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. 2024 Oct 15;5(11):1681–1696. doi: 10.1038/s43018-024-00840-y

Fig. 1. Genetic analysis of familial lung cancer caused by inherited T790M mutation in the EGFR gene.

Fig. 1

a, Pedigree of a family with multiple cases of lung adenocarcinoma, in which the index case (III-1) was diagnosed with six primary carcinomas (first resection), followed by resection of seven tumors 10 years later. Individuals shown in black have a confirmed or obligate germline T790M-EGFR mutation and those who have developed lung adenocarcinoma are denoted LUAD. The pedigree was minimally altered to preserve confidentiality (males, square; females, circles). b, CT scans of two tumors from patient III-4, one in the right middle lobe (RML) and the other in the right lower lobe (RLL). c, Histology of tumors from T790M-EGFR family patients showing the range of invasiveness encountered in our cohort, from precancerous AAH (patient III-4 lesion T2), to AIS (patient III-4 lesion T2), to MIA (patient III-1 lesion T2), to invasive adenocarcinoma (patient III-1; lesion T12). Panels are at ×40 magnification, with insets at ×200. Scale bars, 1 mm. d, Schematic of the tumor locations in patient III-1, at the first resection (left) and the second resection 10 years later (right). e, Copy number data for two tumors from the first resection of patient III-1. f, Phylogenetic lineage tracing of multiple tumors from patient III-1 based on WES. The tumors from the first resection, T1–T6, share no mutations outside of EGFR, as represented on the tree by no intersection point for clones 1, 6, 7, 12, 13 and 14 and, in the pie charts, by no colors shared between them. In contrast, the tumors from the second resection, T7–T13, share 29 mutations, as represented by the long trunk leading from cl1 to cl2 before branching into cl4, -5, -8 and -10. In addition, the pie charts for these tumors are complex mixtures of these four clones and clones are shared among multiple tumors. Numbers on branches are mutations that accumulated between two nodes, which represent distinct clones identified by WES. Numbers in parentheses are exonic mutations that are not in the FFPE context.