Case A (Case 30 in Table 1 and Table S2)

A 74-year-old man had two tumors in the right upper lobe that were resected through right upper lobectomy. Both tumors morphologically had an irregular surface; thus, they were diagnosed as primary lung cancers (Figure 3A,B). Pathologically, the peripheral lesion was identified as an adenosquamous carcinoma comprised of squamous cell carcinoma and acinar-predominant adenocarcinoma, whereas the central lesion was identified as papillary-predominant adenocarcinoma (Figure 3C,D). On the basis of the histopathological differences, the tumors were judged as double primary tumors. Pathologically, the cancer stage was determined to be pT1cN2M0, stage IIIA. However, the genetic mutation profiles were completely consistent between these two tumors, suggesting they are metastases (Figure 3E). Moreover, their mutation profiles were also consistent with the mutation profile of the metastatic lymph node. (Figure 3E). Based on the genetic diagnosis, the cancer stage was ultimately upgraded to T3N2M0, stage IIIB. At the patient's request, he was placed on follow-up without any postoperative adjuvant chemotherapy. The patient has remained alive for 2 years postoperatively without any recurrence.

**Figure 3.** Radiological, histopathological and genomic findings in case A. (**A**,**B**) Right upper lobe nodules: one tumor was located in the peripheral region, whereas the other was located in the central region. (**C**) Histologically, the peripheral tumor (T1) was identified as an adenosquamous carcinoma. (**D**) The central tumor (T2) was histologically identified as an adenocarcinoma. Each scale bar indicates 100 μm. (**E**) The heatmap revealed that the same mutation profiles were shared by the two tumors and the lymph node metastasis. AF, allele fraction; LN, lymph node
