Using Genomics to Differentiate Multiple Primaries From Metastatic Lung Cancer

Area of Science:

• Genomics
• Oncology
• Molecular Pathology

Background:

• Distinguishing primary tumors from metastases in non-small cell lung cancer (NSCLC) is clinically challenging.
• Histologic review, the current standard, can misclassify tumor lineage.

Purpose of the Study:

• To evaluate the utility of discordant mapping somatic junctions from chromosomal rearrangements in diagnosing metastatic NSCLC.
• To compare genomic analysis with standard histologic review for classifying tumor lineage.

Main Methods:

• Mate-pair sequencing of DNA from 76 tumors across 37 NSCLC cases.
• Assessment of discordant mapping junctions and chromosomal copy levels.
• Germline DNA analysis and lung cancer next-generation sequencing panel on tumor pairs.

Main Results:

• Mate-pair sequencing accurately classified lineage in all tumor pairs, unlike histology which misclassified 27% of same-histology pairs.
• Histopathologic lineage was indeterminate in 7 cases due to pathologist disagreement.
• Genomic analysis identified independent primaries in two cases where histology suggested metastasis.

Conclusions:

• Chromosomal rearrangements in lung cancer offer a definitive method for determining tumor lineage in multifocal cases.
• Genomic technologies provide a more accurate approach than histology for diagnosing metastatic NSCLC.