Extended Data Fig. 3: TP53 inactivation is associated with BM across primary carcinomas.
a, Correlation of TP53 inactivation with BM prevalence across carcinomas, for female (left) and male (right) tumors. Each dot represents a primary carcinoma (for lung and kidney, the highest-ranking subtypes were considered). Female: one-sided Spearman’s ρ = 0.58, p = 0.04. Male: one-sided Spearman’s ρ = 0.80, p = 0.003. b, Pan-cancer analysis of TP53 perturbation prevalence: TP53 alterations, and biallelic TP53 inactivation in particular, are enriched in BM in comparison to primary tumors and to other metastatic sites (MSK-IMPACT cohort17). Two-sided Fisher’s exact test, TP53 inactivation vs. TP53-WT: BM vs. primary tumor, ****p = 1 × 10−5, BM vs. other metastasis, ****p = 1 × 10−5. TP53 biallelic inactivation vs. TP53-WT: BM vs. primary tumor, ****p = 1 × 10−5, BM vs. other metastasis ****p = 1 × 10−5. Primary n = 2947, brain n = 126, chest wall n = 79, liver n = 658, lymph node n = 571, pleura n = 111, soft tissue n = 80, lung n = 265, bone n = 252, peritoneum n = 48, ovary, skin n = 47, pleural fluid n = 33, adrenal gland n = 34. c–e, Association between TP53 perturbation BM potential in carcinoma cell lines. c, In total, 367 carcinoma cell lines were grouped by their BM potential (top vs. low 25%). Panel c was created with BioRender.com. d, High-BM carcinoma cell lines show enrichment of TP53 biallelic inactivation (two-sided Fisher’s exact test *p = 0.03). e, High-BM carcinoma cell lines show decreased p53 signaling, as evaluated by GSEA. Oncogenic signatures: ‘P53_DN.V1_DN’ p = 0.015, rank #3. ‘P53_DN.V1_UP p = 0.027’, rank #4. See Supplementary Table 3. f–i, TP53 alterations are enriched in BM vs. other metastases from primary lung tumors. f, Non-small cell lung cancer metastasis. Two-sided Fisher’s exact test, TP53 inactivation vs. TP53-WT: BM vs. primary tumors ****p = 1 × 10−5, BM vs. other metastasis ***p = 8 × 10−4. TP53 biallelic inactivation vs. TP53-WT: BM vs. primary tumors ****p = 1 × 10−5, BM vs. other metastasis ****p = 1 × 10−5. Primary n = 915, brain n = 59, chest wall n = 11, liver n = 68, lung n = 10, soft tissue n = 12, lymph node n = 211, bone n = 48, adrenal gland n = 19, pleura n = 73, pleural fluid n = 25. g, Lung adenocarcinoma metastasis. Two-sided Fisher’s exact test, TP53 inactivation vs. TP53-WT: BM vs. primary tumors ****p = 1 × 10−5, BM vs. other metastasis **p = 0.0017. TP53 biallelic inactivation vs. TP53-WT: BM vs. primary tumors ****p = 1 × 10−5, BM vs. other metastasis ***p = 1 × 10−4. Primary n = 781, brain n = 53, chest wall n = 10, liver n = 65, lung n = 10, lymph node n = 152, bone n = 40, soft tissue n = 10, pleural fluid n = 24, pleura n = 68, adrenal gland n = 16, other n = 425. h, Lung squamous cell carcinoma metastasis. Two-sided Fisher’s exact test, TP53 inactivation vs. TP53-WT: BM vs. primary tumors p = 0.13, BM vs. other metastasis p = 0.55. TP53 biallelic inactivation vs. TP53-WT: BM vs. primary tumor p = 0.57, BM vs. other metastasis **p = 0.01. Primary n = 122, brain n = 3, pleura n = 4, bone n = 7, lymph node n = 14. i, Poorly differentiated, non-small cell lung cancer. Two-sided Fisher’s exact test, TP53 inactivation vs. TP53-WT: BM vs. primary tumors p = 1, BM vs. other metastasis p = 1. TP53 biallelic inactivation vs. TP53-WT: BM vs. primary tumors p = 0.4, BM vs. other metastasis *p = 0.045. Primary n = 12, brain n = 3, bone n = 1, lymph node n = 5, pleura n = 1, adrenal gland n = 1, liver n = 1. j,k, GSEA of primary lung adenocarcinomas. j, Comparison of tumors based on their TP53 status. Panel j was created with BioRender.com. k, TP53-deficient primary lung adenocarcinomas show increased expression of BM signatures (TCGA PanCancer Atlas). TP53 inactivation vs. TP53-WT, ‘Smid_breast_cancer_relapse_in_brain_up’ p = 0.002, ‘Smid_breast_cancer_relapse_in_brain_dn’ p = 0. TP53 inactivation: n = 366, TP53-WT: n = 185 tumor samples. l, ssGSEA comparison shows that TP53 inactivation is associated with increased BM expression signatures. Two-sided t-test, ‘Smid_breast_cancer_relapse_in_brain’ ****p = 2.1 × 10−23, ‘Smid_breast_cancer_relapse_in_brain_up’ ****p = 1.5 × 10−11, ‘Smid_breast_cancer_relapse_in_brain_dn’ ****p = 2.7 × 10−18. m, ssGSEA comparison shows that TP53 inactivation is associated with decreased bone-metastasis expression signatures. Two-sided t-test, ‘Smid_breast_cancer_relapse_in_bone’ ****p = 1.2 × 10−9, ‘Smid_breast_cancer_relapse_in_bone_up’ ****p = 4.8 × 10−8, ‘Smid_breast_cancer_relapse_in_bone_dn’ ****p = 5.9 × 10−5.. n, TP53-deficient primary lung adenocarcinomas with biallelic inactivation show increased expression of BM signatures (TCGA PanCancer Atlas). ‘Smid_breast_cancer_relapse_in_brain_up’ p = 0.01, ‘Smid_breast_cancer_relapse_in_brain_dn’ p = 1 × 10−4. TP53-null n = 169, TP53-WT n = 185. o, ssGSEA comparison shows that TP53 biallelic inactivation is associated with increased BM expression signatures. Two-sided t-test, ‘Smid_breast_cancer_relapse_in_brain’ ****p = 2.3 × 10−27, ‘Smid_breast_cancer_relapse_in_brain_up’ ****p = 8.2 × 10−15, ‘Smid_breast_cancer_relapse_in_brain_dn’ ****p = 1.1 × 10−19. p, ssGSEA comparison shows that TP53 biallelic inactivation is associated with decreased bone-metastasis expression signatures. Two-sided t-test, ‘Smid_breast_cancer_relapse_in_bone’ ****p = 1.69 × 10−10, ‘Smid_breast_cancer_relapse_in_bone_up’ ****p = 1.75 × 10−8, ‘Smid_breast_cancer_relapse_in_bone_dn’ ****p = 1.7 × 10−5. See Source Data.
