Lymph node metastasis in oral cancer is strongly associated with chromosomal instability and DNA repair defects

Abstract

Oral squamous cell carcinoma (OSCC) is highly prevalent in south and southeast Asia. Many (30–50%) OSCC patients develop lymph node metastasis (LNM), which is the most important prognostic factor in OSCC. To identify genomic correlates of LNM, we compared exome sequences and copy number variation data of blood and tumor DNA from highly contrasting subgroups of patients to reduce false inferences—(i) patients with LNM and (ii) patients with late stage disease but without LNM. We found that LNM is associated with (i) specific hotspot somatic mutations in TP53 and CASP8; (ii) rare nonsilent germline mutations in BRCA2 and FAT1; (iii) mutations in mito‐G2/M and nonhomologous end joining (NHEJ) pathways; (iv) recurrent deletion of genes for DNA repair by homologous recombination; and (v) chromosomal instability. LN+ patients with NHEJ pathway mutations have longer disease‐free survival. Five genomic features have a high predictive value of LNM.

Exosomal cargoes in OSCC: current findings and potential functions

“…For example, the same mutations in susceptibility genes were found in exosomal DNA and parental cells of pheochromocytomas and paragangliomas (Wang et al, 2018a), and mutant KRAS, TP53, NOTCH1, and BRCA2 DNA in exosomes from pancreatic cancer were also detected (San Lucas et al, 2016;Yang et al, 2017a). Exosomes in OSCC may play similar roles, as mutant genes were discovered in OSCC cells as well (Biswas et al, 2019;Natsuizaka et al, 2017).…”

The Impact of the Ubiquitin System in the Pathogenesis of Squamous Cell Carcinomas

“…Mechanistically, aneuploidy is mainly due to aberrant mitotic events, and aberrant mitotic figures such as anaphase bridges and multipolar mitotic divisions have been documented in HNSCC primary tumors and oral cancer cell lines [137][138][139]. Remarkably, the chromosomal instability (CIN) status is associated with an unfavorable prognosis of oral cancer patients [140].…”

Increased PD1 and Glycolysis in CD4+ T Cell Promotes Lymph Node Metastasis in Oral Squamous Cell Carcinoma Patients

“…The lymph node metastasis is one of the poorest prognostic factors in OSCC patients [2]. The fresh sample of metastatic lymph nodes (LN+) and negative lymph node (LN-) was showed in Fig.…”

“…Oral squamous cell carcinoma (OSCC) is a major devastating oral cancer subtype, accounting for over 90% of malignant tumor in the oral cavity [1]. The presence of cervical lymph node metastasis is one of the poorest prognostic factors in OSCC with 50% reduction in survival of patients with lymph node positive involvement compared to those without [2]. Hence, the underlying molecular mechanism of cervical lymph node metastasis was fully illuminated to decrease the mortality of patients with OSCC.…”