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Colorectal

Colorectal Parallel Session

25: GNAS Driver Mutations in Primary and Metastatic Nonmucinous Appendiceal Adenocarcinoma Versus Analogous Colorectal Cancers. An AACR Project GENIE Analysis.

Friday, March 22, 2024
11:02am – 11:12am ET
Location: C101

    Abstract Presenter(s)

  • Andrew M. Fleming, MD

    Surgery Resident
    Department of Surgery, University of Tennessee Health Science Center
    Memphis, Tennessee, United States

    • Submitter(s)

  • Andrew M. Fleming, MD

    Surgery Resident
    Department of Surgery, University of Tennessee Health Science Center
    Memphis, Tennessee, United States

    • Author(s)

  • Andrew M. Fleming, MD

    Surgery Resident
    Department of Surgery, University of Tennessee Health Science Center
    Memphis, Tennessee, United States

  • Leah E. Hendrick, MD, MS

    Surgical Oncology Fellow
    Moffitt Cancer Center, United States

  • JP

    Julia P. Pedo Freitas, MD

    Surgery Resident
    Department of Surgery, The University of Tennessee Health Science Center, United States

  • SS

    Suraj Sarvode Mothi, MPH

    Senior Biostatistician
    Department of Biostatistics, St. Jude Children’s Research Hospital, United States

  • IS

    Ian B. Solsky, MD

    Assistant Professor of Surgery
    Department of Surgery, The University of Tennessee Health Science Center, United States

  • DY

    Danny Yakoub, MD, PhD, FACS

    Chief of Surgical Oncology
    Department of Surgery, Medical College of Georgia, Augusta University, Augusta, GA, USA, United States

  • AM

    Andrew J. Murphy, MD

    Chief, General Pediatric Surgery Division
    Department of Surgery, St. Jude Children’s Research Hospital, United States

  • EG

    Elizabeth Gleeson, MD, MPH

    Assistant Professor of Surgery
    Department of Surgery, University of North Carolina, United States

  • Evan S. Glazer, MD, PhD, FACS, FSSO (he/him/his)

    Associate Professor of Surgery
    Department of Surgery, University of Tennessee Health Science Center
    Memphis, Tennessee, United States

  • David Shibata, MD, FACS, FSSO, FASCRS

    Professor and Chair of the Department of Surgery
    University of Tennessee Health Science Center, Department of Surgery
    Memphis, TN, United States

  • Jeremiah L. Deneve, DO (he/him/his)

    Associate Professor of Surgery
    University of North Carolina at Chapel Hill
    Chapel Hill, North Carolina, United States

Disclosure(s):
Andrew M. Fleming, MD: No financial relationships to disclose
Evan S. Glazer, MD, PhD, FACS, FSSO: Anviron: Consultant (Ongoing); Delcath Systems: Research Grant (Ongoing)
Jeremiah L. Deneve, DO: No financial relationships to disclose
Introduction:

Systemic therapy recommendations for appendiceal adenocarcinoma (AA) are based on data from colorectal cancer (CRC) studies. A more nuanced understanding of the genomic underpinnings of AA could help drive the development of more precise and effective systemic therapies.  The current study assessed distinct driver mutations in primary and metastatic AA and CRC using the largest publicly accessible cancer clinicogenomic dataset.



Methods:

The American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE) dataset “GENIE Cohort v14.0-public,” released September 2023, was queried for CRC and AA samples via cBioPortal for Cancer Genomics. Exclusion criteria included non-adenocarcinoma histology, mucinous histology, and missing data regarding primary versus metastatic site of origin. Sample-level genomic alterations were compared using Fisher’s exact tests, with multiple hypothesis testing corrected via the Benjamini-Hochberg method. q-values < .01 denoted statistical significance. Volcano plots of log2 alteration ratios and -log10 p-values were used to visualize differential rates of mutations between groups.



Results:

15,117 CRC samples (10,056 primary, 5,061 metastatic) and 300 AA samples (133 primary, 167 metastatic) were included. In primary samples, there were no differences between groups in age, sex, or race, (all q >.05). In metastatic samples, patients with AA were more often female (59.3% vs. 46.0%, q < .01), but similar to those with CRC in age and race (both q >.05). Compared to primary CRC, primary AA had higher rates of GNAS mutations (24.2% vs. 4.8%, q < .0001). Metastatic AA also had higher rates of GNAS mutations than metastatic CRC (15.7% vs. 4.5%, q < .0001). Among GNAS mutations in metastatic AA, R201H (9.2% vs. 0.8%, q < .0001) and R201C (6.1% vs. 0.4%, q < .0001) missense putative driver mutations in the switch I domain on exon 8 of the GNAS protein were more commonly identified than in metastatic CRC. APC mutations were less common in AA than CRC in primary (13.7% vs. 67.0%, q < .0001) and metastatic (8.4% vs. 66.4%,  q < .0001) samples. TP53 mutations were also less common in both primary AA (39.4% vs. 68.7%, q < .0001) and metastatic AA (34.0% vs. 73.1%, q < .0001) than in analogous CRC samples.



Conclusions:

Higher rates of oncogenic GNAS mutations are observed in AA than CRC in both primary and metastatic samples, even when excluding mucinous histologies. Investigating GNAS as a potential therapeutic target in GNASR201H and GNASR201C-mutant AA should be prioritized.

Learning Objectives:

  • Upon completion, participant will be able to discuss the current systemic treatment recommendations for primary and metastatic appendiceal adenocarcinoma.
  • Upon completion, participant will be able to discuss key differences between the genetic driver mutations of metastatic appendiceal adenocarcinoma and colorectal cancer.
  • Upon completion, participant will be able to identify specific missense putative driver mutations in metastatic appendiceal adenocarcinoma.