Deletions of 11q22.3-q25 are associated with atypical lung carcinoids and poor clinical outcome

Abstract

Carcinoids are slow-growing neuroendocrine tumors that, in the lung, can be subclassified as typical (TC) or atypical (AC). To identify genetic alterations that improve the prediction of prognosis, we investigated 34 carcinoid tumors of the lung (18 TCs, 15 ACs, and 1 unclassified) by using array comparative genomic hybridization (array CGH) on 3700 genomic bacterial artificial chromosome arrays (resolution ≤1 Mb). When comparing ACs with TCs, the data revealed: i) a significant difference in the average number of chromosome arms altered (9.6 versus 4.2, respectively; P = 0.036), with one subgroup of five ACs having more than 15 chromosome arms altered; ii) chromosomal changes in 30% of ACs or more with additions at 9q (≥1 Mb) and losses at 1p, 2q, 10q, and 11q; and iii) 11q deletions in 8 of 15 ACs versus 1 of 18 TCs (P = 0.004), which was confirmed via fluorescence in situ hybridization. The four critical regions of interest in 45% ACs or more comprised 11q14.1, 11q22.1-q22.3, 11q22.3-q23.2, and 11q24.2-q25, all telomeric of MEN1 at 11q13. Results were correlated with patient clinical data and long-term follow-up. Thus, there is a strong association of 11q22.3-q25 loss with poorer prognosis, alone or in combination with absence of 9q34.11 alterations (P = 0.0022 and P = 0.00026, respectively).

Figure 1

Analysis of chromosomal alterations in lung carcinoid tumors. A: Representative array CGH profiles of a typical carcinoid (TC) and two atypical carcinoids (ACs). Case 5 (TC; see Supplemental Table S1 at http://ajp.amjpathol.org) demonstrates deletion of chromosome 13q; case 27 (AC), deletion (≥10 Mb) of chromosomes 6pq and 11pq and gain of chromosome 22pq; and case 29 (AC), gain of chromosomes 1q, 5p, 6p, 13q, 18q, and 20q and loss of chromosomes 3p, 5q, 8p, 9q, 10q, 11q, 13p, 17p, and Xq. Furthermore, case 29 exhibits amplification at 8q24, the region containing the oncogene MYC (arrow). B: Difference in number of chromosome arms containing at least one altered region ≥10 Mb per tumor between TCs and ACs (4.2 ± 3.4 versus 9.5 ± 8.7, respectively; P = 0.036). Black bar indicates the mean number of altered chromosome arms. C: Graph shows frequency of deletion of specific regions at chromosome arm 11q comparing ACs (blue) with TCs (red). D–F: Fluorescence in situ hybridization (original magnification ×630) of (D) centromere 1 (green) and centromere 7 (red) in case 13 (see Supplemental Table S1 at http://ajp.amjpathol.org) exhibiting two copies of chromosome 7 and one copy of chromosome 1. E: An 11q probe located at the MEN1 locus at 11q13 (green) and a probe located at 11q13.4–21 (red) in case 23 (see Supplemental Table S1 at http://ajp.amjpathol.org), showing loss at 11q telomeric of the MEN1 gene. F: Vysis LSI MYC Dual Color, Break Apart Rearrangement Probe in case 29 (see Supplemental Table S1 at http://ajp.amjpathol.org) shows three copies for the Spectrum Green–labeled probe target located 1.6 Mb telomeric of MYC (green) and three copies for the Spectrum Orange–labeled probe target 120 kb centromeric of MYC in approximately 75% of the nuclei (red). Multiple copies of the Spectrum Orange–labeled probe target were observed in the remaining 25% of nuclei, indicating amplification of this region.

Figure 2

Survival analysis based on histopathologic classification. Kaplan-Meier curve comparing overall 10-year survival of typical carcinoids (TCs; dotted line) and atypical carcinoids (ACs; solid line). +, Censored cases.

Figure 3

Survival analysis based on array CGH data. Kaplan-Meier curve comparing overall 10-year survival of all carcinoids (A) and atypical carcinoids (ACs) (B) with (solid line) or without (dotted line) 11q22.3-q23.2 deletion; all carcinoids (C) and ACs (D) with (solid line) or without (dotted line) 9q34.11 gain; all carcinoids (E) and ACs (F) with 11q22.3-q23.2 deletion but no 9q34.11 gain (solid line) compared with cases without 11q22.3-q23.2 deletion or with 11q22.3-q23.2 deletion in the presence of 9q34.11 gain (dotted line). +, Censored cases.