From: Cellular senescence in cancer: clinical detection and prognostic implications
Malignancy | Sample specification | Senescence markera | Type of senescenceb | Prognostic implication | Reference |
---|---|---|---|---|---|
NSCLC | Resected NSCLC | Lipofuscin | CS | High expression associated with worse OS | [126] |
p21WAF1/Cip1, cyclin E and Ki67 | [127] | ||||
Resected NSCLC SCC | p21WAF1/Cip1 | Positive expression associated with improved survival | [128] | ||
Resected NSCLC AC / SCC | Reduced expression in stage III compared to stage I or II | ||||
NSCLC SCC | p16INK4a | High expression associated with improved OS | [129] | ||
Resected NSCLC AC / SCC | Loss of expression associated with worse OS | [130] | |||
macroH2A1.1 | Low expression associated with worse DFS | [131] | |||
Resected NSCLC AC | Tumoral senescence signature (lipofuscin, p16INK4a, p21WAF1/Cip1 and Ki67c) | Tumoral senescence signature associated with worse DFS and OS | [132] | ||
Resected NSCLC AC / SCC / other histology | TIS: platinum-based CT with or without RT | Evidence of TIS as treatment outcome | |||
NSCLC AC | Senescence-related gene signature: FOXM1, HJURP, PKM, PTTG1 and TACC3 | CS | High expression associated with: - disease progression and worse OS - immune-suppressive and protumorigenic TME - high expression of immune checkpoint genes and TMB levels | [133] | |
Senescence marker genes: VPS26A and LANCL1 | High expression associated with decreased survival | [134] | |||
NSCLC AC | Senescence marker genes: VAMP3, STX4 and ARMX3 | High expression associated with increased survival | |||
NSCLC AC / SCC | Senescence marker genes: NTAL, DEP1 and B2MG | High expression associated with mixed survival outcomes depending on histology | |||
Resected NSCLC | SA-β-Gal and CDK1 | TIS: CB/PTX | Expression demonstrates TIS as treatment outcome | [37] | |
SA-β-Gal | TIS: CB/PTX or CRTd | Expression associated with worse OS | [135] | ||
NSCLC AC | CS gene score | CS | Lower CS gene score in primary tumors compared to adjacent normal solid tissue | [136] | |
NSCLC SCC | |||||
Malignant pleural mesothelioma | Resected MPM | SA-β-Gal, p21WAF1/Cip1 and PAI1 and mRNA p21WAF1/Cip1 and PAI1 | TIS: platinum-based CT | - Increased expression after neoadjuvant CT - Stable disease associated with PAI1 expression, time-to-progression and worse OS | [137] |
Breast cancer | Breast cancer | Senescence marker gene panel: DEP1, NTAL, EBP50, STX4, VAMP3, ARMX3, B2MG, LANCL1, VPS26A and PLD3 | CS | High expression associated with increased OS | [134] |
CS gene score | Lower score in primary tumors compared to adjacent normal solid tissue | [136] | |||
Resected primary invasive ductal carcinoma | p16INK4a and p53 | Expression associated with worse DFS and OS | [138] | ||
Resected breast cancer | p16INK4a | Overexpression associated with unfavorable prognostic indicators (high grading, negative estrogen receptor status, inverse progesterone receptor status and high Ki67 expression) and indicative of a more undifferentiated malignant phenotype | [139] | ||
p21WAF1/Cip1 and p53 | Low p21WAF1/Cip1 expression along with p53 overexpression associated with short DFS and OS, suggesting p53 overexpression reflects complete abrogation of p53 function | [140] | |||
p21WAF1/Cip1 | Expression associated with worse DFS and OS | ||||
Early breast cancer | uPA-PAI1 | - High levels associated with worse DFS - Patients with high levels benefit more strongly from adjuvant CT | |||
Resected triple negative breast cancer | macroH2A1.1 mRNA ratio | High ratio associated with worse DFS | [146] | ||
