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Genetics of Colorectal Cancer (PDQ®): Genetics - Health Professional Information [NCI] - Major Genetic Syndromes

Table 10. Cumulative Cancer Risks in Peutz-Jeghers Syndrome Up To Specified Agea continued...

Juvenile polyposis syndrome (JPS)

JPS is a genetically heterogeneous, rare, childhood-onset, autosomal dominant disease that presents characteristically as hamartomatous polyposis throughout the GI tract and can present with diarrhea, GI tract hemorrhage, and protein-losing enteropathy.[410,411] While most patients with juvenile polyposis appear to represent sporadic illness, this may be due to reduced penetrance. Juvenile polyposis syndrome is due to germline mutations in the MADH4 gene, also known as SMAD4/DPC4, at chromosome 18q21 [412] in approximately 15% to 20% of cases, and to mutations in the gene-encoding bone morphogenic protein receptor 1A (BMPR1A) residing on chromosome band 10q22 in approximately 25% to 40% of cases.[413,414] The lifetime CRC risk in JPS has been reported to be 39%.[415]

A severe form of JPS, in which polyposis develops in the first few years of life, is referred to as JPS of infancy. JPS of infancy is often caused by microdeletions of chromosome 10q22-23, a region that includes BMPR1A and PTEN. (Refer to the Cowden Syndrome/Bannayan-Riley-Ruvalcaba Syndrome Gene(s) section of this summary for more information about PTEN.) The phenotype often includes features such as macrocephaly and developmental delay, possibly as a result of loss of PTEN function.[416] Recurrent gastrointestinal bleeding, diarrhea, exudative enteropathy, in addition to associated developmental delay, are associated with a very high rate of morbidity and mortality in these infants, thereby limiting the heritability of such cases.[416]

Hereditary mixed polyposis syndrome (HMPS)

HMPS is a rare cancer family syndrome characterized by the development of a variety of colon polyp types, including serrated adenomas; atypical juvenile polyps; and adenomas, and colon adenocarcinoma. Although initially mapped to a locus between 6q16-q21, the HMPS locus is now believed to map to 15q13-q14.[417,418] While there is considerable phenotypic overlap between JPS and HMPS, one large family has been linked to a locus on chromosome 15, raising the possibility that this may be a distinct disorder.


Evidence demonstrates that a subset of families with hereditary breast and colon cancer may have a cancer family syndrome caused by a mutation in the CHEK2 gene.[419,420,421] Although the penetrance of CHEK2 mutations is clearly less than 100%, additional studies are needed to determine the risk of breast, colon, and other cancers associated with CHEK2 germline mutations. One large study showed that truncating mutations in CHEK2 were not significantly associated with CRC; however, a specific missense mutation (I157T) was associated with modest increased risk (odds ratio [OR], 1.5; 95% CI, 1.2–3.0) of CRC.[422]

Similar results were obtained in another study conducted in Poland.[423] In this study, 463 probands from LS and LS–related families and 5,496 controls were genotyped for four CHEK2 mutations, including I157T. The missense I157T allele was associated with LS–related cancer only for MMR mutation-negative cases (OR, 2.1; 95% CI, 1.4–3.1). There was no association found with the truncating mutations. Further studies are needed to confirm this finding and to determine whether they are related to familial CRC type X.


WebMD Public Information from the National Cancer Institute

Last Updated: February 25, 2014
This information is not intended to replace the advice of a doctor. Healthwise disclaims any liability for the decisions you make based on this information.
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