Abstract A081: Molecular phenotyping and risk stratification of intraductal papillary mucinous neoplasms

Abstract Objective: Morphological subtyping of intraductal papillary mucinous neoplasms of the pancreas (IPMNs) into pancreatobiliary-type, intestinal-type, or gastric-type is a prognostic factor, however, molecular foundations explaining the difference of clinical behaviors are unknown. Our research aimed to elucidate the molecular phenotypes associated with subtypes of IPMNs and establish a risk stratification model. Design: In 171 IPMNs with high-grade dysplasia (HGD) and invasive carcinoma, we analyzed protein expressions of p16, p53, SMAD4, STK11, and β-catenin by immunohistochemistry, and mutations and copy number variations of KRAS and GNAS by droplet digital PCR, and analyzed the association with clinicopathological factors. Results: In HGD components of IPMNs of pancreatobiliary- (n=66), intestinal- (n=70), and gastric-type (n=35), alterations were detected respectively as follows: KRAS mutation; 98%, 62%, and 83% (P<0.05), GNAS mutation; 11%, 82%, and 51% (P<0.05), p53; 59%, 33%, and 20% (P<0.05), SMAD4; 67%, 1%, 37% (P<0.05), STK11; 43%, 3%, and 6% (P<0.05), β-catenin; 48%, 68%, and 23% (P<0.05), and p16; 65%, 52%, and 40% (P=0.105). Aberrations of 4 driver genes, p16, p53, SMAD4, and STK11, were succeeded from components of low-grade dysplasia to invasive carcinoma and associated with the risk of invasion of intraductal neoplasms and the patients’ outcomes. The combinatorial system by the number of accumulated gene alterations well stratified the risk of invasion (0–1 vs 2; odds ratio (OR) 4.62, 0–1 vs 3–4; OR 12.90) and patients’ outcome (0–1 vs 2; hazard ratio (HR) 4.01, 2 vs 3–4; HR 3.98, 0–1 vs 3–4; HR 15.99 in disease-free survival, 0–1 vs 2; HR 6.62, 2 vs 3–4; HR 4.43, 0–1 vs 3–4; HR 29.32 in overall survival). Moreover, GNAS amplification was an independent risk factor of invasion (OR 7.79) and showed poor prognosis (overall survival, log-rank P<0.05) in intestinal-type IPMNs, while sole GNAS activating mutation was an independent low risk factor for invasion (OR 0.33). KRAS amplification might be a poor prognostic factor in pancreatobiliary-type IPMNs (HR 2.7, P=0.07). Conclusion: The molecular patterns involving the malignant progression are different among epithelial subtypes of IPMNs. The molecular phenotypes of combinatorial genomic alterations of tumor suppressor genes with signature of KRAS and GNAS of intraductal components may stratify the risk of invasion and survival in IPMN patients. Molecular phenotyping using liquid biopsy of pancreatic juice during the surveillance might be additional value of decision making for operative timing in IPMNs showing equivocal radiological findings. Citation Format: Yuko Omori, Yusuke Ono, Takashi Kokumai, Fumiko Date, Ryota Higuchi, Goro Honda, Yusuke Mizukami, Takanori Morikawa, Michiaki Unno, Toru Furukawa. Molecular phenotyping and risk stratification of intraductal papillary mucinous neoplasms [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr A081.