Resected breast cancer | SA-β-Gal | TIS: CP/DOX/5-FU | Expression demonstrated TIS as treatment outcome | [147] | |
p21WAF1/Cip1, p27Kip1, p53 and cyclin D3 | TIS: CP/MTX/5-FU or ECX/DOC | [148] | |||
p21WAF1/Cip1, H3K9Me3 and lamin B1c | TIS: DOC/DOX/CP, PTX/DOX/CP, DOX/CP, DOC/CP, 5-FU/EPX/CP or 5-FU/EPX/CP followed by DOC | [149] | |||
mRNA of p16INK4a, p21WAF1/Cip1 and CCNA1 | TIS: EPX/CP | - High expression demonstrated TIS as treatment outcome - Persistent senescent cells evaded immune clearance | [150] | ||
Lipofuscin | CS | Expression present in TME | [151] | ||
TIS: CTd | |||||
Cervical, uterine, UCEC and ovarian cancer | Normal cervical epithelium | p16INK4a, p21WAF1/Cip1, p15INK4a and p14ARF | OIS | Almost completely negative expression | |
Cervical dysplastic and SCC | Overexpression | ||||
Normal cervical epithelium, CIN and cervical carcinoma | p21WAF1/Cip1 | Higher expression in cervical carcinoma compared to normal cervical epithelium and CIN | [154] | ||
Expression associated with advanced stage | [155] | ||||
Cervical AC | Expression associated with favorable prognosis | [156] | |||
Cervical SCC | CS gene score | CS | Positively correlated with PD-L1 protein expression and T cell cytotoxicity | [136] | |
UCEC | Lower score in primary tumors compared to adjacent normal solid tissue | ||||
Resected pEOC | SA-β-Gal | Expression demonstrated spontaneous CS | [157] | ||
p21WAF1/Cip1 and p53 | Low p21WAF1/Cip1 expression along with p53 overexpression associated with higher recurrence rate, suggesting p53 overexpression reflects complete abrogation of p53 function | [158] | |||
Resected HGSOC | SA-β-Gal and γH2AX | Higher expression in older patients | [159] | ||
Resected OC | p53, p16INK4a and pRb | Negative or high p53, high p16INK4a and reduced pRb expression associated with worse OS | [160] | ||
Primary OC | SA-β-Gal, p16INK4a, H1-β and Ki67c | Identification of senescent CAFs adjacent to epithelial ovarian cancer cells suggested to promote ovarian cancer tumorigenesis | [161] | ||
Normal ovary, primary OC, metastasis of OC, recurrent OC | p21WAF1/Cip1 | - Expression gradually increased from normal ovary through primary OC, metastasis of OC and recurrent OC - Expression associated with decreased time-to-progression | [162] | ||
Advanced-stage serous OC and suboptimally debulked OC | Senescence marker genes: VAMP3, ARMCX3 and B2MG | CS/TISd | High expression associated with decreased survival | [134] | |
Senescence marker genes: EBP50 and NTAL | High expression associated with increased survival | ||||
Resected HGSOC | p16INK4a and lamin B1c | TIS: CB/PTX | High expression associated with improved 5-year OS | [163] | |
Esophageal cancer | Precursor and ESCC lesions | Dec1 | OIS | Expression demonstrated OIS as tumor-suppressive mechanism | [164] |
Resected ESCC | Low expression: - correlated with poor clinicopathological parameters (i.e., T-stage, lymph node metastasis and pathological TNM-stage) - associated with worse DFS | ||||
p16INK4a, p21WAF1/Cip1, pRb, Bax protein and cyclin D1 | Combined high expression and low cyclin D1 expression associated with improved OS | [165] | |||
Normal tissue, precursor lesions and ESCC | p16INK4a, p14ARF and p15INK4b | Increased expression in ESCC and in poorly differentiated specimens with lymph node metastasis, suggesting involvement of CS in cancer progression | [166] | ||
p21WAF1/Cip1 | - Expression frequently found in precursor lesions and invasive ESCC compared to normal tissue - High expression associated with worse OS in curatively treated ESCC | [167] | |||
EC | Senescence gene signature: ADH1B, IL1A, SERPINE1, SPARC, EZH2 and TNFAIP2 | Enriched senescence gene signature in noncancerous cells of TME associated with improved OS | [168] | ||
