Genome-wide analysis of noncoding regulatory mutations in cancer
Open accessAbstract
Cancer primarily develops because of somatic alterations in the genome. Advances in sequencing have enabled large-scale sequencing studies across many tumor types, emphasizing the discovery of alterations in protein-coding genes. However, the protein-coding exome comprises less than 2% of the human genome. Here we analyze the complete genome sequences of 863 human tumors from The Cancer Genome Atlas and other sources to systematically identify noncoding regions that are recurrently mutated in cancer. We use new frequency- and sequence-based approaches to comprehensively scan the genome for noncoding mutations with potential regulatory impact. These methods identify recurrent mutations in regulatory elements upstream of PLEKHS1, WDR74 and SDHD, as well as previously identified mutations in the TERT promoter. SDHD promoter mutations are frequent in melanoma and are associated with reduced gene expression and poor prognosis. The non-protein-coding cancer genome remains widely unexplored, and our findings represent a step toward targeting the entire genome for clinical purposes.
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Genetic predisposition plays an important role in the initial transformation and is driven by both germline variants and multiple myeloma-specific loci influencing risk.
“Genetic predisposition plays an important role in the initial transformation and is driven by both germline variants and MM-specific loci influencing risk.”
From Evolution of Multiple Myeloma from a Genomic Perspective (2026) · cites this paper as [46]
The Abstract (page unavailable) describes a study of somatic regulatory mutations across cancer types, not inherited susceptibility to multiple myeloma. A search for germline variants, myeloma-specific risk loci, and initial transformation found no passage in our copy addressing that claim; the References list a multiple myeloma sequencing study but do not report the asserted finding. (LLM, conf=0.75)
Experimental — accuracy not yet measuredA list of loci specific to multiple myeloma and MGUS/SMM exists.
“The second group included a list of loci that are specific to multiple myeloma and MGUS/SMM .43-46”
From Evolution of Multiple Myeloma from a Genomic Perspective (2026) · cites this paper as [46]
The Results section identifies recurrently mutated regulatory regions across cancers but does not identify a list of loci specific to multiple myeloma and MGUS/SMM. A multiple-myeloma study appears in the References; searches for myeloma, MGUS, SMM, and monoclonal gammopathy found no passage making the attributed claim (page unavailable). (LLM, conf=0.76)
Experimental — accuracy not yet measuredTERT promoter mutations are the most common non-coding mutations in cancer and are found in a growing list of cancers.
“These mutations are the most common mutations in non-coding sequences in cancer and are found in a long, and almost certainly growing, list of cancers153–158.”
From Telomeres in cancer: tumour suppression and genome instability (2017) · cites this paper as [158]
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- Authors
- Weinhold, N., Jacobsen, A., Schultz, N., Sander, C., & Lee, W.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- Corresponding author
- Lee, William
- Venue
- Nature Genetics
- Published
- 2014-09-28
- Volume
- 46
- Issue
- 11
- Pages
- 1160-1165
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- PMC
- PMC4217527
- OpenAlex
- W1995837988
- Cited by
- 484
- References
- 46
- Citations by year
- 2026: 10 · 2025: 14 · 2024: 15 · 2023: 35 · 2022: 32 · 2021: 40 · 2020: 53 · 2019: 45 · 2018: 61 · 2017: 68 · 2016: 60 · 2015: 48 · 2014: 2
- FWCI
- 19.01
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- Funders
- National Cancer Institute (U24CA143840, P30CA008748)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer-related molecular mechanisms research
- Keywords
- regulatory mutations, cancer, mutational hotspots, promoter mutations, SDHD, TERT promoter, melanoma, gene expression, prognosis, cancer genomics
- MeSH terms
- Humans, Mutation, Neoplasms, Succinate Dehydrogenase, Gene Expression Regulation, Neoplastic, Telomerase, Computational Biology, Gene Expression Profiling, Genomics, Regulatory Elements, Transcriptional, Molecular Sequence Annotation
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