Genome‐wide association study identifies gastric cancer susceptibility loci at 12q24.11‐12 and 20q11.21

Tanikawa, Chizu; Kamatani, Yoichiro; Toyoshima, Osamu; Sanada, Hiromi; Ito, Hidemi; Takahashi, Atsushi; Momozawa, Yukihide; Hirata, Makoto; Fuse, Nobuo; Toda, Takako; Shimizu, Atsushi; Sasaki, Makoto; Yamaji, Taiki; Sawada, Norie; Iwasaki, Motoki; Tsugane, Shoichiro; Naito, Mariko; Hishida, Asahi; Wakai, Kenji; Furusyo, Norihiro; Murakami, Yoshinori; Nakamura, Yusuke; Imoto, Issei; Inazawa, Johji; Oze, Isao; Sato, Naomi; Tanioka, Fumihiko; Sugimura, Haruhiko; Hara, Hiroshi; Yoshida, Teruhiko; Matsuo, Keitaro; Kubo, Michiaki; Matsuda, Koichi

doi:10.1111/cas.13815

Cited by 37 publications

(30 citation statements)

References 54 publications

(95 reference statements)

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“…Patient T989 had synchronously occurring bilateral EACSCC of both ears ( Figure 3A Although both primary tumors (T939L and T939R) had pathogenic somatic mutations in TP53, their genomic positions were different ( Figure 3C and Table S2). These results suggest that these tumors Fraction of Mutations (%) T 9 3 9 L T 9 3 9 R T 5 0 1 T 7 0 4 T 2 1 0 T 4 6 5 T 3 2 8 T 9 8 1 T 0 9 7 T 3 3 34,35 despite the functional contribution in the onset of EACSCC being unknown (Table S3).…”

Section: Intrapatient Heterogeneity Of Synchronous Bilateral Externmentioning

confidence: 98%

Genetic landscape of external auditory canal squamous cell carcinoma

et al. 2020

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External auditory canal squamous cell carcinoma (EACSCC) is an extremely rare and aggressive malignancy. Due to its rarity, the molecular and genetic characteristics of EACSCC have not yet been elucidated. To reveal the genetic alterations of EACSCC, we performed whole exome sequencing (WES) on 11 primary tumors, 1 relapsed tumor and 10 noncancerous tissues from 10 patients with EACSCC, including 1 with a rare case of synchronous bilateral EACSCC of both ears. WES of the primary tumor samples showed that the most frequently mutated gene is TP53 (63.6%). In addition, recurrent mutations in CDKN2A, NOTCH1, NOTCH2, FAT1 and FAT3 were detected in multiple samples. The mutational signature analysis of primary tumors indicated that the mutational processes associated with the activation of apolipoprotein B mRNA‐editing enzyme catalytic polypeptide‐like (APOBEC) deaminases are the most common in EACSCC, suggesting its similarity to SCC from other primary sites. Analysis of arm‐level copy number alterations detected notable amplification of chromosomes 3q, 5p and 8q as well as deletion of 3p across multiple samples. Focal chromosomal aberrations included amplifications of 5p15.33 (ZDHHC11B) and 7p14.1 (TARP) as well as deletion of 9p21.3 (CDKN2A/B). The protein expression levels of ZDHHC11B and TARP in EACSCC tissues were validated by immunohistochemistry. Moreover, WES of the primary and relapsed tumors from a case of synchronous bilateral EACSCC showed the intrapatient genetic heterogeneity of EACSCC. In summary, this study provides the first evidence for genetic alterations of EACSCC. Our findings suggest that EACSCC mostly resembles other SCC.

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Section: Intrapatient Heterogeneity Of Synchronous Bilateral Externmentioning

confidence: 98%

Genetic landscape of external auditory canal squamous cell carcinoma

et al. 2020

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“…The association of 9 SNPs with other diseases was evaluated in the pleiotropy analysis. GWAS results in BioBank Japan for another hormone-related uterine disease (endometriosis (n = 705)) and malignant tumours (endometrial cancer (n = 931), ovarian cancer (n = 681), breast cancer (n = 5,272), oesophageal cancer (n = 1,225), colorectal cancer (n = 6,692), gastric cancer (n = 6,171), lung cancer (n = 3,874) and prostate cancer (n = 5,088)) [57][58][59] were used in this study.…”