ESCC | CS gene score | CS | Lower score in primary tumors compared to adjacent normal solid tissue | [136] | |
Gastric cancer | Resected gastric cancer | Senescence gene signature: ADH1B, IL1A, SERPINE1, SPARC, EZH2 and TNFAIP2 | CS | Enriched senescence gene signature in noncancerous cells of TME associated with: - improved DFS and OS - related to MSI, higher TMB and improved benefit from immunotherapy | [168] |
Senescore based on proteins ADH1B, IL1A, SERPINE1, SPARC, EZH2 and TNFAIP2 | High-senescore protein expression associated with improved OS | ||||
Gastric AC | CS gene score | Lower score in primary tumors compared to adjacent normal solid tissue | [136] | ||
Gastric cancer | p21WAF1/Cip1 and mRNA of p21WAF1/Cip1 | Increased expression associated with improved OS | [169] | ||
Primary gastric adenocarcinoma | p21WAF1/Cip1 and p53 | Low p21WAF1/Cip1 expression along with p53 overexpression associated with more aggressive tumoral characteristics, higher recurrence rate and poorer survival, suggesting p53 overexpression reflects complete abrogation of p53 function | [170] | ||
Colorectal cancer | KRAS and BRAF mutated benign serrated polyps | SA-β-Gal, p16INK4a and Ki67c | OIS | - Expression demonstrated OIS - OIS increased with degree of dysplasia | |
Colon adenoma | SA-β-Gal, p16INK4a, p53, HP1α, HP1γ, H3K9me3 and Ki67c | Expression demonstrated OIS as tumor-suppressive mechanism | |||
Dysplastic aberrant crypt foci and adenomas | p21WAF1/Cip1 | Lower expression suggesting dysregulated expression of cell-cycle controlling genes in tumorigenesis of CRC | [173] | ||
Early invasive colorectal carcinoma | SA-β-Gal, p16INK4a, p53, HP1α, HP1γ, H3K9me3 and Ki67c | Reduced or lost expression demonstrated loss of OIS | |||
Resected primary CRC | p21WAF1/Cip1, NTAL, ARMCX3, EBP50 and γH2AX | CS | - Absent and extensive expression associated with negative prognosis, moderate expression with best prognosis - Distance between senescent cells and CD8+ T cells and a higher % CD8+ T cells near senescent cells linked to increased DSS and PFS, suggesting tumor-suppressive potential of CS is determined by TME and immune cell-mediated elimination of senescent tumor cells | [174] | |
p16INK4a and Ki67c | - Intratumoral senescence (high p16INK4a and low Ki67) associated with reduced T cell infiltrates and low-grade inflammatory cell infiltrate - Low p16INK4a expression associated with decreased survival | [175] | |||
CRC | Senescence marker genes: VPS26A, ARMCX3 and B2MG | High expression associated with decreased survival | [134] | ||
Senescence marker genes: NTAL | High expression associated with increased survival | ||||
Senescence gene signature: ADH1B, IL1A, SERPINE1, SPARC, EZH2 and TNFAIP2 | Enriched senescence gene signature in noncancerous cells of TME associated with improved OS | [168] | |||
Metastasized CRC | p-ERK, HP1γ and PAI1 | TIS: 5-FU/leucovorin | - Expression demonstrated TIS - TIS associated with longer PFS | [176] | |
Resected CRC | SA-β-Gal and mRNA of p21WAF1/Cip1, p16INK4a and IL-8 | TIS: 5-FU and concomitant RT | - Increased expression demonstrated TIS - TIS increased rectal cancer invasiveness by upregulation of EMT related genes | [177] | |
CRC | p21WAF1/Cip1 | TIS: bevacizumab-based CT | - Increased expression demonstrated TIS - TIS associated with longer PFS | [178] | |
CRC AC | CS | Decreased expression associated with higher Dukes stage, metastasis and worse survival | [179] | ||
CRC | Downregulation and negative expression associated with MSI | ||||
