Multiple alternative splicing of HER2 transcripts and exon skipping with potential consequences on function and antibody-based therapy.

TY - JOUR

T1 - Multiple alternative splicing of HER2 transcripts and exon skipping with potential consequences on function and antibody-based therapy.

AU - Albitar, Maher

AU - Zhang, Hong

AU - Charifa, Ahmad

AU - Ip, Andrew

AU - Agersborg, Sally

AU - Mohtashamian, Arash

AU - Graham, Deena Mary Atieh

AU - McNamara, Donna M.

AU - Waintraub, Stanley E.

AU - Gutierrez, Martin

AU - Pecora, Andrew L.

AU - Goy, Andre

N1 - Publisher Copyright: © 2024 by American Society of Clinical Oncology

PY - 2024

Y1 - 2024

N2 - Background: Multiple studies have demonstrated that ERBB2 (HER2) exon 16 skipping is associated with resistance to antibody-based therapy. However, ERBB2 gene contains 30 exons with potential for alternative splicing involving all exons. With the increasing utilization of antibody-drug conjugates (ADC) in treating patients, it is important to evaluate the various ERBB2 isoforms that are expressed in various tumors. Toward this goal we evaluated the various splicing forms and exons skipping in domains II and III that are involved in dimerization and binding to pertuzumab, and in domain IV, which is a juxtamembrane domain and involved in trastuzumab binding. Methods: RNA was extracted from 3170 FFPE tissue from various types of tumors including breast, ovary, endometrium, lung, colon, stomach, esophagus, and others. RNA was sequenced using a hybrid capture-targeted panel. Data analysis is focused on ERBB2 gene. Results: Of the 3170 tested solid tumor samples, 824 (26%) showed high expression meeting the criteria for gene amplification and “low-HER2”. Of these cases, 199 (24%) samples showed exon skipping in domains II and III ranging from exons 6 to 14. Skipping in domain IV was detected in 236 cases (29%) involving exons from 13 to 29. However, 107 samples of the 824 (13%) showed skipping of exons in both domains II/III and domain IV. The most common exon skipping were in exons 6 to 7 and in exon 16. Most of the cases with exon 16 skipping (1.5% of total) also showed skipping in exons 6 and 7. Conclusions: Alternative splicing and exon skipping in HER2 transcripts is common and involves critical functional domains of the protein. The percentage of skipped transcripts is low. However, since these isoforms have deficiency in critical domains for membrane anchoring and for dimerization, the biological effects might be more significant than that expected from percentage of abnormal protein. Further studies are needed to correlate exon skipping with efficacy and outcome of antibody-based therapy.

AB - Background: Multiple studies have demonstrated that ERBB2 (HER2) exon 16 skipping is associated with resistance to antibody-based therapy. However, ERBB2 gene contains 30 exons with potential for alternative splicing involving all exons. With the increasing utilization of antibody-drug conjugates (ADC) in treating patients, it is important to evaluate the various ERBB2 isoforms that are expressed in various tumors. Toward this goal we evaluated the various splicing forms and exons skipping in domains II and III that are involved in dimerization and binding to pertuzumab, and in domain IV, which is a juxtamembrane domain and involved in trastuzumab binding. Methods: RNA was extracted from 3170 FFPE tissue from various types of tumors including breast, ovary, endometrium, lung, colon, stomach, esophagus, and others. RNA was sequenced using a hybrid capture-targeted panel. Data analysis is focused on ERBB2 gene. Results: Of the 3170 tested solid tumor samples, 824 (26%) showed high expression meeting the criteria for gene amplification and “low-HER2”. Of these cases, 199 (24%) samples showed exon skipping in domains II and III ranging from exons 6 to 14. Skipping in domain IV was detected in 236 cases (29%) involving exons from 13 to 29. However, 107 samples of the 824 (13%) showed skipping of exons in both domains II/III and domain IV. The most common exon skipping were in exons 6 to 7 and in exon 16. Most of the cases with exon 16 skipping (1.5% of total) also showed skipping in exons 6 and 7. Conclusions: Alternative splicing and exon skipping in HER2 transcripts is common and involves critical functional domains of the protein. The percentage of skipped transcripts is low. However, since these isoforms have deficiency in critical domains for membrane anchoring and for dimerization, the biological effects might be more significant than that expected from percentage of abnormal protein. Further studies are needed to correlate exon skipping with efficacy and outcome of antibody-based therapy.

UR - https://www.scopus.com/pages/publications/105012998363

U2 - 10.1200/JCO.2024.42.16_suppl.1033

DO - 10.1200/JCO.2024.42.16_suppl.1033

M3 - Article

SN - 0732-183X

VL - 42

SP - 1033

JO - Journal of Clinical Oncology

JF - Journal of Clinical Oncology

IS - 16

ER -