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

• Published in: International journal of cancer 2019-11, Vol.145 (9), p.2568-2579
• Main Authors: Biswas, Nidhan K., Das, Chitrarpita, Das, Subrata, Maitra, Arindam, Nair, Sudhir, Gupta, Tejpal, D'Cruz, Anil K., Sarin, Rajiv, Majumder, Partha P.
• Format: Article
• Language: English
• Subjects: Adult; Aged; BRCA2 protein; Breast cancer; Cancer; Carcinoma, Squamous Cell - genetics; Carcinoma, Squamous Cell - pathology; chromosomal instability; Chromosomal Instability - genetics; Chromosome deletion; Clonal deletion; Copy number; deletions; Deoxyribonucleic acid; Disease-Free Survival; DNA; DNA Copy Number Variations - genetics; DNA repair; DNA Repair - genetics; Female; Gene Deletion; Genomic instability; Homologous recombination; Homology; Humans; Lymph; Lymph nodes; Lymph Nodes - pathology; Lymphatic Metastasis - genetics; Lymphatic Metastasis - pathology; Lymphatic system; Male; Medical research; Metastases; Metastasis; Middle Aged; Mouth Neoplasms - genetics; Mouth Neoplasms - pathology; Mutation; Mutation - genetics; Non-homologous end joining; Nucleotide sequence; Oral cancer; Oral squamous cell carcinoma; p53 Protein; Squamous cell carcinoma
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.32305

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. What's new? Oral squamous cell carcinoma (OSCC) is a significant cause of cancer‐related morbidity and mortality. OSCC outcome may be predicted by lymph node (LN) metastasis, though this requires careful clinico‐radiological evaluation to avoid false inferences. Here, to improve LN evaluation, the authors identified and correlated genomic alterations in OSCC with pathological nodal stage. Comparison of exome sequences with copy number variations in blood and tumor DNA revealed associations between LN metastasis and chromosomal instability, DNA repair defects, and mutations in various biological pathways. Mutations in the mito‐G2/M pathway, BRCA2, the NHEJ pathway, FAT1, and CASP8 were highly predictive of LN metastasis.