TY - JOUR
T1 - Detection of Alternative Lengthening of Telomeres via Chromogenic In Situ Hybridization for the Prognostication of PanNETs and Other Neoplasms
AU - Heaphy, Christopher M.
AU - Patel, Simmi
AU - Smith, Katelyn
AU - Wondisford, Anne R.
AU - Lynskey, Michelle L.
AU - O'Sullivan, Roderick J.
AU - Fuhrer, Kimberly
AU - Han, Xiaoli
AU - Seethala, Raja R.
AU - Liu, Ta Chiang
AU - Cao, Dengfeng
AU - Ertunc, Onur
AU - Zheng, Qizhi
AU - Stojanova, Marija
AU - Zureikat, Amer H.
AU - Paniccia, Alessandro
AU - Lee, Kenneth
AU - Ongchin, Melanie C.
AU - Pingpank, James F.
AU - Zeh, Herbert J.
AU - Hogg, Melissa E.
AU - Geller, David
AU - Marsh, James Wallis
AU - Brand, Randall E.
AU - Chennat, Jennifer S.
AU - Das, Rohit
AU - Fasanella, Kenneth E.
AU - Gabbert, Charles
AU - Khalid, Asif
AU - McGrath, Kevin
AU - Lennon, Anne Marie
AU - Sarkaria, Savreet
AU - Singh, Harkirat
AU - Slivka, Adam
AU - Hsu, Dennis
AU - Zhang, Janie Y.
AU - Nacev, Benjamin A.
AU - Nikiforova, Marina N.
AU - Wald, Abigail I.
AU - Vaddi, Neel
AU - De Marzo, Angelo M.
AU - Singhi, Anju H.
AU - Bell, Phoenix D.
AU - Singhi, Aatur D.
N1 - Publisher Copyright:
© 2024 The Authors
PY - 2025/3
Y1 - 2025/3
N2 - Molecular studies have shown alternative lengthening to telomeres (ALT) to be an important prognostic biomarker of shorter relapse-free survival (RFS) for patients with pancreatic neuroendocrine tumors (PanNETs) and other neoplasms. However, the preferred method of detecting ALT in tissue is by fluorescence in situ hybridization (FISH), which has several clinical limitations. These issues necessitate the creation of a chromogenic ALT assay that can be easily implemented into routine practice. A chromogenic in situ hybridization (CISH) assay was developed using genetically modified osteosarcoma cell lines, 20 normal pancreata, 20 ALT-positive PanNETs, and 20 ALT-negative PanNETs. Thereafter, it was validated on a multiinstitutional cohort of 360 surgically resected PanNETs and correlated with multiple clinicopathologic features, RFS, and FISH results. Separately, 109 leiomyosarcomas (LMS) were evaluated by both CISH and FISH, and, similarly, the prognostic significance of ALT status was assessed. Upon optimization, ALT–CISH was identified in 112 of 360 (31%) primary PanNETs and was 100% concordant with FISH testing. ALT correlated with several adverse prognostic findings and distant metastasis (all P <.004). The 5-year RFS for patients with ALT-positive PanNETs was 35% as compared with 94% for ALT-negative PanNETs. By multivariate analysis, ALT was an independent prognostic factor for shorter RFS. Similarly, ALT was associated with shorter RFS in patients with LMS and, analogous to PanNETs, a negative, independent prognostic factor. ALT–CISH was developed and validated in not only PanNETs but also sarcomas, specifically LMS. CISH testing has multiple advantages over FISH that facilitate its widespread clinical use in the detection of ALT and prognostication of patients with diverse neoplasms.
AB - Molecular studies have shown alternative lengthening to telomeres (ALT) to be an important prognostic biomarker of shorter relapse-free survival (RFS) for patients with pancreatic neuroendocrine tumors (PanNETs) and other neoplasms. However, the preferred method of detecting ALT in tissue is by fluorescence in situ hybridization (FISH), which has several clinical limitations. These issues necessitate the creation of a chromogenic ALT assay that can be easily implemented into routine practice. A chromogenic in situ hybridization (CISH) assay was developed using genetically modified osteosarcoma cell lines, 20 normal pancreata, 20 ALT-positive PanNETs, and 20 ALT-negative PanNETs. Thereafter, it was validated on a multiinstitutional cohort of 360 surgically resected PanNETs and correlated with multiple clinicopathologic features, RFS, and FISH results. Separately, 109 leiomyosarcomas (LMS) were evaluated by both CISH and FISH, and, similarly, the prognostic significance of ALT status was assessed. Upon optimization, ALT–CISH was identified in 112 of 360 (31%) primary PanNETs and was 100% concordant with FISH testing. ALT correlated with several adverse prognostic findings and distant metastasis (all P <.004). The 5-year RFS for patients with ALT-positive PanNETs was 35% as compared with 94% for ALT-negative PanNETs. By multivariate analysis, ALT was an independent prognostic factor for shorter RFS. Similarly, ALT was associated with shorter RFS in patients with LMS and, analogous to PanNETs, a negative, independent prognostic factor. ALT–CISH was developed and validated in not only PanNETs but also sarcomas, specifically LMS. CISH testing has multiple advantages over FISH that facilitate its widespread clinical use in the detection of ALT and prognostication of patients with diverse neoplasms.
KW - ATRX
KW - DAXX
KW - endocrine tumor
KW - sarcoma
UR - http://www.scopus.com/inward/record.url?scp=85212540752&partnerID=8YFLogxK
U2 - 10.1016/j.modpat.2024.100651
DO - 10.1016/j.modpat.2024.100651
M3 - Article
C2 - 39522643
AN - SCOPUS:85212540752
SN - 0893-3952
VL - 38
JO - Modern Pathology
JF - Modern Pathology
IS - 3
M1 - 100651
ER -