Fig. 6. Genetic distinctions between multiple lung cancers with inherited, mosaic and metastatic origin.

Schematic representation of three distinct mechanisms underlying multiple EGFR-mutant lung tumors. The average percentage of somatic mutations shared among different tumors is shown on the right (range in parentheses). a, In cases with inheritance of an attenuated mutant EGFR allele (either familial or apparent sporadic), the mutation presenting in the germline (lightning bolt) is shared by all somatic tissues. A second canonical EGFR mutation arises somatically at high frequency in predisposed lung cells, leading to multiple tumors with no shared somatic mutations. The evolutionary distance to the most common shared ancestor between different tumors (arrow) extends to the germline; 0 nongermline mutations are shared between tumors. b, Cases with mosaic predisposition arising from acquisition of an EGFR mutation during development (lightning bolt). This timing determines the proportion of normal cells containing the variant allele and the likelihood of developing multiple tumors. In addition to the activating EGFR mutation, a small number of additional somatic genetic variants are shared before the mosaic tissues diverge and acquire independent tumor-associated mutations. c, In sporadic cancers without genetic susceptibility, a single EGFR mutation arises in a somatic lung epithelial cell (lightning bolt), generating a single tumor. Metastases from this tumor share extensive mutational profiles and the most recent common ancestor for these multiple tumors is the primary tumor. n, number of analyzed cases in cohort.