Polyposis Syndrome, Hereditary Mixed, 1

A number sign (#) is used with this entry because of evidence that hereditary mixed polyposis syndrome can be caused by heterozygous duplication on chromosome 15q13-q14 that causes increased and ectopic expression of the GREM1 gene (603054).

Description

The hereditary mixed polyposis syndrome (HMPS) is characterized by atypical juvenile polyps, colonic adenomas, and colorectal carcinomas (CRC).

Genetic Heterogeneity of Hereditary Mixed Polyposis

HMPS2 (610069) is caused by mutation in the BMPR1A gene (601299) on chromosome 10q23.

Clinical Features

Thomas et al. (1996) noted that HMPS patients may also have an increased propensity to develop inflammatory and metaplastic polyps. The authors stated that in a large HMPS family identified at St. Mark's Hospital, London, HMPS appeared to be inherited as an autosomal dominant. Most older individuals presented with colorectal carcinoma; younger individuals, most of whom had undergone screening by colonoscopy, tended to present with benign colonic lesions, often the characteristic polyp of the hereditary mixed polyposis syndrome. Linkage analysis data did not support linkage to the APC locus (611731) on chromosome 5 or to any of the loci for hereditary nonpolyposis colorectal cancer known at that time.

Tomlinson et al. (1999) described an Ashkenazi Jewish family with a dominantly inherited predisposition to colorectal adenomas and carcinomas in which no evidence of linkage was found to previously identified colorectal susceptibility loci.

Mapping

Tomlinson et al. (1999) demonstrated linkage of the disorder in their Ashkenazi family to a locus, which they called CRAC1, on chromosome 15q, with a multipoint lod score of 3.06 at marker D15S118. Thomas et al. (1996) had found linkage of the disorder in their large Ashkenazi family to a locus (HMPS) on chromosome 6q, but repeat of linkage studies using stringent criteria of phenotype and additional genetic markers showed significant evidence of linkage only to a region on 15q13-q14 encompassing the CRAC1 locus (Jaeger et al., 2003). Jaeger et al. (2003) found that affected individuals from both Ashkenazi families shared a haplotype between D15S1031 and D15S118; the haplotype was rare in the general Ashkenazi population. A third informative family showed linkage of the disorder to HMPS/CRAC1 and shared the putative ancestral haplotype, as did a further 2 families. Although there are probably several causes of the multiple colorectal adenoma and cancer phenotype in Ashkenazim, mutation at the HMPS/CRAC1 locus on 15q13-q14 is an important one.

Park et al. (2000) performed a high density loss of heterozygosity (LOH) study for 13 polymorphic microsatellite markers, including D15S118, spanning 15q15.3-q22.1, in 70 cases of a sporadic form of colorectal tumors (26 adenomas and 44 carcinomas). The results of deletion mapping showed that a locus at D15S968 in subband 15q21.1 may harbor a tumor suppressor gene in an area less than 0.521 Mb in physical map distance.

Colorectal Cancer Susceptibility

Jaeger et al. (2008) performed fine mapping with additional members of the Ashkenazi families with hereditary mixed polyposis syndrome, originally studied by Thomas et al. (1996) and Tomlinson et al. (1999), and identified a 0.6-Mb critical region on chromosome 15 containing 3 known genes, SGNE1 (173120), GREM1 (603054), and FMN1 (136535). In a large series involving a total of 7,961 colorectal carcinoma cases and 6,803 controls, the authors found a strong association between SNPs near GREM1 and SGNE1 and increased risk of CRC (for rs4779584, P = 4.44 x 10(-14)).

Tomlinson et al. (2008) found strong association between the SNP rs4779584 and risk of colorectal cancer in a large genomewide association study (P = 4.7 x 10(-7)).

FitzGerald et al. (2010) performed genomewide SNP linkage analysis of 96 families with hereditary prostate cancer, each of which had 1 or more first-degree relatives with colon cancer. The strongest linkage signal was identified at chromosome 15q14 for a 31.04-cM interval spanning rs732165 and rs1989223, when both prostate and colon cancer phenotypes were considered to be affected in families with 2 or more colon cancer cases (recessive HLOD = 3.88).

Molecular Genetics

Using a custom oligonucleotide array, Jaeger et al. (2012) detected a heterozygous single-copy duplication of approximately 40 kb centered on chromosome 15:30.77 Mb (UCSC Genome Browser) in 2 affected individuals from an Ashkenazi Jewish family with HMPS that was not present in 3 unaffected relatives. Testing of 40 affected and 50 unaffected family members from 6 Ashkenazi Jewish families with HMPS, previously studied by Thomas et al. (1996), Whitelaw et al. (1997), Tomlinson et al. (1999), and Jaeger et al. (2003), revealed perfect concordance between presence of a duplication-specific 190-bp amplification product and affected status. The 190-bp product was not found in 188 unselected Ashkenazi controls. Screening of 718 familial colorectal cancer (CRC) cases and 935 controls from the Colorectal Tumour Gene Identification (CORGI) study identified 1 additional case with the duplication, which was not detected in any of the controls; on further investigation, the family of the duplication-positive case was found be of Ashkenazi descent and to have a phenotype of multiple polyps and CRC, consistent with HMPS. The duplication extended from intron 2 of the SCG5 gene to a site just upstream of the GREM1 (603054) CpG island, and functional analysis demonstrated that whereas only normal SCG5 mRNA species was found with no difference in expression relative to controls, the duplication was associated with increased and ectopic GREM1 expression.