Familial adenomatous polyposis-associated desmoids display significantly more genetic changes than sporadic desmoids

Abstract

Desmoid tumours (also called deep or aggressive fibromatoses) are potentially life-threatening fibromatous lesions. Hereditary desmoid tumours arise in individuals affected by either familial adenomatous polyposis (FAP) or hereditary desmoid disease (HDD) carrying germline mutations in APC. Most sporadic desmoids carry somatic mutations in CTNNB1. Previous studies identified losses on 5q and 6q, and gains on 8q and 20q as recurrent genetic changes in desmoids. However, virtually all genetic changes were derived from sporadic tumours. To investigate the somatic alterations in FAP-associated desmoids and to compare them with changes occurring in sporadic tumours, we analysed 17 FAP-associated and 38 sporadic desmoids by array comparative genomic hybridisation and multiple ligation-dependent probe amplification. Overall, the desmoids displayed only a limited number of genetic changes, occurring in 44% of cases. Recurrent gains at 8q (7%) and 20q (5%) were almost exclusively found in sporadic tumours. Recurrent losses were observed for a 700 kb region at 5q22.2, comprising the APC gene (11%), a 2 Mb region at 6p21.2-p21.1 (15%), and a relatively large region at 6q15-q23.3 (20%). The FAP-associated desmoids displayed a significantly higher frequency of copy number abnormalities (59%) than the sporadic tumours (37%). As predicted by the APC germline mutations among these patients, a high percentage (29%) of FAP-associated desmoids showed loss of the APC region at 5q22.2, which was infrequently (3%) seen among sporadic tumours. Our data suggest that loss of region 6q15-q16.2 is an important event in FAP-associated as well as sporadic desmoids, most likely of relevance for desmoid tumour progression.

Figure 1. Examples of copy number abnormalities identified by array CGH analysis.

Graphs show the log₂ ratio profiles for the BACs aligned along the X-axis from chromosome 1 to chromosome Y. (A) FAP-associated desmoid tumour HDD-I without any CNAs. (B) FAP-associated desmoid tumour HDD-H with loss of the 5q21.1-q31.1 region involving the APC gene. (C) Non-FAP-associated desmoid tumour P9A with loss at 6p21.2-p12 and 6q12-qter. (D) Non-FAP-associated desmoid tumour 114T with gain of chromosome 8q.

Figure 2. Composite array CGH profiles.

The results for all chromosomes of the genome are presented with red lines indicating loss and green lines indicating gain. Losses and gains are shown for non-FAP-associated desmoid tumours (light color) and for FAP-associated desmoid tumours (dark color).

Figure 3. MLPA data overview verifying losses on chromosomes 5 and 6 as detected by array CGH analysis.

The MLPA results for the indicated gene probes are presented with dots and diamonds, indicating loss and no loss, respectively. Losses on chromosomes 5 (A) and 6 (B) as detected by array CGH are shown for non-FAP-associated desmoid tumours (light red color) and FAP-associated desmoid tumours (dark red color).