Melanoma in patients with Li‑Fraumeni syndrome (Review)

Abstract

Li-Fraumeni syndrome (LFS) is a cancer-prone, autosomal dominant syndrome caused by underlying germline gene mutations of TP53, a tumor-suppressor gene encoding the p53 protein with a major role in apoptosis, DNA repair and cell cycle regulation. Cumulative cancer incidence for LFS patients by the age of 70 years is 80-100%, mostly involving adrenocortical carcinoma, brain tumors, bone and soft tissue sarcomas, leukemia and female breast cancer from the age of 20 years. Dominant negative TP53 variant is correlated with an increased tumorigenesis risk in LFS. Sporadic TP53 mutations are related to almost half of global cancers since p53 in addition to p73 protein represent essential players in anticancer cellular protection. Epidemiological aspects concerning skin cancers, especially malignant melanoma (MM), in LFS are less clear. A low level of statistical evidence demonstrates LFS cases with pediatric MM, multiple MM, spitzoid MM, atypical presentations, mucosal and uveal MM. Retrospective cohorts indicate a higher cumulative risk than the general population by the age of 70 years for MM and basal cell carcinoma. Non-syndromic and syndromic TP53 mutations are a major pathway of metastasis, including MM. In LHS, an important level of awareness involves skin cancers despite not being a part of the typical malignancy-containing picture. Additional data are crucially needed. However, at least one dermatologic control is a step in the multidisciplinary panel of surveillance of these patients; but in cases with benign and pre-malign pigmentations, serial dermatoscopy and full body photography are recommended for early melanoma detection in order to improve the prognosis and to reduce the overall malignancy burden. Contents 1. Introduction 2. Aim of the review 3. Genetic background: TP53 mutations 4. Tumorigenesis in Li-Fraumeni syndrome 5. Melanoma in patients with Li-Fraumeni syndrome 6. Future considerations 7. Conclusions

TINF2 is a major susceptibility gene in Danish patients with multiple primary melanoma

“… 40 ), however, also risk of other cancers including melanoma (Sandru et al. 41 ) a All variants were identified heterozygous in one study participant, respectively, except MITF p.Glu318Lys (two heterozygous carriers) and MC1R R-alleles (view Table S3 for details). b Known prior to inclusion.…”

Cancer Risks Associated With TP53 Pathogenic Variants: Maximum Likelihood Analysis of Extended Pedigrees for Diagnosis of First Cancers Beyond the Li-Fraumeni Syndrome Spectrum

“…8 A number of primarily observational studies report an increased risk of noncore cancer types in LFS families, including melanoma, lung cancer, GI cancers, thyroid cancer, prostate cancer, ovarian cancer, leukemias, and lymphomas, among others. 4,[9][10][11][12][13][14][15][16][17] As some of these cancers are relatively common in the general population, the studies to date have not been able to provide conclusive evidence to determine if these are causally linked to germline TP53 variants. Even for the core LFS cancers, with a firmly established association with TP53 pathogenic variant status, the specific age-related risk for these has not been clearly established or validated across different cohorts.…”

Genetic Testing for Successive Cancer Treatment

“…Cancer genetic counseling and testing prove particularly advantageous in syndromes such as hereditary breast cancer syndromes, hereditary nonpolyposis colorectal cancer syndrome, Peutz-Jeghers syndrome, and juvenile polyposis [ 9 ]. However, certain hereditary cancer syndromes lack available or medically impactful testing, such as Li-Fraumeni syndrome and hereditary malignant melanoma [ 10 ]. Comprehensive medical care necessitates the identification of families with probable hereditary cancer susceptibility syndrome, warranting referral to cancer genetics professionals.…”