Gene expression changes in tumor free tongue tissue adjacent to tongue squamous cell carcinoma

Boldrup, Linda; Gu, Xiaolian; Coates, Philip J.; Norberg‐Spaak, Lena; Fåhræus, Robin; Laurell, Göran; Wilms, Torben; Nylander, Karin

doi:10.18632/oncotarget.14288

Cited by 28 publications

(29 citation statements)

References 31 publications

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“…This concept has been modified to include exposure of the tissue microenvironment to damaging/mutagenic agents, termed ‘etiologic field effects’ . The recently identified changes in gene expression profiles in clinically tumor‐free tongue in patients with SCCOT compared to healthy controls provide definitive evidence for field effects in this disease . Therefore, SCCOT patients with high cytolytic activity in the tumor‐free parts of the tongue could be indicative of immunogenicity to cells with high mutation burden in the cancer field and/or immune responses due to etiologic field effects.…”

Section: Discussionmentioning

confidence: 99%

“…Tissue biopsies had been consecutively collected and some patients were included in our previous studies with different objectives . Biopsies taken from the lateral border of the tongue from 14 healthy volunteers not exposed to classic oral cancer risk factors (smoking and alcohol) had also been collected previously . The size of tumor biopsies for mRNA analysis varied between patients, with a minimum of around 3 mm.…”

Section: Methodsmentioning

confidence: 99%

“…Biopsies were fresh‐frozen in liquid nitrogen and stored at −80 °C until RNA extraction. Procedures for RNA isolation and gene expression profiling for 18 tumors, 12 tumor‐free samples, and 14 healthy controls have been previously reported and raw data were deposited in ArrayExpress accession number E‐MTAB‐4678 . For the rest of the samples, RNA isolation was performed using AllPrep DNA/RNA/miRNA Universal Kit (Qiagen, Hilden, Germany).…”

Section: Methodsmentioning

confidence: 99%

“…RNA quality was confirmed by Agilent RNA 6000 Nano kit (Agilent 2100 Bioanalyzer, Agilent Technologies, Santa Clara, CA, USA). As reported previously, 200 ng of total RNA was processed for gene expression profiling using Illumina HumanHT‐12 v4 Expression BeadChip (Illumina Inc., San Diego, CA, USA) . Raw data were deposited in ArrayExpress and are available under accession number E‐MTAB‐5534.…”

Section: Methodsmentioning

confidence: 99%

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High immune cytolytic activity in tumor‐free tongue tissue confers better prognosis in patients with squamous cell carcinoma of the oral tongue

Boldrup

Coates

et al. 2019

The Journal of Pathology CR

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Immune cells and cytolytic activity within the tumor microenvironment are being intensively studied. Through transcriptome profiling, immune cell enumeration using the xCell tool and cytolytic activity quantification according to granzyme A (GZMA) and perforin (PRF1) mRNA levels, we investigated immunoreactivity in tumor and/or tumor‐free tongue tissue samples from 31 patients with squamous cell carcinoma of the oral tongue and 14 healthy individuals (control tongue tissues). We found significantly altered immune cell compositions (p < 0.001) and elevated cytolytic activity (p < 0.001) in tumor compared to tumor‐free samples, and altered infiltration of a subset of immune cells (e.g. CD8+ T cells, p < 0.01) as well as increased cytolytic activity (p < 0.001) in tumor‐free compared to control samples. Controlling for patient age at diagnosis and tumor stage, Cox regression analysis showed that high cytolytic activity in tumor‐free samples associated with improved disease‐free survival (hazard ratio= 4.20, 95% CI = 1.09–16.20, p = 0.037). However, the degree of cytolytic activity in tumor samples did not provide prognostic information. Taken together, our results show the presence of cancer‐related immune responses in clinically tumor‐free tongue in patients with squamous cell carcinoma of the oral tongue. Measuring cytolytic activity in tumor‐free tongue samples contralateral to tumor might thus be an effective approach to predict clinical outcome.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

High immune cytolytic activity in tumor‐free tongue tissue confers better prognosis in patients with squamous cell carcinoma of the oral tongue

Boldrup

Coates

et al. 2019

The Journal of Pathology CR

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“…Looking at the adjacent clinically tumour-free tongue tissue in patients with SCCOT we have identified 554 genes to be dysregulated compared to healthy tongue (15). Among these KRT36 was shown to be tongue-specific.…”

