Clinical and genomic features of non‐small cell lung cancer occurring in families
Abstract Background Exposure to environmental carcinogens, such as through smoking, is a major factor in the carcinogenesis of non‐small cell lung cancer (NSCLC). However, genetic factors may also contribute. Methods To identify candidate tumor suppressor genes for NSCLC, we included 23 patients (10...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2023-04-01
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| Series: | Thoracic Cancer |
| Subjects: | |
| Online Access: | https://doi.org/10.1111/1759-7714.14825 |
| _version_ | 1797854239261720576 |
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| author | Shingo Miyabe Shin Ito Ikuro Sato Jiro Abe Keiichi Tamai Mai Mochizuki Haruna Fujimori Kazunori Yamaguchi Norihisa Shindo Hiroshi Shima Tomoko Yamazaki Makoto Abue Yoshinori Okada Jun Yasuda |
| author_facet | Shingo Miyabe Shin Ito Ikuro Sato Jiro Abe Keiichi Tamai Mai Mochizuki Haruna Fujimori Kazunori Yamaguchi Norihisa Shindo Hiroshi Shima Tomoko Yamazaki Makoto Abue Yoshinori Okada Jun Yasuda |
| author_sort | Shingo Miyabe |
| collection | DOAJ |
| description | Abstract Background Exposure to environmental carcinogens, such as through smoking, is a major factor in the carcinogenesis of non‐small cell lung cancer (NSCLC). However, genetic factors may also contribute. Methods To identify candidate tumor suppressor genes for NSCLC, we included 23 patients (10 related pairs and 3 individuals) with NSCLC who had other NSCLC‐affected first‐degree relatives in a local hospital. Exome analyses for both germline and somatic (NSCLC specimens) DNA were performed for 17 cases. Germline exome data of these 17 cases revealed that most of the short variants were identical to the variants in 14KJPN (a Japanese reference genome panel of more than 14 000 individuals) and only a nonsynonymous variant in the DHODH gene, p.A347T, was shared between a pair of NSCLC patients in the same family. This variant is a known pathogenic variant of the gene for Miller syndrome. Results Somatic genetic alterations in the exome data of our samples showed frequent mutations in the EGFR and TP53 genes. Principal component analysis of the patterns of 96 types of single nucleotide variants (SNVs) suggested the existence of unique mechanisms inducing somatic SNVs in each family. Delineation of mutational signatures of the somatic SNVs with deconstructSigs for the pair of germline pathogenic DHODH variant‐positive cases showed that the mutational signatures of these cases included SBS3 (homologous recombination repair defect), SBS6, 15 (DNA mismatch repair), and SBS7 (ultraviolet exposure), suggesting that disordered pyrimidine production causes increased errors in DNA repair systems in these cases. Conclusion Our results suggest the importance of the detailed collection of data on environmental exposure along with genetic information on NSCLC patients to identify the unique combinations that cause lung tumorigenesis in a particular family. |
| first_indexed | 2024-04-09T20:02:39Z |
| format | Article |
| id | doaj.art-f6b04ac76aea4d25b1664d736625be2f |
| institution | Directory Open Access Journal |
| issn | 1759-7706 1759-7714 |
| language | English |
| last_indexed | 2024-04-09T20:02:39Z |
| publishDate | 2023-04-01 |
| publisher | Wiley |
| record_format | Article |
| series | Thoracic Cancer |
| spelling | doaj.art-f6b04ac76aea4d25b1664d736625be2f2023-04-03T00:42:21ZengWileyThoracic Cancer1759-77061759-77142023-04-01141094095210.1111/1759-7714.14825Clinical and genomic features of non‐small cell lung cancer occurring in familiesShingo Miyabe0Shin Ito1Ikuro Sato2Jiro Abe3Keiichi Tamai4Mai Mochizuki5Haruna Fujimori6Kazunori Yamaguchi7Norihisa Shindo8Hiroshi Shima9Tomoko Yamazaki10Makoto Abue11Yoshinori Okada12Jun Yasuda13Division of Thoracic Surgery Miyagi Cancer Center Hospital Natori JapanDivision of Molecular and Cellular Oncology Miyagi Cancer Center Research Institute Natori JapanDivision of Pathology Miyagi Cancer Center Hospital Natori JapanDivision of Thoracic Surgery Miyagi