Decreased expression associated with lymph node and/or liver metastasis and worse survival | |||||
p53 | Absent expression associated with MSI | [181] | |||
CRC AC | CS gene score | Lower score in primary tumors compared to adjacent normal solid tissue | [136] | ||
Rectal AC | |||||
Rectal cancer | p21WAF1/Cip1 | TIS: concurrent CRT (5-FU alone or with OXP) | Increased expression demonstrated TIS of inflammatory CAFs with a pronounced stromal response | [184] | |
Senescence gene signature | |||||
PC caused by cancer of the appendix, colon, rectosigmoid or rectum | SA-β-Gal, p16INK4a, p21WAF1/Cip1, H3K9me3 and Ki67c | OIS | - Increased expression demonstrated that PC is characterized by senescent tumor cells, and showed features of stemness - Low or absent SA-β-Gal expression in primary tumor and liver metastasis samples compared to high SA-β-Gal expression in PC samples, suggesting that the peritoneal cavity is a metastatic niche that induces senescence, whereas no signs of senescence induction within the metastatic environment of the liver - Absent SA-β-Gal expression in TILs of primary tumor and liver metastasis samples compared to elevated SA-β-Gal expression in TILs of PC samples, suggesting that senescent PC cells induce senescence in TILs | [185] | |
Senescence-associated and SASP genes | Upregulated in PC compared to primary tumor samples, and have a distinct SASP, demonstrating that senescent PC with stem cell-like features express a unique SASP | ||||
Pancreatic cancer | Resected PanIN and PDAC | p16INK4a and Ki67c | OIS | High expression in low-grade PanINs, no expression in PDAC | [186] |
p21WAF1/Cip1 | Expression increased with increasing grade of malignancy, demonstrating that aberrant cell cycle regulatory genes may be important in early development and progression of PanIN | [187] | |||
Precursor lesions (acinar to ductal metaplasia), PanINs and PDAC | SA-β-Gal | Expression only in precursor lesions (acinar to ductal metaplasia) and PanINs, no expression in PDAC | [188] | ||
Normal pancreas, pancreatitis and PDAC | SIN3B | - Absent or low expression in control pancreas and PDAC - Strong expression in pancreatitis and PanINs and correlated with IL-1α | [189] | ||
Hepatocellular carcinoma | Cirrhosis, dysplasia and HCC | Senescence-related genes: FAM38D, ATAD2, TOP2A, CCNE2, CRNDE, EPCAM, TMEM27, TFPI2, FOS, NAT2, GPR128, CYP39A1, FAM134B, SDCBP2 and MUM1L1 | CS | Increased expression in liver cirrhosis, dysplasia being a transitional state to HCC and HCC that displayed immortal gene expression phenotypes | [190] |
Chronic hepatitis C and cirrhosis | SA-β-Gal | Expression correlated with fibrosis progression in cirrhosis and chronic hepatitis C, suggesting CS predispose to HCC development | |||
p21WAF1/Cip1 | Expression higher in cirrhosis compared to chronic hepatitis and associated with HCC development, suggesting p21WAF1/Cip1-related tumorigenesis in HCC | [193] | |||
Biliary cirrhosis | p21WAF1/Cip1/Ki67c ratio | Increased expression ratios | [194] | ||
Cirrhosis and HCC | p21WAF1/Cip1 and p16INK4a | Increased expression in cirrhosis, strongly reduced in HCC | [195] | ||
Normal, chronic hepatitis C and HCC | SA-β-Gal | - Expression gradually increased from normal through chronic hepatitis C samples and HCC - Expression in non-tumoral liver tissue correlated with HCC in surrounding liver | [192] | ||
HCC | CS gene score | Lower score in primary tumors compared to adjacent normal solid tissue | [136] | ||
