Josephine Mun-Yee Ko1, Chen Guo1, Conghui Liu1, Lvwen Ning1, Wei Dai1, Lihua Tao1, Anthony Wing-Ip Lo2, Carissa Wing-Yan Wong1, Ian Yu-Hong Wong3, Fion Siu-Yin Chan3, Claudia Lai-Yin Wong3, Kwan Kit Chan3, Tsz Ting Law3, Nikki Pui-Yue Lee3, Zhichao Liu4, Haoyao Jiang4, Zhigang Li5, Simon Law6, Maria Li Lung7. 1. Department of Clinical Oncology, University of Hong Kong, Hong Kong (Special Administrative Region), People's Republic of China. 2. Division of Anatomical Pathology, Queen Mary Hospital, Hong Kong (Special Administrative Region), People's Republic of China. 3. Department of Surgery, University of Hong Kong, Hong Kong (Special Administrative Region), People's Republic of China. 4. Department of Thoracic Surgery, Section of Esophageal Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, People's Republic of China. 5. Department of Thoracic Surgery, Section of Esophageal Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, People's Republic of China. dr_lizhigang@163.com. 6. Department of Surgery, University of Hong Kong, Hong Kong (Special Administrative Region), People's Republic of China. slaw@hku.hk. 7. Department of Clinical Oncology, University of Hong Kong, Hong Kong (Special Administrative Region), People's Republic of China. mlilung@hku.hk.
Abstract
BACKGROUND: The patients with dual oesophageal squamous cell carcinoma (ESCC) and hypopharyngeal cancer (HPC) have poor prognosis; their underlying genetic pathogenesis is unclear. We hypothesise that development of synchronous ESCC/HPC depends on multicentricity or independent origin, rather than multifocality due to local or lateral spreading. METHOD: Multiple region whole-exome sequencing (M-WES) and clonality analysis were used to assess clonal relationship and spatial inter- or intra-tumour heterogeneity (ITH) in 62 tumour regions from eight dual ESCC/HPC and ten ESCC patients. RESULTS: All synchronous ESCC/HPC patients had COSMIC 16 mutation signatures, compared to only 40% ESCC in the current study (p = 0.013) and public data set (n = 165, p = 0.003). This alcohol consumption-related mutation signature 16, commonly involved in multiple alcohol-related cancers, was significantly associated with drinking and alcohol metabolism-related ADH1B rs1229984. The mutational landscape and copy number profiles were completely distinct between the two primary tumours; clonality analysis further suggested the two primary tumours shared no or only one clone accompanying independent subclone evolution. M-WES strategy demonstrated higher sensitivity and accuracy for detection of mutational prevalence and the late branch mutations among different regions in the ESCC tumours, compared to traditional sequencing analysis based on single biopsy strategy. Patients with high ITH assessed by cancer cell fraction analysis after M-WES were significantly associated with both relapse and survival. CONCLUSIONS: Our hypothesis-generating M-WES ITH assessment data have implications for prognostication. Collectively, our findings support multicentric independent clonal evolution, the field cancerisation theory, and suggest novel insights implicating an aetiologic role of alcohol metabolism in dual ESCC/HPC carcinogenesis.
BACKGROUND: The patients with dual oesophageal squamous cell carcinoma (ESCC) and hypopharyngeal cancer (HPC) have poor prognosis; their underlying genetic pathogenesis is unclear. We hypothesise that development of synchronous ESCC/HPC depends on multicentricity or independent origin, rather than multifocality due to local or lateral spreading. METHOD: Multiple region whole-exome sequencing (M-WES) and clonality analysis were used to assess clonal relationship and spatial inter- or intra-tumour heterogeneity (ITH) in 62 tumour regions from eight dual ESCC/HPC and ten ESCC patients. RESULTS: All synchronous ESCC/HPC patients had COSMIC 16 mutation signatures, compared to only 40% ESCC in the current study (p = 0.013) and public data set (n = 165, p = 0.003). This alcohol consumption-related mutation signature 16, commonly involved in multiple alcohol-related cancers, was significantly associated with drinking and alcohol metabolism-related ADH1B rs1229984. The mutational landscape and copy number profiles were completely distinct between the two primary tumours; clonality analysis further suggested the two primary tumours shared no or only one clone accompanying independent subclone evolution. M-WES strategy demonstrated higher sensitivity and accuracy for detection of mutational prevalence and the late branch mutations among different regions in the ESCC tumours, compared to traditional sequencing analysis based on single biopsy strategy. Patients with high ITH assessed by cancer cell fraction analysis after M-WES were significantly associated with both relapse and survival. CONCLUSIONS: Our hypothesis-generating M-WES ITH assessment data have implications for prognostication. Collectively, our findings support multicentric independent clonal evolution, the field cancerisation theory, and suggest novel insights implicating an aetiologic role of alcohol metabolism in dual ESCC/HPC carcinogenesis.
Authors: Noemi Andor; Trevor A Graham; Marnix Jansen; Li C Xia; C Athena Aktipis; Claudia Petritsch; Hanlee P Ji; Carlo C Maley Journal: Nat Med Date: 2015-11-30 Impact factor: 53.440
Authors: Oswens Siu-Hung Lo; Simon Law; William I Wei; Wai-Man Ng; Kam-Ho Wong; King-Hung Tong; John Wong Journal: Ann Surg Oncol Date: 2008-03-18 Impact factor: 5.344