Comprehensive genomic profiling of appendiceal adenocarcinoma.

Abstract

298 Background: Appendiceal adenocarcinomas (AAs) are orphan tumors. Little is known about their molecular profile limiting understanding of their biology and development of novel targeted therapies. The purpose of this study was to delineate the molecular landscape of AAs. Methods: We performed a retrospective review of AAs patients (pts) who were evaluated at MD Anderson Cancer Center between October 2012 and April 2017 and underwent next-generation sequencing (NGS) with internal or external assays (at least 45 genes) using either tumor tissue specimens or peripheral blood for circulating cell-free DNA (cfDNA). The primary outcome was to assess the prevalence of genomic alterations (GAs) in AAs. We then performed comparative exploratory analyses of GAs using TCGA colorectal cancer (CRC) sequencing. Results: A total of 78 patients were identified of which 57 (73%) and 18 (23%) underwent tissue based and ctDNA based sequencing, respectively (3 cases had both). At least 1 GA was found in 61 (78%) of AA specimens, with a mean (SD) of 2.8 (1.6) GAs per case. Of these 44 (72%) had ≥ 2 GAs and 31 (51%) had ≥ 3 GAs. The most frequent GAs were KRAS (38 [62%]), TP53 (22 [36%]), GNAS (17 [28%]), SMAD4 (11 [18%]), PIK3CA (10 [16%]), APC (9 [15%]), ATM (8 [13%]), BRAF (5 [8%]), KIT (5 [8%]), NRAS (3 [5%]) and MET (3 [5%]). GNAS mutations frequently co-occurred with KRAS mutations (42% v 5%, OR 14.3, P < 0.001). No GA was associated with grade, mucinous histology or overall survival (OS). Besides these mutations, we also found unusual cases with targetable mutations such as ALK, EGFR, MET, IDH1 and ERBB2. In our comparative analyses, mutations in KRAS (p = 0.009), TP53 (p = 0.020), GNAS (p < 0.001) and APC (p < 0.001) genes were significantly different from CRC whereas there was no difference in prevalence of PIK3CA, SMAD4 and ATM genes. Conclusions: To date, our analysis of one of the largest cohorts of AAs, demonstrate a majority of AAs harbor at least 1 GAs. Although treatment paradigms in AAs are extrapolated from CRC, the molecular profile of these tumors differs significantly. Molecular characterization of these rare tumors is a necessary first step towards discovery of opportunities for use of targeted therapies in these patients.

Genomic Landscape of Appendiceal Neoplasms

“…10 There is also a growing body of data showing that there are clear molecular differences between appendiceal and colorectal cancers. [11][12][13][14] Here we present a cohort of 703 molecularly profiled appendiceal neoplasms, the largest such cohort to date in this rare disease. Comparing the mutational landscapes across histologic subtypes we find significant differences in KRAS, GNAS, and FAT3 mutation prevalence and confirm that mutational profiles of appendiceal neoplasms are distinct from CRC and other GI cancers.…”

The Promise of Epigenetics Research in the Treatment of Appendiceal Neoplasms

“…Although alterations in KRAS (62%), TP53 (36%), GNAS (28%), and APC (15%) genes occur quite frequently in AC as a whole and have a significantly different mutational pattern from colorectal cancer, no clear associations with histology, grade, or survival have been identified [18]. For example, when stratifying survival based on GNAS vs. TP53 mutations, outcomes were similar to a histopathological stratification.…”

“…Despite the limitations detailed above, it has become apparent that appendiceal cancers have a unique molecular profile, and their molecular characteristics differentiate AC from other gastrointestinal cancers [17][18][19][20][21]. Even the appendiceal adenocarcinoma, widely considered closest to colorectal cancer among the appendiceal cancer subtypes, demonstrates a distinct molecular profile [38].…”

“…However, findings have remained inconclusive, and therefore, further molecular studies are needed to improve therapeutic strategies and develop molecular biomarkers for screening, early diagnosis, monitoring, and surveillance. In addition, although there is evidence that appendiceal cancers differ from the pathophysiology of other gastrointestinal cancers based on molecular studies, our understanding of the pathophysiology of appendiceal cancer is limited and remains to be further elucidated [17][18][19][20][21]. Cancer epigenetics have been shown in recent years to play a key role in the pathophysiology of gastrointestinal neoplasms, leading to discoveries and the development of biomarkers for detection, monitoring, surveillance, and therapeutic strategies [22].…”