Peritumoral HCC tissue | Senescence-related gene signature: FAM38D, ATAD2, TOP2A, CCNE2, CRNDE, EPCAM, TMEM27, TFPI2, FOS, NAT2, GPR128, CYP39A1, FAM134B, SDCBP2 and MUM1L1 | OIS | Presence associated with: - early recurrence and poor survival - associated with chemokine (CCL2, CCL5 and CXCL11) and myeloid-specific gene expression and depletion in NK cell-specific gene activity | [196] | |
p16INK4a and p21WAF1/Cip1 | Expression correlated with increased presence of CCR2 + myeloid cells | ||||
HCC | Senescence-related genes: LRP4, OPRK1, PRAC2, N4BP3, GAL, CORO2B, FZD7, SEPTIN3, SMOX, EPO, MSC, GLP1R, HOXC6, PAPPA2, STK39, DLGAP5, THEM64, UNC5B, SLC16A11, CDH1, PRR15L, CCDC146, FAM117A, SLC2A4, CD2 and STAT4 | High senescence score: - negatively correlated with the infiltration level of immunostimulating cells (plasma cells, CD8 T cells, activated CD4 memory T cells, gamma delta T cells and M1 macrophages) and positively correlated with the infiltration of immune-suppressive cells (memory B cells, naive CD4 T cells, M0 macrophages, M2 macrophages and eosinophils) - negatively correlated with the expression levels of immune checkpoint related genes (i.e., CD274, LAG3, PDCD1L, SIGLE and TIFIT) and lower response rate to immunotherapy - related to immune dessert subtype of HCC - associated with worse survival | [197] | ||
Senescence marker protein 30 | - Decreased expression in adjacent non-tumor tissue, larger tumor size and enhanced TMN-stage - Decreased expression associated with worse OS | [198] | |||
Cholangiocarcinoma | Premalignant bile duct adenomas, ductular reactions and CCA | p16INK4a | OIS | Expression in most premalignant bile duct adenomas and ductular reactions whereas barely expression in CCA, demonstrating OIS as tumor-suppressive mechanism | |
CCA | CS gene score | CS | Lower score in primary tumors compared to adjacent normal solid tissue | [136] | |
Prostate cancer | Prostate IN | SA-β-Gal and CXCR2 | CS | Expression demonstrates CS as tumor-suppressive mechanism | [122] |
BPH and prostate IN | SA-β-Gal, HP1α and HP1γ | ||||
Primary prostate cancer | GLB1 | Expression associated with: - favorable clinicopathologic features (T stage and non-metastatic samples) - improved prostate specific antigen-free survival | [202] | ||
Resected prostate cancer | TIS: ADTd | Increased expression in tissues undergoing ADT longer than 5Â months and in clinically more favorable intermediate grade cancers, demonstrating TIS as treatment outcome | [203] | ||
GLB1, HP1γ and Ki67c | Increased expression suggests TIS might be responsible for incomplete tumor regression | [204] | |||
mRNA of p16INK4a and p21WAF1/Cip1 | TIS: MIT | Increased expression and expression of a SASP (increased mRNA levels encoding IL-6, IL-8, GM-CSF, GRO-α, IGFBP-2, and IL-1β), demonstrating TIS with SASP expression as treatment outcome | [73] | ||
mRNA of p16INK4a, p21WAF1/Cip1 and CCNA1 | TIS: MIT and MIT/DOC | - High expression demonstrated TIS as treatment outcome - Persistent senescent cells evaded immune clearance | [150] | ||
p21WAF1/Cip1 | CS | Increased expression associated with high Gleason score and worse survival | |||
TIS: ADTd | - Increased expression associated with p53 accumulation after ADT, suggesting TIS as treatment outcome - Increased expression associated with worse survival | [206] | |||
Prostate AC | CS gene score | CS | - Lower score in primary tumors compared to adjacent normal solid tissue - Positively correlated with PD-L1 protein expression and T cell cytotoxicity - High score associated with improved PFS and OS - Lower score associated with higher Gleason score, T and N stages - Predicted active immune response and better prognosis | [136] | |
