Multiple primary colorectal cancer: Individual or familial predisposition?

Table 1 Different studies about the prevalence of multiple primary colorectal carcinomaand the main clinical risk factors

Ref.	Study design	Prevalence of MPCRCNo. of cases (% of global)	Risk factors for MPCRC
[4]	10283 CRC patients. Study of MCRC vs solitary CRC	135 (1.3)	Previous SCRC. OR = 3.4, 95%CI (1.9-5.9) Less frequent in rectum. OR = 0.3, 95%CI (0.1-0.6) Not associated with the development of MCRC: Sex, age, TNM stage, or grade of differentiation of the initial CRC
[2]	1298 CRC patients. Study of MPCRC features	53 (4) MPCRC 33 (2.5) SCRC 20 (1.5) MCRC	Lynch > sporadic (P < 0.001) MCRC (5.8% vs 1.3%) SCRC (5.8% vs 2.4%)
[8]	1793 CRC patients. Study of SCRC features	102 (3.6) SCRC	Frequencies of predisposing disease in SCRC patients: 5% FAP (5) 6% SP (6) 2% UC (2)
[9]	1537 CRC patients 69 FAP 780 UC 685 de novo CRC		Prevalence of SCRC in special populations: 21% of CRC in FAP 18% of CRC in UC 2.5% of sporadic CRC
[37]	382 CRC patients Study of SCRC vs solitary CRC	28 (7.3%) SCRC 208 (54.5%) synchronous adenomas	Male gender: OR = 1.97, 95%CI (1.13-3.45) Age ≥ 59 yr: OR = 2.57, 95%CI (1.54-4.29) History of adenomas: OR= 3.04, 95%CI: 1.04-8.85 Obstructive tumours: OR = 0.48, 95%CI: 0.27-0.85
[32]	15562 CRC cases. SCRC vs solitary CRC	596 (3.8%) SCRC	Male gender: OR = 1.41, 95%CI (1.19 -1.68) Adenomas present: OR = 2.02, 95%CI (1.69-2.41) Aged over 75: OR = 1.31, 95%CI (1.08 -1.59)
[12]	1522 CRC patients. Study of SCRC vs solitary CRC	27 (1.8%) SCRC	Male gender SCRC (70%); solitary CRC (56%), P = 0.001. Personal history of adenoma SCRC (4%); solitary CRC (1%), P = 0.001 Right sided tumour location SCRC (32%); solitary CRC (25%), P = 0.003
[57]	382 patients with CRC. Study of MCRC features	28 (7.3%)	Statistical differences: Older than 59 years OR = 2.57, 95%CI (1.54-4.29) History of adenoma OR = 3.04, 95%CI (1.04-8.85) Obstructive CRC OR = 0.48, 95%CI (0.27-0.85) Alcohol univariate analysis P = 0.006, no significance in multivariate analysis No statistical significance: Personal history of other tumours History of cancer in first-degree family members Revised Bethesda criteria (at least one criterion) BMI Predominant symptom Predominant localitation
[13]	18782 CRC cases MPCRC features	134 (0.71%) SCRC 300 (1.60%) MCRC	SCRC Men: OR = 1.45; 95%CI: 1.02-2.06 Age older than 65: OR = 1.50, 95%CI (1.02-2.21) Located in proximal colon: OR = 1.70, 95%CI (1.20-2.41) Risk of CRC of first-degree relatives of SCRC patients (OR= 1.86; 95%CI: 1.37-2.53) MCRC: (OR = 2.34; 95%CI: 1.62–3.36) Solitary CRC (OR = 1.75; 95%CI: 1.63-1.88)

CRC: Colorectal cancer; MCRC: Metachronous CRC; SCRC: Synchronous CRC; SSAs: Sessile serrated adenomas; UC: Ulcerative colitis; SP: Serrated polyposis; BMI: Body mass index; HR: Hazard ratio; OR: Odds ratio.

Table 2 Summary of studies about the prevalence of multiple primary colorectal carcinoma and the main molecular features of synchronous and metachronous colorectal carcinoma

Ref.	Study design	Prevalence of MPCRC (% of global)	Risk factors for MPCRC	Carcinogenetic pathways
[10]	Solitary (29) MPCRC (12) Study of MPCRC features		No differences: Age Gender Body mass index Tumour location History of CRC of MSI	CIMP-high 17.2% solitary vs 66.7% MPCRC P = 0.004
[36]	57 MPCRC Comparison of methylation status of solitary CRC vs MPCRC 57			Higher methylation for p14 MGMT in MPCRC P < 0.05 Correlations: MINT1 (r = 0.8) p16 (r = 0.8), MLH1 (r = 0.9) MGMT (r = 0.6) at the same site
[16]	4760 CRC patients Study of SCRC vs solitary CRC	58 (1.2%) SCRC: 42 (72%) sporadic 4 (7%) UC 8(14%)Lynch 1 (2%) FAP 3 (5%) SP	Older patients (P = 0.001) Right colon (P = 0.0003) Synchronous polyps (P = 0.0001) Classical adenoma 47% vs 12% SSAs 16% vs 0%	(MSI-H) 36% vs 12%; (P = 0.0005) 92% if SSA precursor
[17]	2884 patients SCRC vs solitary CRC	77 (2.7%) SCRC	21 (27%) had a family history of Lynch	54 (32%) MSI-H (> in women and elderly) congruence (MSS/MSI) Yes: 67 patients (87%) No: 10 patients (13%)
[30]	2884 CRC Study of MPCRC methylation state in SCRC vs MCRC	33 (1.1%) MCRC 77 (2.6%) SCRC	MSI-H MCRC were younger (64 vs 76 years, P =0.01)	MSI-H tumors in 12 (36%) MCRC 29 (38%) SCRCP Promoter methylation 50% MCRC 83% SCRCP P = 0.03
[35]	2,068 CRC patients SCRC vs solitary CRC	47 (2.3%) SCRC	Mean age 68.9 vs 65.5 (P =0.016) No difference: Family history of CRC BMI	MSI-high (P = 0.037). > BRAF (P = 0.0041) > CIMP-high (P = 0.013) Correlation pairs LINE-1 (r = 0.82; P = 0.0072) CpG islands (P < 0.0001)

CRC: Colorectal cancer; MCRC: Metachronous CRC; SCRC: Synchronous CRC; SSAs: Sessile serrated adenomas; UC: Ulcerative colitis; SP: Serrated polyposis; BMI: Body mass index; HR: Hazard ratio; OR: Odds ratio; MSI: Microsatellite instability; FAP: Familial adenomatous polyposis.