limitations in the 76-patient UCSD cohort included the single-institution element, small sample size, and relatively limited time of follow-up. The researchers also struggled to analyze interactions between genotype and specific drugs because most patients previously received multiple lines of chemotherapy.
The authors noted that the study "highlights the benefit of performing molecular profiling on rare tumors to identify prognostic and predictive biomarkers and new therapeutic targets."
In a statement, Shen added, "For tumors that are rare like appendix cancer, obtaining molecular profiles will help identify potential treatment options since we don't have the clinical trial data to help guide treatments as we do in common tumors. [The] mutation profile can be used a biomarker to separate high-risk patients, who need intensive treatment, from low-risk patients who may not need such an intensive treatment."