Section: Pleiotropy Association Analysismentioning

confidence: 99%

Identification of a novel uterine leiomyoma GWAS locus in a Japanese population

Sakai

Tanikawa

Hirasawa

et al. 2020

Sci Rep

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Uterine leiomyoma is one of the most common gynaecologic benign tumours, but its genetic basis remains largely unknown. Six previous GWAS identified 33 genetic factors in total. Here, we performed a two-staged GWAS using 13,746 cases and 70,316 controls from the Japanese population, followed by a replication analysis using 3,483 cases and 4,795 controls. The analysis identified 9 significant loci, including a novel locus on 12q23.2 (rs17033114, P = 6.12 × 10 −25 with an OR of 1.177 (1.141-1.213), LINC00485). Subgroup analysis indicated that 5 loci (3q26.2, 5p15.33, 10q24.33, 11p15.5, 13q14.11) exhibited a statistically significant effect among multiple leiomyomas, and 2 loci (3q26.2, 10q24.33) exhibited a significant effect among submucous leiomyomas. Pleiotropic analysis indicated that all 9 loci were associated with at least one proliferative disease, suggesting the role of these loci in the common neoplastic pathway. Furthermore, the risk T allele of rs2251795 (3q26.2) was associated with longer telomere length in both normal and tumour tissues. Our findings elucidated the significance of genetic factors in the pathogenesis of leiomyoma. Uterine leiomyoma is one of the most common gynaecologic benign tumours. Its estimated lifetime risk is 30-50% in Japan 1 and 70-80% in European populations 2,3. Although leiomyoma is a benign neoplasm, patients exhibit many types of symptoms, such as vaginal bleeding, pelvic pain, or infertility 4. Over 600,000 hysterectomies were performed per year in the USA due to leiomyomas, and 9.4 billion dollars for annual medical expenses were needed in the USA 5. Therefore, leiomyomas are gaining much attention in health economics. Leiomyoma growth is stimulated by sex steroids, such as oestrogen and progesterone, and several aetiological factors, such as age, early age at menarche, obesity, and parity, are linked to an increased leiomyoma risk 2,6-11. In

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“…DNA genotyping and imputation were conducted at RIKEN Center for Integrative Medical Sciences in the previous studies for cases [23] and controls [24]. Genomic DNA samples were extracted from peripheral blood leukocytes using a standard method.…”

Section: Gwas Genotyping and Imputationmentioning

confidence: 99%

“…Allele calling algorithm used to compute the genotyping data was GenomeStudio V2011.1. A quality control was applied to the raw genotyping data to filter unqualified SNPs following the criteria as previously described [24]. We excluded SNPs that met the following criteria: minor allele frequency (MAF) < 0.01; Hardy-Weinberg equilibrium (HWE) P-value < 1 × 10 −6 ; call rate < 0.99.…”

Section: Gwas Genotyping and Imputationmentioning

confidence: 99%

Genome-wide association study (GWAS) of ovarian cancer in Japanese predicted regulatory variants in 22q13.1

et al. 2018

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Genome-wide association studies (GWAS) have identified greater than 30 variants associated with ovarian cancer, but most of these variants were investigated in European populations. Here, we integrated GWAS and subsequent functional analyses to identify the genetic variants with potential regulatory effects. We conducted GWAS for ovarian cancer using 681 Japanese cases and 17,492 controls and found that rs137672 on 22q13.1 exhibited a strong association with a P-value of 1.05 × 10 −7 and an odds ratio of 0.573 with a 95% confidence interval of 0.466-0.703. In addition, three previously reported SNPs, i.e., rs10088218, rs9870207 and rs1400482, were validated in the Japanese population (P < 0.05) with the same risk allele as noted in previous studies. Functional studies including regulatory feature analysis and electrophoretic mobility shift assay (EMSA) revealed two regulatory SNPs in 22q13.1, rs2072872 and rs6509, that affect the binding affinity to some nuclear proteins in ovarian cancer cells. The plausible regulatory proteins whose motifs could be affected by the allele changes of these two SNPs were also proposed. Moreover, the protective G allele of rs6509 was associated with a decreased SYNGR1 expression level in normal ovarian tissues. Our findings elucidated the regulatory variants in 22q13.1 that are associated with ovarian cancer risk.

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Genome‐wide association study identifies gastric cancer susceptibility loci at 12q24.11‐12 and 20q11.21

Cited by 37 publications

References 54 publications

Genetic landscape of external auditory canal squamous cell carcinoma

Genetic landscape of external auditory canal squamous cell carcinoma

Identification of a novel uterine leiomyoma GWAS locus in a Japanese population

Genome-wide association study (GWAS) of ovarian cancer in Japanese predicted regulatory variants in 22q13.1

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