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. 2011 Dec 15;17(24):7776-84.
doi: 10.1158/1078-0432.CCR-11-1791. Epub 2011 Oct 12.

Mapping of chromosome 1p deletions in myeloma identifies FAM46C at 1p12 and CDKN2C at 1p32.3 as being genes in regions associated with adverse survival

Kevin D Boyd  1 , Fiona M Ross, Brian A Walker, Christopher P Wardell, William J Tapper, Laura Chiecchio, Gianpaolo Dagrada, Zoe J Konn, Walter M Gregory, Graham H Jackson, J Anthony Child, Faith E Davies, Gareth J Morgan; NCRI Haematology Oncology Studies Group
Affiliations

Mapping of chromosome 1p deletions in myeloma identifies FAM46C at 1p12 and CDKN2C at 1p32.3 as being genes in regions associated with adverse survival

Kevin D Boyd et al. Clin Cancer Res. .

Abstract

Purpose: Regions on 1p with recurrent deletions in presenting myeloma patients were examined with the purpose of defining the deletions and assessing their survival impact.

Experimental design: Gene mapping, gene expression, FISH, and mutation analyses were conducted on patient samples from the MRC Myeloma IX trial and correlated with clinical outcome data.

Results: 1p32.3 was deleted in 11% of cases, and deletion was strongly associated with impaired overall survival (OS) in patients treated with autologous stem cell transplant (ASCT). In patients treated less intensively, del(1)(p32.3) was not associated with adverse progression-free survival (PFS) or OS. The target of homozygous deletions was CDKN2C, however its role in the adverse outcome of cases with hemizygous deletion was less certain. 1p22.1-21.2 was the most frequently deleted region and contained the candidate genes MTF2 and TMED5. No mutations were identified in these genes. 1p12 was deleted in 19% of cases, and deletion was associated with impaired OS in univariate analysis. The target of homozygous deletion was FAM46C, which was mutated in 3.4% of cases. When cases with FAM46C deletion or mutation were considered together, they were strongly associated with impaired OS in the intensive treatment setting.

Conclusion: Deletion of 1p32.3 and 1p12 was associated with impaired OS in myeloma patients receiving ASCT. FAM46C was identified as a gene with potential pathogenic and prognostic significance based on the occurrence of recurrent homozygous deletions and mutations.

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Figures

Figure 1
Figure 1
OS of patients undergoing non-intensive treatment comparing patients with del(1)(p32.3) to those without deletion.
Figure 2
Figure 2
PFS (2A) and OS (2B) of patients treated in the intensive pathway, landmarked at time of ASCT and comparing cases with del(1)(p32.3) with patients without deletion.
Figure 3
Figure 3
OS of patients ≤70 years of age in the non-intensive pathway, comparing patients with del(1)(p32.3) with patients without deletion.
Figure 4
Figure 4
OS of cases with any abnormality of FAM46C (incorporating loss of heterozygosity and mutation) compared to cases with normal FAM46C.
Figure 5
Figure 5
Mutations of FAM46C described to date in myeloma.
None
See this image and copyright information in PMC

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