Evaluation of the colorectal cancer risk conferred by rare UNC5C alleles

Table 1 Patients with familial colorectal or Lynch-associated cancers included in the study

	Patients with CRC (fulfilling Amsterdam II and/or Bethesda criteria)	Patients with family history of CRC and personal history of colorectal polyposis or of cancer in the Lynch syndrome tumor spectrum	Patients with Lynch syndrome (with identified MMR mutation or variant of unknown significance)
Total number of patients	120	581	132
MSI	50	13	132
MSS	37	16	0
Unknown	33	29	0
Revised Bethesda criteria	97	17	132
MSI	38	4	132
MSS	31	3	0
Unknown	28	10	0
Amsterdam II criteria	41	15	ND
MSI	14	4
MSS	14	3
Unknown	13	8
First-degree relatives with CRC	23	13	ND
MSI	12	3
MSS	6	3
Unknown	5	7
Polyps (> 10 polyps)	0	0	0
Polyps ( ≤ 10 polyps) at age < 50 +/- first-degree relatives with polyps, MUTYH-negative	0	41	ND
MSI		9
MSS		13
Unknown		19

¹Including 35 patients with personal history of colorectal polyposis and 23 patients with personal history of cancers included in the Lynch syndrome tumor spectrum (peritoneal carcinomatosis, oligoastrocytoma, endometrial carcinoma, gastric adenocarcinoma, or duodenal adenocarcinoma). CRC: Colorectal cancer; MSI: Microsatellite instability; MSS: Microsatellite stable; ND: Not data; MMR: Mismatch repair.

Table 2 Conditional maximum likelihood estimation of the associations between UNC5C variants and risk for colorectal cancer n (%)

Type of cancer	Patients mut/total	Controls mut/total	OR (95%CI)	P value
Variant A628K1
Familial CRCs without MMR mutations	0/120 (0.00)	2/1121 (0.18)	NA	NA
Familial CRCs or Lynch-associated cancers without MMR mutations	1/178 (0.56)	2/1121 (0.18)	3.2 (0.29-35.05)	0.348
Familial CRCs or Lynch-associated cancers with or without MMR mutations	3/310 (0.97)	2/1121 (0.18)	5.5 (0.91-32.87)	0.063
Sporadic CRCs (ASTERISK)	4/1023 (0.39)	2/1121 (0.18)	2.2 (0.40-12.02)	0.364
Familial and sporadic CRCs	7/1333 (0.53)	2/1121 (0.18)	3.0 (0.61-14.25)	0.177
Variants R603C, T617I, A628K, or Q630E2
Familial CRCs without MMR mutations	2/120 (1.67)	37/4300 (0.86)	2.0 (0.47-8.20)	0.3613
Familial CRCs or Lynch-associated cancers without MMR mutations	3/178 (1.69)	37/4300 (0.86)	2.0 (0.60-6.47)	0.2613
Familial CRCs or Lynch-associated cancers with or without MMR mutations	5/310 (1.61)	37/4300 (0.86)	1.9 (0.74-4.84)	0.1853

¹Estimates of the risk associated with variant A628K inferred from genotyping data obtained in patients with familial colorectal or Lynch-associated forms of cancer and in patients with sporadic colorectal cancers (CRCs) and healthy controls from the ASTERISK population;

²Estimates of the risk associated with heterozygosity for variants R603C, T617I, A628K, or Q630E by comparison of the present study familial cancer cases with Caucasian individuals from the NHLBI GO Exome Sequencing Project used as controls Exome Variant Server, NHLBI Exome Sequencing Project (ESP), Seattle, WA [http://evs.gs.washington.edu/EVS/(date 08/2013 accessed)];

³Applying Bonferroni correction, significance threshold was lowered to 0.05/4 = 0.0125. NA: Not available; MMR: Mismatch repair.