Clinical utility of anti-p53 auto-antibody: Systematic review and focus on colorectal cancer

Table 2 Anti-p53 auto-antibody in all published colorectal cancer studies and key findings n (%)

Ref.	Method and manufacturer	Samples	Follow-up	Key findings
Suppiah et al[130]	ELISA (p53 ELISAPLUS, Calbiochem, Darmstadt, Germany)	20/92 (21.7); 0/20 (0)10/8 (0)2	Median 97 mo	No correlation with tumour stage, differentiation or location. Multivariate analysis show only Stage (Dukes’ and TNM) to be independent prognostic factors
Nozoe et al[97]	ELISA (Pharmacell, France)	17/36 (47.2)	Not stated	Anti-p53-ab (+) associated with greater lymphatic invasion (94.1%; 16/17 vs 68.4%; 13/19), nodal involvement (70/6%; 12/17 vs 17.6%; 3/17) and advanced stage (P = 0.02). Anti-p53 frequency higher in p53 protein expressing tumours (74%; 14/19 vs 18%; 3/17). Only 3 patients with Dukes’ A CRC, all sero-negative
Muller et al[123]	Immunoblot	Colon 63/197 (32); Rectum 7/46 (15.2); 0/57 (0)1 0/379 (0)2	CRC patients enrolled into trial with 5 year follow-up	No correlation with clinico-pathological parameters or prognosis. Trend toward higher anti-p53 sero-positivity in N2/3 disease, poor differentiation and metastases. There were no patients with Dukes’ A in this study. Anti-p53 independent of CEA and CA19-9 with 16% information gain. This is the only study to report negative to positive sero-conversion (3.6%, 11/303)
Chang et al[85]	ELISA (p53-AK, Dianova, Hamburg, Germany)	47/167 (28.1); 0/40 (0)1	Median 36.3 mo (4-58)	Anti-p53 correlates with p53 mutation (43% vs 18%) but not tumour p53 expression, clinico-pathological features or prognosis. p53 mutations, advanced stage and pre-operative CEA > 5 ng/mL were independent prognostic factors (in that order). p53 mutation strongly associated with advanced stage and poor differentiation
Lechpammer et al[88]	ELISA (ELISAPLUS Oncogene Research Products, Cambridge, United States)	40/220 (18.2); 0/42 (0)1	40 patients up to 20 wk; 8 patients up to 48 wk	Anti-p53 had higher tumour p53 expression (70% vs 52%). Anti-p53 frequency shows highest increase in Dukes’ A (0%, 0/28) →Dukes’ B: (24%, 21/87) but no increase in progression to Dukes’ C (18%,19/105). No correlation with overall tumour grade or metastases. Anti-p53 reflects tumour load following surgery, during chemotherapy and with disease recurrence
Shimada et al[82]	ELISA (Anti-p53 EIA Kit II, MESACUP anti-p53 Test; MBL; Nagoya, Japan)	46/192 (23.9); 10/205 (4.9)1; 13/189 (6.9)2	Not reported	Validation study for MESACUP ELISA using prevalence of anti-p53 in various cancers. Good intra- and inter-assay coefficient of variation of 1.85-2.37% and 0.3-3.2% respectively. Demonstrates stability of anti-p53 titres at room temperature for 7 d and following 10 freeze-thaw cycles. No comment on correlation with clinico-pathological parameters or prognosis
Forslund et al[84]	ELISA (Dianova, Hamburg, Germany)	24/88 (27)	Not reported	Cross-sectional study on relationship between p53 mutations and anti-p53 presence. Frequency of p53 mutation higher in anti-p53 sero-positive group (92%, 22/64 vs 34%, 22/64) Correlation with clinico-pathological and survival parameters not reported
