World’s Largest Whole Genome Sequencing of Renal Cancer:
mutational signature linked to an unknown exposure discovered in 70% of Japanese samples

Highlights

• An international study involving 11 countries including Japan conducted whole genome sequencing on 962 renal cell carcinoma case samples, the largest dataset of its kind.
• The analysis revealed a mutational signature in 70% of Japanese renal cell carcinoma samples, which is rarely seen in other countries.
• The signature is caused by exposure to an unknown mutagen, work is ongoing to identify the nature and source of the mutagen, and whether mutations linked to exposure are enough to cause cancer.
• The study also looked into known risk factors associated with renal cell carcinoma, finding smoking directly damaged genes, whereas other risk factors promoted development of renal cell carcinoma by other means.

Summary

Tatsuhiro Shibata’s team at the National Cancer Center Research Institute took part in an international collaborative study, analysing 962 clear cell renal cell carcinoma samples from 11 countries, their findings were published in Nature on 1 May 2024. The project was part of Cancer Grand Challenges team Mutographs, in partnership with the Wellcome Sanger Institute and International Agency for Research on Cancer (IARC). The Mutographs team is funded by Cancer Research UK, through Cancer Grand Challenges, a £400m+ global funding initiative co-founded by Cancer Research UK and the National Cancer Institute in the US. Dr Shibata is Chief of the Division of Cancer Genomics at the National Cancer Center Research Institute, doubly appointed as Professor of the Laboratory of Molecular Medicine, the Human Genome Center, the Institute of Medical Science of the University of Tokyo.

Results demonstrated that more than 70 percent of Japanese renal cell carcinoma samples were related to an unknown mutational signature very rarely observed in other countries. Of the known risk factors associated with renal cell carcinoma, obesity, high blood pressure and diabetes promoted cancer via non-mutagenic mechanisms,, whilst smoking seemed to directly trigger mutations.

Further studies will be conducted, to elucidate the unknown mutagenic factors, and whether mutations linked to exposure are enough to cause cancer, towards developing prevention strategies for renal cell carcinoma. Whole genome sequencing analyses of tumour samples from various regions are anticipated to shed light onto the relationship of incidence variations to ethnicity and lifestyle factors, towards forming a global prevention strategy. The renal cell carcinoma study follows the team’s previous esophageal squamous cell cancer study.

The study is funded by Cancer Research UK, through the Cancer Grand Challenges initiative, and Japan Agency for Medical Research and Development (AMED). The data will be made available to researchers through the International Cancer Genome Consortium-Accelerating Research in Genomic Oncology (ICGC-ARGO).

Prospects

This epidemiological study paired with whole genome sequencing was conducted with international partners, following the esophageal squamous cell cancer study. It demonstrates the effectiveness of whole genome sequencing, in unraveling the molecular mechanisms of carcinogenesis in each country. Of significance is the mutational signature specific to Japanese cases. Causative agents are still unclear, whole genome analysis of samples from multiple regions within Japan is planned with several institutions. The identification of causative substances, and their mechanisms, may lead to developing new prevention and treatments for clear cell renal cell carcinoma. A whole genome sequencing project is ongoing at a national level, with funds from the Japan Agency for Medical Research and Development (AMED), aggregating whole genome sequencing data of many cancer types. Further analysis of mutational signatures is anticipated to unravel the carcinogenic molecular mechanisms in Japan, leading the way to developing prevention methods.

Publication

Journal

Nature

Title

Geographic variation of mutagenic exposures in kidney cancer genomes

Authors

Sergey Senkin, Sarah Moody, Marcos Diaz-Gay, Behnoush Abedi-Ardekani, Thomas Cattiaux,Aida Ferreiro-Iglesias, Jingwei Wang, Stephen Fitzgerald, Mariya Kazachkova, Raviteja Vangara,Anh Phuong Le, Erik N. Bergstrom, Azhar Khandekar, Burçak Otlu, Saamin Cheema, Calli Latimer,Emily Thomas, Joshua Ronald Atkins, Karl Smith-Byrne, Ricardo Cortez Cardoso Penha,Christine Carreira, Priscilia Chopard, Valérie Gaborieau, Pekka Keski-Rahkonen, David Jones,Jon W. Teague, Sophie Ferlicot, Mojgan Asgari, Surasak Sangkhathat, Worapat Attawettayanon,Beata Świątkowska, Sonata Jarmalaite, Rasa Sabaliauskaite, Tatsuhiro Shibata, Akihiko Fukagawa, Dana Mates, Viorel Jinga, Stefan Rascu, Mirjana Mijuskovic, Slavisa Savic, Sasa Milosavljevic, John M.S. Bartlett, Monique Albert, Larry Phouthavongsy, Patricia Ashton Prolla,Mariana R. Botton, Brasil Silva Neto, Stephania Martins Bezerra, Maria Paula Curado,Stênio de Cássio Zequi, Rui Manuel Reis, Eliney Faria, Nei Soares Menezes, RenataSpagnoli Ferrari, Rosamonde E. Banks, Naveen S. Vasudev, David Zaridze, Anush Mukeriya,Lenka Foretova, Marie Navratilova, Ivana Holcatova, Anna Hornakova, Vladimir Janout, Mark Purdue, Stephen J. Chanock, James McKay, Ghislaine Scelo, Estelle Chanudet, Laura Humphreys,Ana Carolina de Carvalho, Sandra Perdomo, Ludmil B. Alexandrov, Michael R. Stratton,Paul Brennan

Publication Date

May1, 2024(BST) May2, 2024 (JST)

DOI

10.1038/s41586-024-07368-2

URL

https://www.nature.com/articles/s41586-024-07368-2(linked at external site)

Enquiries

Study Inquiries

Tatsuhiro Shibata
Chief, Division of Cancer Genomics, National Cancer Center Research Institute
(double appointment: Professor, Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, University of Tokyo)

E-mail: tashibat●ncc.go.jp

Media Inquiries

Office of Public Relations, Strategic Planning Bureau, National Cancer Center Japan

Tel: +81-3-3542-2511

E-mail: ncc-admin●ncc.go.jp