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

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.