Pan-colonic field defects are detected by CGH in the colons of UC patients with dysplasia/cancer

Abstract

BAC arrays were used to evaluate genomic instability along the colon of patients with ulcerative colitis (UC). Genomic instability increases with disease progression and biopsies more proximal to dysplasia showed increased instability. Pan-colonic field copy number gain or loss involving small (<1Mb) regions were detected in most patients and were particularly apparent in the UC progressor patients who had dysplasia or cancer. Chromosomal copy gains or losses affecting large regions were mainly restricted to dysplastic biopsies. Areas of significant chromosomal losses were detected in the UC progressors on chromosomes 2q36, 3q25, 3p21, 4q34, 4p16.2, 15q22, and 16p13 (p-value⩽0.04). These results extend our understanding of the dynamic nature of pan-colonic genomic instability in this disease.

Figure 1. Instability along the colon of UC progressor patients

Shown are whole genome plots illustrating the copy number instability in biopsies sampled taken along the colons of ten UC progressor patients (A–J). Left, maps of the respective colons showing relative spatial locations and histological diagnoses. Blue, negative for dysplasia; green, indefinite for dysplasia; yellow, low grade dysplasia; pink, high grade dysplasia; red, cancer; blank, no histological diagnosis available. Right, whole genome plots showing normalized log2 ratios for chromosomes 1–22 and X (ordered from left to right). Roman numerals correspond to the biopsy position on the respective colon maps. The horizontal line indicates log2 ratio of zero, or normal copy number of 2. Spots above the line indicate BACs with copy number gain; spots below the line indicate BACs with copy number loss.

Figure 2. BAC alterations affected by distance to dysplasia but not distance to rectum

Shown are scatterplots of number of BACs with copy number gain or loss as detected by wavelet. A, Alterations plotted as a function of distance to dysplasia (cm). B, Alterations plotted relative to distance to rectum (cm). Negative for dysplasia, open blue triangles; dysplasia, open red squares. This data suggests that a single non-dysplastic biopsy from the rectum could detect genomic instability.

Figure 3. The number and max size of copy number alterations increases with UC progression

A & C, The number of regions of copy number gain (A) and loss (C) increase with UC disease progression. Shown is the average number of regions of copy gain +/− SEM for non-UC, UC non-progressors, UC progressors at sites negative for dysplasia (located > 10 cm or < 10 cm from a site of dysplasia) and UC progressors at dysplastic sites. Asterisks indicate significant difference for comparisons to UC NP using Mann Whitney * p<0.05; ** p-value <0.01. B & D, The maximum size of regions of copy number gain (B) or loss (D) increase with UC disease progression. Shown is the maximum size (Mb) of regions of copy gain +/− SEM for non-UC, UC non-progressors, UC progressors at sites negative for dysplasia (located > 10 cm or < 10 cm from a site of dysplasia) and UC progressors at dysplastic sites. Asterisks indicate significant difference for comparisons to UC NP using Mann Whitney * p<0.05; ** p-value <0.01.

Figure 4. MAD (median absolute deviation) values of global genomic instability increase with neoplastic progression

Shown are boxplots of the MAD values for the BAC arrays. The lines indicate the median values and the boxes denote the 75% and 25% for the arrays within each group. The error bars indicate the 90% and 10% for the arrays within each group. The MAD values for genomic instability sufficiently overlap between UC non-progressors (UC-NP) and UC progressors (UC-P), prevent the use of this measure as a clinically meaningful biomarker of neoplasia.