Table 2.
TP53 germline coding mutations and the noncoding variant in cancer patients
| Characteristic | LFSa | PASb |
|---|---|---|
| Altered loci | Coding (>100 mutation sites) | Noncoding (1 site) |
| Tumor spectrum | Breast cancer | Protective against breast cancer [h, m] |
| Brain tumor (glioma) | Brain tumor (glioma) [h, m] | |
| Soft-tissue sarcoma | Soft-tissue sarcoma [h] | |
| Osteosarcoma | Prostate cancer [h] | |
| Adrenocortical carcinoma | Colorectal adenoma [h] | |
| Choroid plexus tumor | Skin basal cell carcinoma [h] | |
| Rhobdomyosarcoma of embryonal anaplastic subtype | Neuroblastoma [h] | |
| Esophageal squamous cell carcinoma [h] | ||
| Uterine leiomyoma [h] | ||
| Mean age at tumor onset | ~25 years | >>25 years |
| Population frequency | ~0.01% | ~2.0% |
| Sex effect on penetrance | Female > Male | Male > female? |
| Epigenetic regulation in susceptibility | miR-34a | miR-382 and miR-325 |
aThe cancer spectrum in LFS was determined by comparing the incidence in LFS patients with that in the general population with similar demographics. Cancers like colorectal, prostate, and lung cancer and leukemia are found in LFS patients, yet they are not considered LFS-specific core cancer types because their incidence in LFS patients is not significantly higher than that in the general population. Li-Fraumeni-like (LFL) syndrome is similar to LFS, but does not meet the stringent classification criteria, i.e., the classic LFS definition established by Drs. Li and Fraumeni in 19884. Birch30, 65 and Eeles66 have suggested two definitions of LFL, respectively. Regardless of the disease definition, TP53 coding mutations are found in 20–40% of LFL families, and like LFS, breast cancer is the most frequent tumor type in LFL patients67. That patients with the TP53 coding mutation have a later cancer onset than those with LFS mutations implies the influence of confounding genetic modifiers and the environment
bThe cancer spectrum was determined by genome-wide association studies (GWAS) of cancer cases and unaffected controls (Supplementary Table 1). The late tumor onset is suggested by our association study and mouse model data. Specific to breast cancer, the variant increases the risk in a Chinese population, but has no effect in a European population. [h, m] denotes that the results are supported by both human and mouse data