P58. Germline Mutation Profiles in Patients with Peritoneal Surface Malignancies of Appendiceal Origin

Peritoneal surface malignancies (PSM) of appendiceal origin are rare and biologically heterogeneous. While somatic alterations have been described, germline predisposition remains poorly characterized. Characterizing germline variants may identify biologically distinct subgroups and inform genetic counseling and therapeutic strategies.


Methods:

 Thirty-eight patients with peritoneal surface malignancies of appendiceal primaries underwent germline mutation testing (Invitae 70-gene hereditary cancer panel) using saliva swabs. Variants were classified as pathogenic or variants of uncertain significance (VUS). Genes were grouped into DNA repair, tumor suppressor, and RTK/oncogenic signaling pathways. Clinicopathologic correlations with tumor grade, histology, peritoneal cancer index (PCI), and overall survival (OS) from time of PSM diagnosis were assessed.


Results:

Thirteen of 38 patients (34%) harbored germline variants, including 2 (5%) with pathogenic mutations and 11 (29%) with variants of unknown significance (VUS). Three patients (23%) had multiple alterations.

Half of all mutations (8/16, 50%) involved DNA repair genes (MUTYH, ATM, BRCA1/2, PALB2, POLD1), followed by tumor suppressor genes (TSC1, FLCN, SMARCA4, POT1, STK11; 5/16, 31%), and RTK/oncogenic signaling genes (RET, PRKAR1A; 3/16, 19%). All pathogenic mutations occurred in DNA repair genes.

No significant association was found between mutation status and tumor grade (p = 0.81), histology (p=0.09), or PCI ( >20 vs ≤20, p= 0.3). Mutation prevalence was highest in goblet cell adenocarcinoma (5/10, 50%) compared with mucinous (0/2, 0%), colonic-type (3/11, 27%), and low-grade appendiceal mucinous neoplasms (5/15, 33%).Patients with DNA repair mutations tended to have higher PCI scores ( >20) (Figure 1).

Median overall survival (OS) was 35.2 months for mutation-positive patients and not reached for mutation-negative patients (p = 0.85). OS did not differ significantly among mutation subgroups.


Conclusions:

Germline variants were present in one-third of patients with appendiceal peritoneal metastases, most frequently affecting DNA repair genes. Although most alterations were variants of uncertain significance, the prevalence exceeded that reported in broader cancer populations (9–28%). These findings suggest underlying biologic heterogeneity and reinforce the value of routine germline testing to uncover hereditary risk and inform patient counseling.