Abstract 3369: Mosaic chromosome X copy-number aberrations in leukocytes of never-smoking lung cancer patients: The Female Lung Cancer Consortium in Asia (FLCCA)
Authors: Wong Jason Y. , Machiela Mitchell , Zhou Weiyin , Seow Wei Jie , Bassig Bryan , Zhang Jinming , Yeager Meredith , Zheng Wei , Shu Xiao-Ou , Shen Hongbing , Matsuo Keitaro , Hsiung Chao Agnes , Wong Maria P. , Hong Yun-Chul , Wang Jiu-cun , Wu Yi-Long , Zhou Baosen , Klein Robert , Yin Zhihua , Wu Tangchun , Yang Pan-Chyr , Xiang Yong-Bing , Seow Adeline , Gao Yu-Tang , Wu Chen , Liu Jianjun , Hu Zhibin , Burdett Laurie , Cai Qiuyin , Dai Juncheng , Lin Dongxin , Chen Kexin , Chanock Stephen , Rothman Nathaniel , Lan Qing 
Published: August 2018

Lung cancer (LC) is a global health burden that accounted for 1.69 million deaths worldwide in 2015. Asian women have high incidence rates of LC, with about half of all diagnoses occurring among never-smokers. Chromosomal copy-number (CN) aberrations can arise de novo in somatic cells with progressing age. These genomic alterations can change the dosage of critical genes and impact biological processes. Gains and losses of Chromosome X in a proportion of cells (ChrX mosaicism) are markers of genomic instability; however, their relationship with LC is unclear. We characterized leukocyte ChrX mosaicism among never-smoking Asian female LC patients and cancer-free controls.

We investigated 5,137 LC cases (4,477 adenocarcinomas (AC) and 660 squamous cell carcinomas (SCC)) and 4,535 controls from 13 case-control studies and one cohort study in the Female Lung Cancer Consortium in Asia. Subjects were aged 19-91 years from China, Singapore, Taiwan, South Korea, and Japan. In case-control studies, blood was drawn after diagnosis and mostly before treatment. Leukocyte DNA was genotyped on Illumina 660W arrays, with a small subset on 610Q and 370K arrays. ChrX mosaicism was detected using normalized log R ratio (LRR) and B allele frequency (BAF) values from probes covering ChrX. ChrX was segmented for mosaic events (gains, losses, and copy-neutral) using circular binary segmentation on BAF values. Segments &lt;2 Mb were excluded. Event CN state was assigned based on LRR values. LRR deviations of 0.01 and −0.01 were used to classify events as gain and losses, respectively, for ChrX-spanning mosaic events; while thresholds of 0.05 and −0.05 were used for those spanning a portion of ChrX. Mosaic proportions were estimated using deviation from the expected BAF given the LRR-defined CN state. Fisher's Exact tests on 2x3 and 2x2 tables were used to compare ChrX mosaic events between LC cases and controls. Exact logistic regression was used to assess associations between combined gain and loss events and AC.

We found 18 detectable mosaic ChrX events (0.19%) in 12 women. LC cases had 5 gains, 3 losses, and 4 copy-neutral mosaic events; while controls had no gains, 1 loss, and 5 copy-neutral events (p=9.8E-2). AC patients had significantly more combined gains and losses (n=7) and fewer copy-neutral events (n=0) compared to controls who had 1 combined gain and loss and 5 copy-neutral events (p=4.7E-3). Notably, all 5 gains were among AC and none among controls (p=3.5E-3). Women with combined gain and loss events had 7 times the odds of AC compared to those without them (p=3.8E-2).

Our preliminary findings suggest a possible role of leukocyte ChrX mosaicism, particularly CN gains, in the biological mechanism of LC development. However, given the rarity of these events and possible disease-effect, larger studies are needed to further evaluate ChrX mosaicism as a risk factor for future occurrence of LC.

Citation Format: Jason Y. Wong, Mitchell Machiela, Weiyin Zhou, Wei Jie Seow, Bryan Bassig, Jinming Zhang, Meredith Yeager, Wei Zheng, Xiao-Ou Shu, Hongbing Shen, Keitaro Matsuo, Chao Agnes Hsiung, Maria P. Wong, Yun-Chul Hong, Jiu-cun Wang, Yi-Long Wu, Baosen Zhou, Robert Klein, Zhihua Yin, Tangchun Wu, Pan-Chyr Yang, Yong-Bing Xiang, Adeline Seow, Yu-Tang Gao, Chen Wu, Jianjun Liu, Zhibin Hu, Laurie Burdett, Qiuyin Cai, Juncheng Dai, Dongxin Lin, Kexin Chen, Stephen Chanock, Nathaniel Rothman, Qing Lan. Mosaic chromosome X copy-number aberrations in leukocytes of never-smoking lung cancer patients: The Female Lung Cancer Consortium in Asia (FLCCA) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3369.