Tang et al[89]	ELISA (Calbiochem-Novabiochem, Darmstadt, Germany)	130/998 (13);2/211 (1)3	Not reported	Anti-p53 sero-positivity increases in progression from N2→N3 (2.9%-10.6%); but not N0→N1 (11.7%-12.3%), N1→N2 (12.3%-10.6%) or M0→M1 (12%-17%). No correlation with CEA, overall TNM stage or metastases. Anti-p53 associated with shorter survival in uni- but not multi-variate analysis. Largest study on anti-p53 in CRC
Broll et al[152]	ELISA (p53-autoantikorpfer ELISA, Dianova, Hamburg, Germany)	20/130 (15); 0/44 (0)1	Median 25.5 mo	Anti-p53 positive predictive value of 100%, but accuracy 37% and negative predictive value 29% due to poor sensitivity (15%). Anti-p53 correlated with p53 expression (P < 0.05), but not TNM stage, grade or location (exact numbers not shown). Approximately 70% of series Stage I/II CRC
Takeda et al[98]	Anti-p53 EIA(PharmaCell, Paris, France)	17/27 (63); 1/38 (2.6)3	Up to 2 yearsMedian not reported	Anti-p53 correlates with p53 protein expression and independent of CEA and CA-19-9. Sero-conversion in 94% (16/17) within 3 wk of endoscopic resection. No correlation with clinico-pathological parameters or prognosis/recurrence as all patients had early superficial CRC (23 mucosal, 4 submucosal invasion). This study reports exceptionally high anti-p53, especially considering very early CRC
Takeda et al[174]	ELISA (anti-p53-EIA kit, Pharmacell, Paris, France)	40 patients with anti-p53 ab from previous studies	Up to 29 mo	No correlation between post-operative anti-p53 sero-positivity and histological (depth, lymphatic or venous invasion) or clinico-pathological features of lymph node or liver metastases. High (96%; 27/28) sero-conversion in patients with complete tumour resection. No sero-conversion in patients with residual disease.
Shiota et al[112]	ELISA (GIF, Munster, Germany)	18/71 (25); 1/18 (6)3	Not stated, median survival 56 mo anti p53 ab negative	Anti-p53 correlates with TNM stage (Stage I-IIIb: 9%, 4/45 vs IV: 56%, 14/25), Dukes’ stage (A-C: 9%, 4/45 vs D: 56%, 14/25), CEA, CA19-9 and tumour p53 protein expression. Anti-p53 associated with shorted survival (56 mo vs 20 mo) and is weak poor prognostic indicator. Anti-p53 prognostic significance secondary to other factors, including weak factors e.g., CEA and CA19-9. Only small number of Stage I-IIIb patients
Bielicki et al[111]	ELISA (Dianova, Hamburg, Germany)	30/145 (21); 0/20 (0)2; 0/8 (0)3	Not stated. Cross sectional study	No correlation with Dukes’ Stage (A/B: 22%, 16/73 vs C/D 19% 14/72), size, location, CEA. Highest increase in anti-p53 frequency from Dukes’ A (0%, 0/6) to Dukes B1 (28%, 5/18) but no further difference in progression to Dukes’ C (19%, 7/36). Only 6 Dukes’ A patients in study, all sero-negative
Soussi[90]	ELISA/WB/IP	307/1244 (24.7)	ELISA/WB/IP	Review combining all studies with different methodologies from 1979-1999. Range of sero-positivity (12.5%-68% in 11 studies)
Total (1999-2009)		479/2409 (19.9)		All modern studies (1999 onwards) using commercial ELISA only, with one exception using Immunoblot (Muller et al, 2006)
Review Total (1979-2009)		786/3653 (21.5)		All studies on anti-p53 in CRC (1979-2009)

Studies prior to 1999 used different methodology and not included (see above). Enzyme-linked immunosorbent assay (ELISA); Western blotting (WB); Immunoprecipitation (IP)

¹healthy,

²benign disease,

³adenoma. The study by Muller et al was included despite using immunoblot technique as it was a recent study with relatively large sample size. CRC: Colorectal cancer; CEA: Carcino-embryonic antigen.