Bladder cancer | Precancerous and cancerous urinary bladder | p16INK4a, HP1α, HP1γ and H3K9me3 | OIS | Expression demonstrated OIS as tumor-suppressive mechanism in precancerous and cancerous lesions | [17] |
Radical cystectomy or transurethral resection | p16INK4a, p21WAF1/Cip1, p53 and pRb | Aberrant individual and/or combined expression associated with recurrence and worse OS | [207] | ||
Transitional cell carcinoma | p21WAF1/Cip1 | - Expression associated with worse DFS and OS in superficial lesions - Loss of expression associated with worse DFS and OS in invasive lesions when accompanied by p53 accumulation | [208] | ||
Bladder urothelial carcinoma | CS gene score | CS | Lower score in primary tumors compared to adjacent normal solid tissue | [136] | |
Skin cancer | Human benign naevi | SA-β-Gal and p16INK4a | OIS | Increased expression demonstrated p16INK4a-dependent OIS as tumor-suppressive mechanism | |
Dermal neurofibroma | [210] | ||||
Dysplastic naevi and radial early melanoma | p16INK4a, p53 and p21WAF1/Cip1 | Less p16INK4a expression and some p53 and p21WAF1/Cip1 expression demonstrated p53-dependent OIS as tumor-suppressive mechanism | [209] | ||
Advanced melanoma | No p16INK4a and p21WAF1/Cip1 expression in advanced melanomas demonstrated escape from p16INK4a-dependent and/or p53-dependent OIS | ||||
Benign melanocytic and dysplastic naevi, in situ, invasive and metastatic melanoma | p16INK4a | Expression gradually decreased with increasing grade of malignancy | |||
Primary melanoma | No association with DFS or OS | [212] | |||
Cutaneous malignant melanoma | Loss of expression correlated with tumor cell proliferation, thicker lesions and invasive stage | ||||
Vertical growth phase melanoma | Loss of expression associated increased tumor cell proliferation and poor prognosis | [215] | |||
Aggressive nodular malignant melanoma | Loss of expression associated with recurrent disease | [216] | |||
Melanoma | CS gene score | CS | - Positively correlated with PD-L1 protein expression and T cell cytotoxicity - Exhibited higher AUCs than the TIDE score for predicting immunotherapy response | [136] | |
Basal cell carcinoma | CS gene scores of malignant cells from non-responders significantly decreased after treatment whereas posttreatment CS scores significantly increased in ICB responders | ||||
Merkel cell carcinoma | |||||
Thyroid cancer | Early-stage papillary thyroid microcarcinoma, PTC and anaplastic thyroid carcinoma | p16INK4a, p21WAF1/Cip1 and IGFBP7 | OIS | Expression gradually decreased with increasing grade of malignancy indicating involvement of OIS in thyroid carcinogenesis | [217] |
V600EBRAF PTC | SA-β-Gal and p16INK4a | Expression next to proliferating cancer cells demonstrating OIS and cells escaping from OIS co-exist in V600EBRAF PTC | [218] | ||
(V600EBRAF) PTC | SA-β-Gal, p16INK4a, and Ki67c and mRNA of p16INK4a | - Senescent tumor cells frequently present at invasive borders with features of collective invasion and high invasive ability with expression of a SASP - Senescent tumor cells existed during lymphovascular invasion and metastasis - Increased expression of CXCL12 in presence of senescent tumor cells in collective invasion area and diffuse CXCR4 expression in all PTC, demonstrating senescent tumor cell involvement in collective invasion and metastasis of PTC | [219] | ||
Bone and soft tissue tumors | High grade sarcoma | p16INK4a | OIS | Decreased expression | [220] |
Dedifferentiated liposarcoma, synovial sarcoma and leiomyosarcoma | Decreased expression associated with reduced survival indicating p16INK4a-dependent OIS as tumor-suppressive mechanism | ||||
Liposarcoma | Senescence marker genes: VPS26A and VAMP3 | High expression associated with increased survival | [134] | ||
