Truncating mutations of TP53AIP1 gene predispose to cutaneous melanoma

Abstract

Genetic predisposition to cutaneous malignant melanoma (CMM) involves highly penetrant predisposing genes and low and intermediate penetrant predisposing alleles. However, the missing heritability in (CMM) is still high. For such and in order to identify new genetic factors for CMM, we conducted an exome sequencing study in high-risk CMM patients. Two rounds of exome sequencing were successively performed in 33 and 27 high-risk patients. We focused on genes carrying rare nonsense, frameshift, and splice variants (allelic frequency <1%) that were present in both series of exomes. An extension study was then conducted in a large cohort (1 079 CMM patients and 1 230 Caucasian ethnically matched healthy controls), and the inactivating variants frequency was compared between groups using two-sided Fisher exact test. Two TP53AIP1 truncating mutations were identified in four patients: a frameshift c.63_64insG, p.Q22Afs*81 in two patients from the same family and in the proband of a second family; and a nonsense mutation c.95 C > A, p.Ser32Stop in a patient with multiple CMMs. In all patients, TP53AIP1 truncating variants were strongly associated with CMM risk (two-sided Fisher exact test = 0.004, OR = 3.3[1.3-8.5]). Additionally, we showed that TP53AIP1 mRNA was strongly down-regulated throughout different phases of melanoma progression. TP53AIP1 gene is a TP53 target which plays a key role by inducting apoptosis in response to UV-induced DNA damage. Constitutional mutations of TP53AIP1 had previously been involved in susceptibility to prostate cancer. Our results show that constitutional truncating TP53AIP1 mutations predispose to CMM in the French population. Replication studies in other populations should be performed.

LncRNA TP53TG1 plays an anti-oncogenic role in cervical cancer by synthetically regulating transcriptome profile in HeLa cells

“…It functions as an oncogene in pancreatic ductal adenocarcinoma (PDAC), retinoblastoma, and nasopharyngeal carcinoma ( Yuan et al, 2017 ; Zhang et al, 2019b ; Shao et al, 2020 ; Tang et al, 2020 ; Cheng et al, 2021a ; Gao et al, 2021 ; Lu et al, 2021 ; Wang et al, 2021 ). In some other cancers, such as non-small cell lung cancer, hepatocellular carcinoma, gastrointestinal cancer, and cutaneous melanoma, TP53TG1 serves as a cancer suppressor ( Benfodda et al, 2018 ; Xiao et al, 2018 ; Chen et al, 2021 ; Masoumi et al, 2021 ). Through TCGA analysis, expression of TP53TG1 is positively or negatively correlated with overall survival time in different cancers ( Zhang et al, 2019b ).…”

“…Previous studies reported that the high expression of TP53TG1 inhibited cancer cell apoptosis in PDAC and breast cancer ( Zhang et al, 2019b ; Shao et al, 2020 ) and promoted cancer cell apoptosis in non-small cell lung cancer, hepatocellular carcinoma, gastrointestinal cancer, and cutaneous melanoma ( Benfodda et al, 2018 ; Xiao et al, 2018 ; Chen et al, 2021 ; Masoumi et al, 2021 ). In this study, we constructed a TP53TG1-OE model in HeLa cell line to explore its role in cervical cancer.…”

Prognosis prediction and risk stratification of breast cancer patients based on a mitochondria-related gene signature

“…We calculated the riskScore using the following formula: riskScore = (0.153 × expr_ACSL1) + (0.022 × expr_ ALDH2) + (0.029 × expr_MTHFD2) + (0.265 × expr_MRPL13) + (− 0.417 × expr_TP53AIP1) + (− 0.086 × expr_ SLC1A1) + (− 0.137 × expr_ME3) + (− 0.302 × expr_BCL2A1). (The detailed descriptions of these 8 MRGs [34][35][36][37][38][39][40][41][42][43][44][45][46][47][48][49][50] are provided in Table 2).…”

Targeting the p53 signaling pathway in cancers: Molecular mechanisms and clinical studies

“…Inhibited TP53AIP1 expression impairs the ability to induce apoptosis in cancer cells. Low TP53AIP1 expression in various cancers promotes cancer progression 296,297 …”

“…Low TP53AIP1 expression in various cancers promotes cancer progression. 296,297 Apoptosis-inducing factor mitochondria-associated 2 (AIFM2) has significant homology to apoptosisinducing factor (AIF) and NADH oxidoreductase but lacks a mitochondrial localization sequence. AIFM2 is transcriptionally activated by p53, binds to DNA in a nonsequence-specific manner, and induces caspaseindependent apoptosis.…”