Abstract
Relations between mutant KRAS and TP53 subtypes and other co-mutations in pancreatic cancer.
Author
Soniya Abraham
Bridgeport Hospital, Yale New Haven Health, Bridgeport, CT
info_outline
Soniya Abraham, Janie Yue Zhang, Zenta Walther, Jay Parekh, Jill Lacy, Michael Cecchini, Yiduo Hu
Full text
Authors
Soniya Abraham
Bridgeport Hospital, Yale New Haven Health, Bridgeport, CT
info_outline
Soniya Abraham, Janie Yue Zhang, Zenta Walther, Jay Parekh, Jill Lacy, Michael Cecchini, Yiduo Hu
Organizations
Bridgeport Hospital, Yale New Haven Health, Bridgeport, CT, University of Pittsburgh, School of Medicine, Pittsburgh, PA, Yale University Dept of Pathology, New Haven, CT, Yale University, New Haven, CT, Yale University School of Medicine, New Haven, CT, Yale New Haven Hospital, New Haven, CT
Abstract Disclosures
Research Funding
No funding received
None.
Background:
The most common mutations in pancreatic cancer are found in the
KRAS
,
TP53
,
CDKN2A
, or
SMAD4
genes. Mutations in genes involved in the DNA damage repair (DDR) pathway are also frequently seen. Despite extensive research on the patho-genomic features of pancreatic cancer, the clinical significance of these recurring mutations remains poorly understood.
Methods:
We identified patients with pancreatic cancer treated at Yale Cancer Center between 2016 and 2021 who underwent Oncomine tumor profiling. The incidence and subtypes of
KRAS
and
TP53
, and their association with other genomic alterations and clinicopathological variables were measured. We compared the overall survival (OS) after the diagnosis of recurrent or metastatic disease using the Kaplan-Meier method and long-rank tests.
Results:
One hundred fifty-nine patients were identified and
KRAS
mutations were seen in 144 (90.6%) patients, including 64 G12D (44.4%), 48 G12V (33.3%), 19 G12R (13.2%), 6 Q61H (4.2%), and 7 others (4.9%).
TP53
mutations were identified in 117 (73.6%) patients, including 80 loss-of-function (LOF) (68.4%), 24 gain-of-function (GOF) (20.5%), and 13 variants of unclear significance (VUS) (11.1%).
TP53
LOF mutations were more common in tumors with
KRAS
WT (40.0%), G12D (56.3%), and G12V (56.3%), than in G12R (31.6%) and others KRAS mutation (30.1%). Conversely,
TP53
GOF mutations were more common in tumors with G12R (26.3%) and other
KRAS
mutations (23.1%), than in
KRAS
WT (6.7%), G12D (14.1%), and G12V (12.5%). There was no difference in OS between
KRAS
subtypes (p=0.48) or
TP53
subtypes (p=0.52). Patients with
TP53
WT had a numerically longer but not statistically significant survival (median 1.65 years versus 1.16 years in patients with
TP53
mutations, p=0.20). When each
KRAS
subtype was examined, patients with tumors with G12V but no
TP53
mutation had longer OS (median 2.42 years) than those with WT
KRAS
or non-G12V mutation (median 1.38 years, p=0.02). Mutations in DDR genes were more frequently seen in the
KRAS
WT (33.3%) and G12D groups (15.6%), compared to that in the G12V (10.4%), G12R (10.5%) groups. Unique co-mutations were observed in certain KRAS subtypes but not others.
Conclusions:
In this retrospective study of comprehensive genomic and clinical data of pancreatic cancers, we found that
KRAS
or
TP53
mutation subtypes had no significant impact on OS. Different
KRAS
subtypes have unique co-occurring genomic alterations, which may be clinically relevant as novel KRAS inhibitors continue clinical development.
Unique co-mutations among different KRAS mutation subtypes.
WT
G12D
G12V
G12R
Q61H
BRAF, MAP2K1, CDKN2B, NBN1, MRE11A, NF1, NF2, ERBB3
BRCA1, ATR, RAD51B, MSH6, MDM2, AKT2, CCNE1, JAK3
RB1, CCND1, CTNNB1, RET, U2AF1
CHEK2, APC, CCND3
TOP1
7 organizations
24 drugs
Organization
Bridgeport HospitalOrganization
Yale New Haven HealthOrganization
University of Pittsburgh, School of MedicineOrganization
Yale University Dept of PathologyOrganization
Yale UniversityOrganization
Yale University School of MedicineOrganization
Yale New Haven HospitalDrug
KRAS inhibitorsDrug
BRAFDrug
MAP2K1Drug
CDKN2BDrug
NBN1Drug
MRE11ADrug
NF1Drug
NF2Drug
ERBB3Drug
BRCA1Drug
ATRADrug
RAD51BDrug
MSH6Drug
NavtemadlinDrug
AKT2Drug
CCNE1Drug
JAK3Drug
RB1Drug
CCND1Drug
CTNNB1Drug
RET TKIsDrug
U2AF1Drug
CHEK2Drug
APC R1468*