Senescence marker genes: STX4 | High expression associated with decreased survival | ||||
Osteosarcoma | Aging-/senescence-induced gene risk score | High score associated with: - worse OS - higher copy number variation score, implying a higher degree of tumor cell malignancy - immune cold tumors: lack of innate immune activation of infiltrating immune cells, less infiltration of antigen presenting cells, high TIDE score and T cell rejection - higher exhaustion and T cell proliferation scores - enriched MIF, CLEC and VEGF signaling pathway which are involved in osteosarcoma growth and metastasis and blood vessel growth | [221] | ||
Renal cell carcinoma | Primary RCC | p400 | OIS | Decreased expression associated with advanced tumor stage, higher grade of malignancy, regional lymph node metastasis and poor prognosis | [222] |
RCC | SA-β-Gal, p53, Dec1, Ki67c and Raf-1c | TIS: sunitinib | Increased expression demonstrates TIS as treatment outcome | [223] | |
CS gene score | CS | - Lower score in primary tumors compared to adjacent normal solid tissue - Exhibited higher AUCs than the TIDE score for predicting immunotherapy response | [136] | ||
KIRP | |||||
Brain malignancies | PA | SA-β-Gal, p16INK4a, p53 and Ki67c | OIS | Identification of OIS responsible for slow growth pattern, lack of progression to higher-grade tumors and high OS | [224] |
Senescence-associated genes: CDKN2A, CDKN1A, CEBPB, GADD45A, and IGFBP7 | |||||
SASP factors: FGF2, IL-15, CSF3, VEGFA, IL-17A, CCL2, CXCL8, CSF2, CCL3, IFNγ, IL-6, IL-13, CCL11 and IL-1β | High expression and upregulation of SASP associated with favorable PFS, demonstrating OIS is regulated by SASP | [225] | |||
High-grade tumors and adult LGG | CDKN2A and TP53 | Homogeneous deletion of CDKN2A and secondary alterations of CDKN2A and TP53 more common | |||
IDH-mutant and lower grade (WHO grade II-III) astrocytoma | Absence of mutations associated with increased survival | ||||
ACP | p21WAF1/Cip1, p53, GLB1, γH2AX, phosphor-DNA-PKc and Ki67c | Identification of senescent cells harboring molecular signature of OIS and SASP, demonstrating OIS and SASP drive cell transformation and tumor initiation | [231] | ||
SASP factors: IL-1β, IL-6, IL-8, IL-10, IL-18, TNFα and IFNγ | Identification of SASP, demonstrating OIS and SASP drive cell transformation and tumor initiation | [232] | |||
Medulloblastoma | CDKN2A and p53 pathway | Frequent CDKN2A promoter methylation and p53 pathway mutations, demonstrating OIS escape underlies tumor progression | |||
Low-grade diffuse astrocytoma | p16INK4a and pRb | Loss of expression associated with shorter survival | [236] | ||
Glioma | Senescence score based on senescence-associated genes: CCL2, CCL7, CDKN1A, COPG, CSF2RB, CXCL1, ICAM-1, IGFBP-3, IL-6, IL-8, SAA4, TNFRSF-11B, TNFSF-11 and TP53 | CS | Senescence score: - associated with poor prognosis - correlated with older age - increases with WHO histological grade (lowest values for low-grade astrocytomas (WHO II), higher values for anaplastic astrocytomas (WHO III) and highest values for glioblastomas (WHO IV) and gliosarcomas), linking senescence-associated gene signature to disease progression | [237] | |
SA-β-Gal and Ki67c | Identification of senescent cells | [238] | |||
Senescence gene signature: ANXA5, APOE, CD151, CDKN1A, CDKN2A, CDKN2B, CTSB, CTSD, CTSL, CTSZ, EMP3, FTH1, LFITM3, LGFBP2, LGFBP3, LAMP1, LAMP2, LGALS1, MT1, OCIAD2, PDLIM4, RBP1, S100A11, SEP11, SDC4, SPARC, TIMP1, TM4SF1, TMSB4X, TNC and TNFRSF12A | Senescence gene signature associated with shorter survival | ||||