Section: Keratin 36 a Specific Marker Of Tongue Filiform Papillae Imentioning

confidence: 99%

Keratin 36, a specific marker of tongue filiform papillae, is downregulated in squamous cell carcinoma of the mobile tongue

et al. 2020

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Human keratin 36 (K36) is a member of the hair keratin family and is a marker of hair cortex differentiation. The human KRT36 gene is located on the long arm of chromosome 17 and belongs to the cluster of structurally unrelated acidic hair keratins. Recently, it has been reported that KRT36 mRNA is specifically expressed in normal tongue epithelium and downregulated in squamous cell carcinomas of the mobile tongue. Furthermore, KRT36 levels have been reported to be downregulated in clinically normal mobile tongue tissue that is adjacent to tumours, suggesting it could be a marker of pre-neoplastic changes. However, the exact role and the potential role of K36 in tongue tumour formation remains unclear. The aim of the present study was to investigate expression of K36 in a series of squamous cell carcinomas of the mobile tongue, normal mobile tongue and a small panel of other human tissues (normal tissue from the appendix, cervix, hair, lip, mamilla, nail, oesophagus, skin, thymus and vagina) and selected cancer tissue (cervical cancer, melanoma and basal cell carcinoma). Affinity purified polyclonal antibodies against K36 were generated and used for immunohistochemical analysis. The results revealed that in the normal tongue, K36 was detected specifically in the filiform papillae of the dorsal surface of the tongue. Additionally, none of the tongue cancer tissue samples were K36-positive. Immunostaining also revealed that K36 was expressed in nail beds, Hassal's corpuscles in the thymus and the hair cortex. However, K36 was not expressed in the squamous epithelia of the skin, cervix and oesophagus, and the squamous cells of cervical carcinomas, basal cell carcinoma or melanoma. The present data indicated that K36 may be inactivated in tumours of the tongue. However, whether this is part of the tumoural process or if it is an effect of the tumour itself remains to be elucidated.

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Evidence for etiologic field changes in tongue distant from tumor in patients with squamous cell carcinoma of the oral tongue

Wang

Coates

et al. 2022

The Journal of Pathology

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Oral cancer is a paradigm of Slaughter's concept of field cancerization, where tumors are thought to originate within an area of cells containing genetic alterations that predispose to cancer development. The field size is unclear but may represent a large area of tissue, and the origin of mutations is also unclear. Here, we analyzed whole exome and transcriptome features in contralateral tumor-distal tongue (i.e. distant from the tumor, not tumor-adjacent) and corresponding tumor tissues of 15 patients with squamous cell carcinoma of the oral tongue. The number of point mutations ranged from 41 to 237 in tumors and from one to 78 in tumor-distal samples. Tumor-distal samples showed mainly clock-like (associated with aging) or tobacco smoking mutational signatures. Tumors additionally showed mutations that associate with cytidine deaminase AID/APOBEC enzyme activities or a UV-like signature. Importantly, no point mutations were shared between a tumor and the matched tumor-distal sample in any patient. TP53 was the most frequently mutated gene in tumors (67%), whereas a TP53 mutation was detected in only one tumor-distal sample, and this mutation was not shared with the matched tumor. Arm-level copy number variation (CNV) was found in 12 tumors, with loss of chromosome (Chr) 8p or gain of 8q being the most frequent events. Two tumor-distal samples showed a gain of Chr8, which was associated with increased expression of Chr8-located genes in these samples, although gene ontology did not show a role for these genes in oncogenic processes. In situ hybridization revealed a mixed pattern of Chr8 gain and neutral copy number in both tumor cells and adjacent nontumor epithelium in one patient. We conclude that distant field cancerization exists but does not present as tumor-related mutational events. The data are compatible with etiologic field effects, rather than classical monoclonal field cancerization theory.

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Gene expression changes in tumor free tongue tissue adjacent to tongue squamous cell carcinoma

Cited by 28 publications

References 31 publications

High immune cytolytic activity in tumor‐free tongue tissue confers better prognosis in patients with squamous cell carcinoma of the oral tongue

High immune cytolytic activity in tumor‐free tongue tissue confers better prognosis in patients with squamous cell carcinoma of the oral tongue

Keratin 36, a specific marker of tongue filiform papillae, is downregulated in squamous cell carcinoma of the mobile tongue

Evidence for etiologic field changes in tongue distant from tumor in patients with squamous cell carcinoma of the oral tongue

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