PMID- 36759885
OWN - NLM
STAT- MEDLINE
DCOM- 20230213
LR  - 20230213
IS  - 1756-994X (Electronic)
IS  - 1756-994X (Linking)
VI  - 15
IP  - 1
DP  - 2023 Feb 9
TI  - Pervasiveness of HLA allele-specific expression loss across tumor types.
PG  - 8
LID - 10.1186/s13073-023-01154-x [doi]
LID - 8
AB  - BACKGROUND: Efficient presentation of mutant peptide fragments by the human 
      leukocyte antigen class I (HLA-I) genes is necessary for immune-mediated killing 
      of cancer cells. According to recent reports, patient HLA-I genotypes can impact 
      the efficacy of cancer immunotherapy, and the somatic loss of HLA-I 
      heterozygosity has been established as a factor in immune evasion. While global 
      deregulated expression of HLA-I has also been reported in different tumor types, 
      the role of HLA-I allele-specific expression loss - that is, the preferential RNA 
      expression loss of specific HLA-I alleles - has not been fully characterized in 
      cancer. METHODS: Here, we use RNA and whole-exome sequencing data to quantify 
      HLA-I allele-specific expression (ASE) in cancer using our novel method 
      arcasHLA-quant. RESULTS: We show that HLA-I ASE loss in at least one of the three 
      HLA-I genes is a pervasive phenomenon across TCGA tumor types. In pancreatic 
      adenocarcinoma, tumor-specific HLA-I ASE loss is associated with decreased 
      overall survival specifically in the basal-like subtype, a finding that we 
      validated in an independent cohort through laser-capture microdissection. 
      Additionally, we show that HLA-I ASE loss is associated with poor immunotherapy 
      outcomes in metastatic melanoma through retrospective analyses. CONCLUSIONS: 
      Together, our results highlight the prevalence of HLA-I ASE loss and provide 
      initial evidence of its clinical significance in cancer prognosis and 
      immunotherapy treatment.
CI  - (c) 2023. The Author(s).
FAU - Filip, Ioan
AU  - Filip I
AD  - Program for Mathematical Genomics, Department of Systems Biology, Columbia 
      University, New York, NY, USA.
FAU - Wang, Anqi
AU  - Wang A
AD  - Program for Mathematical Genomics, Department of Systems Biology, Columbia 
      University, New York, NY, USA.
FAU - Kravets, Oleksandr
AU  - Kravets O
AD  - Program for Mathematical Genomics, Department of Systems Biology, Columbia 
      University, New York, NY, USA.
FAU - Orenbuch, Rose
AU  - Orenbuch R
AD  - Program for Mathematical Genomics, Department of Systems Biology, Columbia 
      University, New York, NY, USA.
AD  - Systems Biology, Harvard Medical School, Boston, MA, USA.
FAU - Zhao, Junfei
AU  - Zhao J
AD  - Program for Mathematical Genomics, Department of Systems Biology, Columbia 
      University, New York, NY, USA.
FAU - Perea-Chamblee, Tomin E
AU  - Perea-Chamblee TE
AD  - Program for Mathematical Genomics, Department of Systems Biology, Columbia 
      University, New York, NY, USA.
FAU - Manji, Gulam A
AU  - Manji GA
AD  - Department of Medicine, Division of Hematology and Oncology, Columbia University, 
      New York, NY, USA.
FAU - Lopez de Maturana, Evangelina
AU  - Lopez de Maturana E
AD  - Genetic and Molecular Epidemiology Group, Spanish National Cancer Research Centre 
      (CNIO), and CIBERONC, Madrid, Spain.
FAU - Malats, Nuria
AU  - Malats N
AD  - Genetic and Molecular Epidemiology Group, Spanish National Cancer Research Centre 
      (CNIO), and CIBERONC, Madrid, Spain.
FAU - Olive, Kenneth P
AU  - Olive KP
AD  - Department of Medicine, Division of Digestive and Liver Diseases, Columbia 
      University, New York, NY, USA.
FAU - Rabadan, Raul
AU  - Rabadan R
AD  - Program for Mathematical Genomics, Department of Systems Biology, Columbia 
      University, New York, NY, USA. rr2579@cumc.columbia.edu.
AD  - Department of Biomedical Informatics, Columbia University, New York, NY, USA. 
      rr2579@cumc.columbia.edu.
LA  - eng
GR  - U01 CA243073/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20230209
PL  - England
TA  - Genome Med
JT  - Genome medicine
JID - 101475844
RN  - 0 (Histocompatibility Antigens Class I)
RN  - 63231-63-0 (RNA)
SB  - IM
MH  - Humans
MH  - Alleles
MH  - *Adenocarcinoma/genetics
MH  - Retrospective Studies
MH  - *Pancreatic Neoplasms/genetics
MH  - Histocompatibility Antigens Class I/genetics
MH  - RNA
PMC - PMC9912643
OTO - NOTNLM
OT  - Allele-specific expression
OT  - HLA
OT  - Immunotherapy
OT  - Loss of heterogeneity
OT  - Pan-cancer analysis
OT  - Pancreatic cancer
COIS- R.R. is a founder and a member of the SAB of Genotwin, a consultant for Arquimea 
      Research, and a member of the SAB of AimedBio. The remaining authors declare that 
      they have no competing interests.
EDAT- 2023/02/11 06:00
MHDA- 2023/02/14 06:00
PMCR- 2023/02/09
CRDT- 2023/02/10 00:06
PHST- 2022/03/21 00:00 [received]
PHST- 2023/01/12 00:00 [accepted]
PHST- 2023/02/10 00:06 [entrez]
PHST- 2023/02/11 06:00 [pubmed]
PHST- 2023/02/14 06:00 [medline]
PHST- 2023/02/09 00:00 [pmc-release]
AID - 10.1186/s13073-023-01154-x [pii]
AID - 1154 [pii]
AID - 10.1186/s13073-023-01154-x [doi]
PST - epublish
SO  - Genome Med. 2023 Feb 9;15(1):8. doi: 10.1186/s13073-023-01154-x.