Abstract
BackgroundMutation analysis using next-generation sequencing highlights the features of tumors with somatic alterations. However, the mutation profile of double cancer remains unclear. Here, we analyzed tumors derived from the same patient using whole exome sequencing (WES) to investigate the coherence of somatic mutations in double cancer.MethodsFirst, the tumor mutational burden (TMB) was investigated using WES of 5521 tumor specimens from a Japanese pan-cancer cohort. The frequencies of mutation concordance were then compared in these cancers. Finally, we calculated the expected value of mutational concordance fitting a Poisson distribution to determine the relationship between double and metastatic cancers.ResultsIn all, 44, 58, and 121 paired samples were diagnosed as double cancer, multifocal lesions (derived from identical tissues), and metastasis, respectively. Our analysis revealed that common somatic mutations were almost entirely absent in double cancer, whereas primary tumors and metastatic foci harbored several identical alterations. Concordance of the mutation profile in the same patient reflects the tumor origin and development, suggesting the potential for identifying double cancer based on common somatic mutations. Furthermore, according to a Poisson distribution, double cancer could be discriminated based on paired samples from the same patient. The probability of double cancer with more than 10 mutations was ≤1 part-per-billion (ppb, 10− 9). In multifocal lesions, 74% of tumor pairs accumulated ≤10 common mutations, implying a difference in tumor origin within identical tissues.ConclusionsThese findings indicate that counting common somatic mutations can indicate the differences in origin between tumors derived from the same patient. Our mutation coherence analysis can thus provide beneficial information for diagnosing double cancer.
Highlights
Mutation analysis using next-generation sequencing highlights the features of tumors with somatic alterations
Tissue distribution in double cancer and metastatic cancer We extracted 44 pairs of double cancer, 58 pairs of multifocal lesions derived from identical tissues, and 121 pairs of primary site and metastatic foci in the same patient from the Japanese version of The Cancer Genome Atlas dataset
Double cancer sometimes occurred in the colorectum (43%, 19/44), lung (39%, 17/ 44), and stomach (34%, 15/44) (Fig. 1a), and 69% of multifocal lesions derived were from identical tissues such as the lung and colorectum (Fig. 1b)
Summary
Mutation analysis using next-generation sequencing highlights the features of tumors with somatic alterations. The primary organ in these cancers is generally determined based on clinicopathological findings (e.g., immunohistochemical staining, tissue specificity, and shape of tumor cells), there are only a few studies on alternative approaches that can support these findings. Pan-cancer analysis of metastatic solid tumors revealed that the mutation profile of metastatic lesions reflects that of the primary tumor types [1]. This partial mutational concordance between primary and metastatic tumors suggests the potential ability for discriminating the primary site. The incidence of mutational concordance in double cancer remains unclear due to the lack of similar mutation analysis in the same patient. Investigating mutational concordance in double cancer is important for understanding the tendency of mutation accumulation in tumors from the same patient
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