No Evidence of Linkage for Chromosome 1q42.2-43 in Prostate Cancer

Abstract

Mutations of UFD1L Are Not Responsible for the Majority of Cases of DiGeorge Syndrome/ Velocardiofacial Syndrome without Deletions within Chromosome 22q11 To the Editor: Deletions of chromosome 22q11 are associated with a wide spectrum of congenital malformation, encompassed by the acronym "CATCH22" (cardiac defects, abnormal facies, thymic hypoplasia, cleft palate, and hypocalcemia on chromosome 22), including velocardiofacial syndrome (VCFS; MIM 192430), DiGeorge syndrome (DGS; MIM 188400), and conotruncal-anomaly face (Emanuel et al. 1998). The major anomalies include outflow-tract congenital heart defects, hypoplasia of the parathyroids and thymus, craniofacial dysmorphism, and learning/behavioral problems (Ryan et al. 1997). Many of these are thought to be due to a defective neural-crest contribution during development. The DiGeorge chromosomal region (DGCR) is entirely cloned (Carlson et al. 1997) and sequenced, and several genes have been reported mapping to the region. Mutation screens of genes mapping to the proximal end of this region, termed the "minimal DiGeorge chromosomal region" (MDGCR; Gong et al. 1996), have been negative (Wadey et al. 1995; Gong et al. 1997; Gottlieb et al. 1997; Lindsay et al. 1998). Attention therefore has turned to the regions adjacent and distal to the MDGCR. Recently, the gene UFD1L was proposed as the major gene haploinsufficient in this group of syndromes (Yamagishi et al. 1999). UFD1L is downstream of dHAND, a gene known to be involved in control of the development of structures affected in DGS, and Ufd1l is expressed in the branchial arches, frontonasal mass, and outflow tract. In addition, a single patient has been reported with a de novo deletion affecting UFD1L and the neighboring gene, CDC45L2 (Yamagishi et al. 1999). CDC45 is required for initiation of DNA replication in yeast, and CDC45 mutants are nonviable. However, CDC45L2 expression is not altered in d-HAND Ϫ/Ϫ embryos. On the basis of these findings, Yamagishi and colleagues concluded that UFD1L hap-conditions can be obtained at the e-mail addresses that follow:

PCAP is the major known prostate cancer predisposing locus in families from south and west Europe

“…15 The second locus called PCaP (Predisposing for Cancer Prostate) was identified on 1q42.2-43 by a combined analysis of French and German families. 10 This result was not confirmed by other groups 16 but positive LOD scores suggestive of linkage were obtained when families were stratified. Indeed, evidence of linkage was observed among a small subset of families with 55 affected individuals 17 or with pedigrees which meet the same criterion, had an average age at diagnosis 566 years and male to male transmission.…”

“…To date, several studies based on Caucasian populations, particularly American, have tried to replicate our results without success. 16,17 Only a small subset of their families might be linked to PCaP. 17,18 This suggests that this locus is most specific to families from south and west Europe.…”

No evidence of linkage to chromosome 1q42.2–43 in 131 prostate cancer families from the ACTANE Consortium

“…Stratification of the family set into sub-groups according to average age at diagnosis and number of affected family members also yielded no evidence of linkage. Our findings are similar to those of Gibbs et al (1999) and Whittemore et al (1999) who also failed to find evidence of linkage after analysis according to a similar stratification. Such conflicting evidence regarding linkage to this region on chromosome 1 may be influenced by various factors, particularly with respect to the sample set.…”

“…However, it seems unlikely that these differences alone could account for the discrepancy in results found between the two groups. Whittemore et al (1999) used only three markers to genotype 82 families of predominantly American origin. Similarly, out of the 152 families used in the study by Gibbs et al (1999) only six were of non-white origin, the rest were white American.…”

“…Further analysis of family subsets, stratified according to mean age of diagnosis and number of affected members, did not provide any significant evidence for linkage. In a further attempt to confirm the findings by Berthon et al, Whittemore et al (1999) conducted a linkage study in 97 families with at least three affected cases using three markers. Multipoint LOD and NPL scores failed to support linkage, even when analysis was restricted to the 14 families in their No evidence of linkage to chromosome 1q42.2-43 in 131 prostate cancer families from the ACTANE Consortium set with early-onset disease.…”