Clinical features and long-term outcomes of patients with colonic oligopolyposis of unknown etiology

Table 1 Colonic adenomatous polyposis of unknown etiology cohort characteristics, n (%)

Cohort characteristics	Number (% of cohort)
Male	48 (69%)
Ethnicity
White non-Hispanic	62 (88.5%)
Hispanic or Latino	5 (7.1%)
Black or African American	2 (2.9%)
Asian	1 (1.4%)
Paternal lineage
Irish	25 (24%)
English	14 (13%)
French	12 (11%)
Scottish	11 (10%)
Italian	9 (9%)
Maternal lineage
Irish	20 (23%)
English	14 (16%)
Italian	14 (16%)
Canadian	6 (7%)
Scottish	6 (7%)
German	5 (6%)
Any metabolic comorbidity reported (Obesity/diabetes mellitus)	29 (41.4%)
Any alcohol usage	34 (49%)
1-7 drinks/week	14 (20%)
More than 1 drink/day	7 (10%).
Any smoking history	41 (58.5%)
Active smokers	15 (21.4)
Mean pack years	17 (30.1)

Data include demographic and clinical features for all 70 patients in the cohort. Leading five paternal and maternal lineages are presented (Full data in supplementary table). Presence of metabolic comorbidities were combined. Data concerning alcohol consumption and smoking were available for 69 patients. Detailed data concerning smoking burden (Pack/years) were available for 17 patients.

Table 2 Genes sequenced in the colonic adenomatous polyposis of unknown etiology cohort

Gene name	Number of patients tested	Percentage (%)
APC	70	100
MUTYH (full seq.)	53	75.7
MLH1	43	61.4
MSH2	43	61.4
MSH6	42	60.0
PMS2	42	60.0
EPCAM	41	58.6
CHEK2	39	55.7
TP53	39	55.7
BMPR1A	38	54.3
CDH1	38	54.3
PTEN	38	54.3
SMAD4	38	54.3
STK11	38	54.3
GREM1	36	51.4
POLD1	36	51.4
POLE	36	51.4
ATM	33	47.1
AXIN2	28	40.0
MUTYH (Y179C and G396D mutations only)	17	24.3
NTHL1	15	21.4
MSH3	13	18.6
BLM	7	10.0
GALNT12	7	10.0
RPS20	4	5.7
MLH3	3	4.3
RNF43	1	1.4

Colorectal cancer related genes sequenced in the colonic adenomatous polyposis of unknown etiology cohort. All had at least APC and MUYTH sequenced. Full list of genes tested in Supplementary Table 1.

Table 3 Malignancies in first-degree relatives of patients with colonic adenomatous polyposis of unknown etiology

Type of cancer in FDR	Number of cases (Total = 113)	Percentage (%)
CRC	25	22.1
Breast	20	17.6
Prostate	14	12.3
Non-melanoma skin cancer	10	8.8
Lung	8	7.0
Gastric	4	3.5
Bladder/Ureter	4	3.5
Brain	4	3.5
Renal	3	2.6
Melanoma	3	2.6
Cervical	3	2.6
Pancreas	2	1.7
Unknown type	2	1.7
Leukemia	2	1.7
Ovarian	2	1.7
Thyroid	2	1.7
Lymphoma	1	0.8
Liver	1	0.8
Malignant meningioma	1	0.8
Esophageal	1	0.8
Liposarcoma	1	0.8

54 patients reported a family history of cancer. Highest frequencies were noted for CRC (22.1%), Breast (17.6%) and Prostate (12.3%). 10 patients (18.5%) had 2 FDRs, 8 patients (14.8%) had 3 FDRs, 1 patient (1.9%) had 4 FDRs, 4 patients (7.4%) had 5 FDRs and 1 patient (1.9%) had 7 FDRs with any malignancy. FDR: First-degree relative; CRC: Colorectal cancer.

Table 4 Clinical features of 11 patients with a significant clinical outcome (cancer, advanced dysplasia, or colectomy)

ID (Gender)	Colectomy (age) (yr)	Colectomy – indication	Surveillance (No. yr to colectomy; Total yr)	Total adenoma burden	No. FDR with CRC	No. SDR with CRC
26 (F)	RHC (62)	IMC	12; 16	Multiple (at least 34)	0	0
29(M)	SIG (52)	IMC	0; 12	Multiple at least 15	0	0
76(F)	IPAA (42)	IMC	0; 14	Multiple (at least 15)	0	0
32(M)	IRA (64)	Polyp burden	0; 1	Multiple (>30, many > 1 cm)	0	0
46(M)	IRA (65)	Polyp burden + recurrent diverticulitis	15; 24	Multiple (at least 47)	0	0
72(M)	IRA (69)	Polyp burden	12; No data post colectomy	Multiple (at least 31)	0	0
62(F)	IPAA (58)	Polyp burden	3; 8.5	Multiple (approx. 83)	0	1 (65)
37(M)	APR (63)	Rectal CRC a	0; 17	27	1 (66)	0
56(F)	SIG (71)	Sigmoid CRC1	0; 4.5	38	1 (68)	0
68(F)	Colectom3(69)	Transverse CRC2	1; No data post colectomy	Multiple (at least 28)	1 (70)	0
82(M)	None(70)	SigmoidMP4	15; 16	16	0	0

¹CRC diagnosed at 1^st colonoscopy.

²CRC diagnosed at 3^rd colonoscopy.

³No data about the type of colectomy.

⁴Resected endoscopically.

Adenoma burden, surgical data and familial burden of CRC (1^st and 2^nd degree relatives) of 11 patients who had a significant clinical outcome. CRC: Colorectal cancer; F: Female; M: Male; MP: Malignant polyp; IMC: Intramucosal carcinoma; RHC: Right hemicolectomy; IRA: Subtotal colectomy with ileorectal anastomosis; IPAA: total proctocolectomy with ileal pouch anal anastomosis; APR: abdominoperineal resection; SIG: sigmoidectomy; FDR: First-degree relative.

Table 5 Extra colonic malignancies in the colonic adenomatous polyposis of unknown etiology cohort

Type of malignancy	Number	%	Incidence rate (Per 1000 person-years)
Non-melanoma skin cancer	25	51	5.1
Prostate	6	12.2	1.2
Melanoma	5	10.2	1
Breast	4	8.2	0.8
Lung	2	4.1	0.4
Uterine	1	2	0.2
Non-Hodgkin's Lymphoma	1	2	0.2
Gallbladder	1	2	0.2
Ovary	1	2	0.2
Bladder	1	2	0.2
Pancreas	1	2	0.2
Merkel cell tumor	1	2	0.2

35 patients reported an extra-colonic malignancy. Highest frequencies were noted for Non-melanoma skin cancer (51%), Prostate (12.2%) and Melanoma (10.2%)

Table 6 Causes of death in the colonic adenomatous polyposis of unknown etiology cohort

Malignancy causes (n = 5)	Age of death (yr)
Lung	71
Unknown (suspected) malignancy	72
Metastatic Merkle cell carcinoma	75
Gallbladder	77
Pancreas	77
Non- malignancy causes (n = 5)
Pulmonary failure.	61
Ruptured aortic aneurysm	78
Unknown	65
Shock and multi-system organ failure.	69
Cardiac arrest	75

There were 10 deaths among CPUE patients. 5 (50%) were secondary to malignancy. CRC was not reported as a cause of death. CPUE: Colonic adenomatous polyposis of unknown etiology cohort; CRC: Colorectal cancer.