Sessile Serrated Polyposis Cancer Syndrome

A number sign (#) is used with this entry because of evidence that sessile serrated polyposis cancer syndrome (SSPCS) is caused by heterozygous mutation in the RNF43 gene (612482) on chromosome 17q22.

Description

Sessile serrated polyposis cancer syndrome (SSPCS) is a rare disorder characterized by the presence of multiple serrated polyps in the colon and an increased personal and familial risk of colorectal cancer. SSPCS is defined by the World Health Organization (WHO) as the presence of at least 5 sessile serrated polyps (also known as 'sessile serrated adenomas,' or SSAs) proximal to the sigmoid colon, with 2 or more that are greater than 10 mm in diameter; or any number of serrated polyps in a person with a first-degree relative with SSPCS; or more than 20 serrated polyps of any size, distributed throughout the colon. SSAs are found in 2% of average-risk individuals undergoing their first screening colonoscopy, and are estimated to be responsible for 20 to 35% of all colon cancers. SSAs exhibit somatic mutations in the BRAF gene (164757), or less commonly in the KRAS gene (190070), early in their development. Individuals with SSPCS have a lifetime risk of colon cancer as high as 54% and may have a strong personal or family history of extracolonic cancers; first-degree relatives have a 32% risk of developing multiple serrated polyps and a 5-fold increased risk of colon cancer. An increased risk of pancreatic cancer has also been observed (summary by Gala et al., 2014).

Clinical Features

Gala et al. (2014) studied 2 women with serrated polyposis, both of whom met the WHO criteria for SSPCS and had a mutation in the RNF43 gene (see MOLECULAR GENETICS). The first was a 62-year-old woman diagnosed at age 51 years. She had more than 30 serrated polyps throughout the colon, and her father had colon and prostate cancer. The second was a 62-year-old woman who developed chronic leukocytic leukemia at age 42 and was diagnosed with SSPCS at age 52. Her 3 sibs all had colonic polyps, and there was a strong family history of cancer: their father had kidney cancer and their mother had breast cancer, and their maternal and paternal aunts and uncles had a variety of cancers, including cancer of the breast, pancreas, stomach, bladder, and colon.

Taupin et al. (2015) reported a family in which a brother and sister had SSPCS. The 23-year-old brother underwent emergency right hemicolectomy for an obstructing colorectal carcinoma (CRC) that arose from a serrated polyp and was negative for microsatellite instability. He had more than 50 large serrated polyps throughout the colon. His 27-year-old sister underwent screening colonoscopy, which revealed more than 20 large serrated polyps; she underwent elective subtotal colectomy, and more than 60 polyps were present in the resected specimen. Their 21-year-old brother had a single adenoma of the rectum on colonoscopy; follow-up colonoscopy a year later was normal. Their mother had died at age 50 years of pancreatic cancer; paternal family history was negative for polyposis or CRC in the father's generation.

Molecular Genetics

Gala et al. (2014) studied 20 probands with serrated polyposis, 16 of whom met the WHO criteria for SSPCS syndrome. A personal history of colon cancer was present in 3, whereas 11 had a family history of colon cancer, and 8 had 1 or more extracolonic neoplasms. The median age of the probands was 52, and the number of sessile serrated adenomas ranged from 3 to more than 50. The authors analyzed SSA tissue from 19 of the SSPCS probands and found that 18 of the genotyped SSAs carried the BRAF V600E mutation (164757.0001); 1 individual's tissue did not harbor an identifiable mutation in the BRAF or KRAS genes. Exome data from the 20 SSPCS probands was analyzed for 'strong' loss-of-function mutations (affecting all isoforms of a given gene) in 233 genes relevant to oncogene-induced senescence pathways in the colon, and germline nonsense or splice site mutations were identified in 5 participants, in the ATM (607585), TELO2 (611140), RBL1 (116957), XAF1 (606717), and PIF1 (610953) genes. Overall, 25% of probands harbored a mutation in that gene set compared to 9.87% of 4,300 control exomes from the Exome Variant Server database (OR, 3.0; p = 0.04). In the remaining 15 probands, the authors further analyzed the exome data for loss-of-function variants in genes at loci implicated by genomewide association studies of all cancers, and identified nonsense mutations in 4 individuals: 2 with a mutation in the ULK4 gene (617010), R862X (rs199884004), which was also found in 45 of the 4,300 control exomes (OR, 10.5; p = 0.02); and 2 with a mutation in the RNF43 gene (R113X; 612482.0001), found in 1 of the 4,300 control exomes (OR, 460; p = 6.8 x 10(-5)). Gala et al. (2014) concluded that germline loss-of-function variants in genes that regulate senescence pathways are associated with the development of multiple SSAs, and that nonsense mutations in RNF43 are associated with a high risk of developing SSAs.

By exome sequencing in a 23-year-old man with SSPCS, who was negative for mutation in the MUTYH gene (604933) and who had developed colorectal carcinoma that was negative for somatic mutation at KRAS codons 12 and 13, Taupin et al. (2015) identified heterozygosity for a nonsense mutation in the RNF43 gene (R132X; 612482.0002). The mutation was present in the proband's affected sister, but was not found in their unaffected father or brother. DNA was unavailable from their mother, who died of pancreatic cancer at age 50 years.

Inheritance

Boparai et al. (2010) analyzed the incidence rate of colorectal cancer in first-degree relatives of patients with hyperplastic polyposis syndrome, who often have multiple sessile or traditional serrated adenomas, and compared this rate with that in the general population. A total of 347 first-degree relatives (41% male) from 57 pedigrees were included, contributing 11,053 person-years of follow-up. During the study period a total of 27 CRC cases occurred among first-degree relatives, compared to 5 expected CRC cases (p less than 0.001). The relative risk of colorectal cancer in first-degree relatives compared to the general population was 5.4 (95% CI, 3.7-7.8). Four first-degree relatives satisfied the criteria for hyperplastic polyposis syndrome. Based on the estimated HPS prevalence of 1 in 3,000 in the general population, the projected relative risk of HPS in first-degree relatives was 39 (95% CI, 13-121). Boparai et al. (2010) suggested that as long as no causative gene has been identified, screening colonoscopies of all first-degree relatives of patients with hyperplastic polyposis syndrome are warranted.

Hazewinkel et al. (2015) evaluated the diagnostic yield of screening colonoscopies in 77 first-degree relatives of 36 probands with serrated polyposis. First-degree relatives had a median age of 52 years with an interquartile range of 41 to 60 years. Colorectal cancer was not diagnosed. One or more significant polyps were detected in 43% of first-degree relatives. No differences based on age, gender, or familial relationship were observed in the detection of polyps. Seven first-degree relatives (9%) had multiple polyps (5 or more); 11 (14%) first-degree relatives fulfilled serrated polyposis syndrome WHO criterion 2 (any number of serrated polyps proximal to the sigmoid colon in a first-degree relative of a patient with serrated polyposis syndrome), of whom 1 sib also met serrated polyposis syndrome WHO criterion 3 (greater than 20 serrated polyps spread throughout the colon).