Normal and reactive brain tissue and glioma | p21WAF1/Cip1 | Increased expression in glioma compared to normal and reactive brain tissue, suggesting p21WAF1/Cip1-related tumorigenesis in glioma | [239] | ||
Astrocytic glioma | Expression associated with worse DFS | [240] | |||
Astrocytic and high-grade glioma | Senescence marker genes: NTAL and STX | High expression associated with decreased survival | [134] | ||
Astrocytic and high-grade glioma and glioblastoma | Senescence marker genes: VPS26A, ARMCX3 and B2MG | High expression associated with increased survival | |||
Glioblastoma multiforme | CS gene score | CS | Positively correlated with PD-L1 protein expression and T cell cytotoxicity | [136] | |
Head and neck cancer | Oropharyngeal SCC | p16INK4a | OIS | Expression associated with favorable prognosis regardless of HPV status | [241] |
Laryngeal, hypopharyngeal or oral SCC | No prognostic value | [242] | |||
Normal, benign hyperplastic skin and oral lesions | Negative expression | ||||
dysplastic and carcinoma in situ skin and oral SCC | Heterogeneous expression | ||||
Advanced skin and oral SCC | Consistent expression at areas of microinvasion and at superficial margins | ||||
deeply invasive skin and oral SCC | Near to complete absent expression, demonstrating p16INK4a-dependent OIS as tumor-suppressive mechanism | ||||
Oral SCC | p16INK4a, p53, pRb and cyclin D1 | - Loss of p16INK4a expression earliest event in tumorigenesis - Deregulation of pRb and p53 associated with malignant transformation and adverse prognosis | [245] | ||
Premalignant dysplastic and SCC of skin and oral epithelium and HNSCC | CDKN2A | High frequency of gene mutation, deletion and promoter silencing | |||
HNSCC | H3K9Me | - Identification of senescent cells in 67.1% of biopsies - More senescent cells in tumor center compared to invasive front - No prognostic impact | [247] | ||
Senescence score based on senescence-associated genes: DUSP16, EHF, ITSN2, DUSP3, HDAC4, TXNIP, KL, MAP4KI, PIK3R5, YPEL3, CDKN2A, MAP2K7, PIAS4, POU5F1, EZH2, DGCR8, TYK2, BTG3, SOCS1, G6PD, TXN, DPY30, AURKA, PDCD10, PSMD14, FXR1, PCGF2, GAPDH, PSMB5, RSL1D1, IL1A, CDK6, LIMA1, CAV1, SERPINE1, HSPA5, NEK6, ASPH, MAP2K1, ACLY, TOP1 | High-senescence score: - associated with worse OS - correlated to poor clinicopathological parameters (histologic grade, TNM-stage, T-stage and lymph node metastasis) | [248] | |||
Pharyngeal and laryngeal HNSCC | p21WAF1/Cip1 | High expression associated with poor OS | [249] | ||
Oral SCC | [250] | ||||
Tonsillar SCC | Expression associated with favorable DSS | [251] | |||
Laryngeal and oral HNSCC | Higher expression associated with improved OS in stage III patients | [252] | |||
Minor salivary gland adenoid cystic carcinoma | p16INK4a and p21WAF1/Cip1 | CS | Strong and intense p21WAF1/Cip1 expression and complete negative p16INK4a expression, suggesting transient senescence insufficient to maintain the senescence-associated cell cycle arrest, avoiding cell death by senescence and favoring tumor growth | [253] | |
HNSCC | H3K9Me | TIS: RT with or without 5-FU/CP or 5-FU/CB | - Less senescent cells in post-RCT samples - No prognostic impact | [247] | |
mRNA of CXCR2 receptor and/or its ligands (CXCL1–3, CXCL5, CXCL7, and CXCL8) | TIS: CRTd | Increased expression associated with impaired DSS, demonstrating TIS and SASP production determines radioresistance | [254] | ||
CS gene score | CS | Lower score in primary tumors compared to adjacent normal solid tissue | [136] | ||
Thymic cancer | Thymic cancer | CS gene score | CS | Positively correlated with PD-L1 protein expression and T cell cytotoxicity | [136] |