TP53
Y220C mutations in pancreatic ductal adenocarcinoma (PDAC): A genomic landscape study.
Authors: Robinson Hannah Ruth , Pavlick Dean , Balmaceda Nicole Baranda , Ueberroth Benjamin Edward , Hayden Alexander , Baiyee Toegel Emily , Lentz Robert William , Leal Alexis Diane , Kim Sunnie S. , Messersmith Wells A. , Lieu Christopher Hanyoung , Ross Jeffrey S. , Davis S. Lindsey 
Published: January 2025

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Background:
A novel targeted therapy designed to restore wild-type function to the p53 Y220C mutant protein has demonstrated promising activity in an early-phase trial (NCT04585750). While the
TP53
Y220C mutation is found in < 1% of all solid malignancies, its prevalence is enriched in certain cancers including PDAC. Here we report results of comprehensive genomic profiling (CGP) in a cohort of patients with advanced PDAC, with a focus on
TP53
Y220C mutations.
Methods:
A total of 27,377 cases of clinically advanced PDAC underwent hybrid capture-based CGP to assess all classes of genomic alterations (GAs). Cases were sequenced to a mean coverage depth of 650X. Microsatellite instability (MSI) status and tumor mutation burden (TMB) were determined using sequencing data; PD-L1 expression was measured by immunohistochemistry (Dako 22C3, tumor proportion score [TPS]).
Results:
TP53
Y220C alterations were identified in 488 (1.8%) PDAC patients (Y220C+). In comparison to PDAC patients lacking the
TP53
Y220C alteration (Y220C-), Y220C+ patients were of similar age, but were more likely to be female (52.9% vs 46.8%; p = 0.0008) and harbor
KRAS
mutations (96.7% vs 92.7%; p = 0.007). Meanwhile, alterations in
ATM
were more frequent in the Y220C- group (4.0% vs 1.4%; p = 0.0008). Frequencies of other GAs were similar between Y220C+ and Y220C- groups, including alterations in the homologous recombination defect-associated genes
BRCA1/2
and
RAD21
, as well as
ERBB2
,
BRAF
,
MTAP
and
PIK3CA
. MSI-high status and elevated TMB (≥ 10 mutations/Mb) were extremely uncommon in both groups. PD-L1 expression was similar in the Y220C+ and Y220C- groups, with positive PD-L1 expression (TPS ≥ 1) observed in 31.5% and 34.9% of patients, respectively.
Conclusions:
The potentially targetable
TP53
Y220C mutation was identified in close to 2% of clinically advanced PDAC cases. Those with
TP53
Y220C mutations were more likely to be female and harbor
KRAS
mutations, and less likely to harbor
ATM
mutations. However,
TP53
Y220C mutations were not associated with other distinct genomic characteristics. These findings are consistent with previous reports of interactions between
TP53
and
KRAS
alterations in PDAC. Given the emergence of drugs aimed at restoring p53 function in cases with the Y220C mutation, further study of this alteration in PDAC is warranted.

Age, number of genomic alterations (GA) per tumor, and alteration frequency of select commonly altered genes based on
TP53
Y220C status.

TP53
Y220C+ (n = 488)

TP53
Y220C- (n = 26,889)

P Value

Median Age, years (range)
66 (36-89+)
66 (21-89+)
NS

GA/tumor
5.2
5.0
NS

KRAS
96.7%
92.7%
0.007

CDKN2A
60.1%
56.6%
NS

CDKN2B
28.6%
29.5%
NS

MTAP
24.4%
23.8%
NS

ARID1A
7.8%
8.7%
NS

ATM
1.4%
4.0%
0.0008

BRCA2
2.3%
3.1%
NS

NS = non-significant.