Abstract 4260: Increased mutation burden in normal-appearing lung tissues with high cancer risk

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Abstract Background: Genetic alterations are considered to be accumulated in normal tissues at extremely low levels by exposure to various carcinogenic factors, and the degree of accumulated alterations, namely mutation burden, is likely to be associated with cancer risk. In lung tissues, smoking is a well-known carcinogenic factor, and is considered to be involved in accumulation of mutation burden. However, due to the limitation of detection methods of such extremely low frequency mutations, the presence of mutation burden in normal human lung tissues has been unclear. To overcome this limitation, we recently developed a new method to detect mutations with extremely low frequency by sequencing 100 DNA molecules using a next generation sequencer[Yamashita, submitted]. Aim: We aimed to reveal 1) the presence of mutation burden in normal lung tissues, and 2) its association with cancer risk. Methods and results: The presence of somatic mutations was analyzed in 55 cancer-related genes (totally 15,724 bp) in normal lung tissues (n = 11) obtained from background tissues of lung metastasis of cancer patients, without smoking history, other than those with lung cancers (''entirely normal lung tissues'') and non-cancerous lung tissues (n = 11) of lung cancer patients with smoking history (''smoking-exposed normal tissues''). The mutation frequency in smoking-exposed normal tissues (2.7 ± 0.8×10-5/bases) was significantly higher than that in entirely normal tissues (1.8 ± 0.5×10-5/bases) (p= 0.0189). C to T transition was most frequent in both smoking-exposed normal tissues (60% of detected base substitutions) and entirely normal tissues (61%), but the fractions were not different between the two groups. In contrast, C to A transversion, the signature mutation of smoking, was more frequent in smoking-exposed normal tissues (4%) than in entirely normal tissues (2%). Accumulation of somatic mutations tended to be associated with cancer risk [OR = 3.75 (95% CI = 0.54-26.046)]. Conclusion: It was shown, for the first time, that somatic mutations were accumulated in normal lung tissues with high cancer risk, possibly by exposure to tobacco smoking. Citation Format: Emi Kubo, Hideyuki Takeshima, Noriko Motoi, Toshikazu Ushijima. Increased mutation burden in normal-appearing lung tissues with high cancer risk [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4260. doi:10.1158/1538-7445.AM2017-4260