The genomic architectures of tumour-adjacent tissues, plasma and saliva reveal evolutionary underpinnings of relapse in head and neck squamous cell carcinoma

Abstract

BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is characterised by a dismal prognosis; nonetheless, limited studies have unveiled the mechanisms underlying HNSCC relapse. METHODS: Next-generation sequencing was performed to identify the somatic mutations in 188 matched samples, including primary tumours, tumour-adjacent tissues (TATs), pre-and post-operative plasma, saliva and peripheral blood lymphocytes (PBLs) from 27 patients. The evolutionary relationship between TATs and tumours were analysed. The dynamic changes of tumour-and TAT-specific mutations in liquid biopsies were monitored together with survival analysis. RESULTS: Alterations were detected in 27 out of 27 and 19 out of 26 tumours and TATs, respectively. TP53 was the most prevalently mutated gene in TATs. Some TATs shared mutations with primary tumours, while some other TATs were evolutionarily unrelated to tumours. Notably, TP53 mutations in TATs are stringently associated with premalignant transformation and are indicative of worse survival (hazard ratio = 14.01). TAT-specific mutations were also detected in pre-and/or post-operative liquid biopsies and were indicative of disease relapse. CONCLUSIONS: TATs might undergo the processes of premalignant transformation, tumorigenesis and eventually relapse by either inheriting tumorigenic mutations from ancestral clones where the tumour originated or gaining private mutations independent of primary tumours. Detection of tumour-and/or TAT-specific genetic alterations in post-operative biopsies shows profound potential in prognostic use.

Field cancerization in breast cancer

“…Technological advances offer the opportunity to gain a deeper understanding of cancer biology and its underlying mechanisms from both a pathological and a molecular aspect. Numerous studies have shown that patches of molecularly altered, cancer-primed, cells are present in HN tissues surrounding breast tumors and that these cells create an environment with a predisposition to progress to cancer [7,[12][13][14][15][16][17][18][19][20]. These studies offer unparalleled insights into the hidden depths of these peritumoral tissues.…”

“…The risk of breast cancer recurrence is determined primarily by histopathological evaluations of the tumor, the results of which are used to guide the therapeutic management of patients. However, genetic, epigenetic, and transcriptomic alterations have been identified in cancer-adjacent tissues of many epithelial cancers, including head and neck [7,12], colorectal [13,[42][43][44], skin [45,46], bladder [13,[47][48][49], lung [14,50], prostate [8,13,51,52], ovarian [53,54], and breast [10,[13][14][15][18][19][20][55][56][57][58][59][60][61][62][63][64][65][66][67][68]. Moreover, persistent exposure to environmental risk factors (e.g.…”

“…For instance, positive associations have been reported between increased body mass index, hip-to-waist ratio and reduced physical activity, and increased risk of breast cancer Field cancerization in breast cancer 569 [99][100][101]. Similarly, epigenetic modifications have been found to be influenced by environmental exposures in women at high risk of breast cancer relative to healthy controls [12,90,102]. While genetic and environmental exposures are known to contribute to breast cancer risk, the magnitude of interaction between these remains undefined for many genes [103][104][105][106][107].…”

“…Studies indicating the importance of HN canceradjacent tissues in the context of their ability to prognosticate outcome and response to treatment highlight the requirement for further investigations [12,57,63]. Understanding the intricacies of field cancerization and developing predictive biomarkers that exploit the characteristics of this cancerized field could help to improve prognostic and therapeutic determinations and inform clinical decision-making.…”

“…For instance, positive associations have been reported between increased body mass index, hip‐to‐waist ratio and reduced physical activity, and increased risk of breast cancer [99–101]. Similarly, epigenetic modifications have been found to be influenced by environmental exposures in women at high risk of breast cancer relative to healthy controls [12,90,102].…”