Cancer Center Hospital Natori JapanDivision of Cancer Stem Cell Miyagi Cancer Center Research Institute Natori JapanDivision of Cancer Stem Cell Miyagi Cancer Center Research Institute Natori JapanDivision of Cancer Stem Cell Miyagi Cancer Center Research Institute Natori JapanDivision of Molecular and Cellular Oncology Miyagi Cancer Center Research Institute Natori JapanDivision of Molecular and Cellular Oncology Miyagi Cancer Center Research Institute Natori JapanDivision of Cancer Chemotherapy Miyagi Cancer Center Research Institute Natori JapanDivision of Molecular and Cellular Oncology Miyagi Cancer Center Research Institute Natori JapanDivision of Cancer Stem Cell Miyagi Cancer Center Research Institute Natori JapanDepartment of Thoracic Surgery, Institute of Development, Aging and Cancer Tohoku University Sendai JapanDivision of Molecular and Cellular Oncology Miyagi Cancer Center Research Institute Natori JapanAbstract Background Exposure to environmental carcinogens, such as through smoking, is a major factor in the carcinogenesis of non‐small cell lung cancer (NSCLC). However, genetic factors may also contribute. Methods To identify candidate tumor suppressor genes for NSCLC, we included 23 patients (10 related pairs and 3 individuals) with NSCLC who had other NSCLC‐affected first‐degree relatives in a local hospital. Exome analyses for both germline and somatic (NSCLC specimens) DNA were performed for 17 cases. Germline exome data of these 17 cases revealed that most of the short variants were identical to the variants in 14KJPN (a Japanese reference genome panel of more than 14 000 individuals) and only a nonsynonymous variant in the DHODH gene, p.A347T, was shared between a pair of NSCLC patients in the same family. This variant is a known pathogenic variant of the gene for Miller syndrome. Results Somatic genetic alterations in the exome data of our samples showed frequent mutations in the EGFR and TP53 genes. Principal component analysis of the patterns of 96 types of single nucleotide variants (SNVs) suggested the existence of unique mechanisms inducing somatic SNVs in each family. Delineation of mutational signatures of the somatic SNVs with deconstructSigs for the pair of germline pathogenic DHODH variant‐positive cases showed that the mutational signatures of these cases included SBS3 (homologous recombination repair defect), SBS6, 15 (DNA mismatch repair), and SBS7 (ultraviolet exposure), suggesting that disordered pyrimidine production causes increased errors in DNA repair systems in these cases. Conclusion Our results suggest the importance of the detailed collection of data on environmental exposure along with genetic information on NSCLC patients to identify the unique combinations that cause lung tumorigenesis in a particular family.https://doi.org/10.1111/1759-7714.14825DHODHexomemutational signaturenon‐small cell lung cancertumor suppressor gene |
| spellingShingle | Shingo Miyabe Shin Ito Ikuro Sato Jiro Abe Keiichi Tamai Mai Mochizuki Haruna Fujimori Kazunori Yamaguchi Norihisa Shindo Hiroshi Shima Tomoko Yamazaki Makoto Abue Yoshinori Okada Jun Yasuda Clinical and genomic features of non‐small cell lung cancer occurring in families Thoracic Cancer DHODH exome mutational signature non‐small cell lung cancer tumor suppressor gene |
| title | Clinical and genomic features of non‐small cell lung cancer occurring in families |
| title_full | Clinical and genomic features of non‐small cell lung cancer occurring in families |
| title_fullStr | Clinical and genomic features of non‐small cell lung cancer occurring in families |
| title_full_unstemmed | Clinical and genomic features of non‐small cell lung cancer occurring in families |
| title_short | Clinical and genomic features of non‐small cell lung cancer occurring in families |
| title_sort | clinical and genomic features of non small cell lung cancer occurring in families |
| topic | DHODH exome mutational signature non‐small cell lung cancer tumor suppressor gene |
| url | https://doi.org/10.1111/1759-7714.14825 |
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