Similar results were obtained in another study conducted in Poland. 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.
Hyperplastic polyposis syndrome (HPPS)
Isolated and multiple hyperplastic polyps (HP) (typically white, flat, and small) are common in the general population and their presence does not suggest an underlying genetic disorder. The clinical diagnosis of hyperplastic polyposis syndrome (HPPS), as defined by the World Health Organization (WHO), must satisfy one of the following criteria:
- At least five histologically diagnosed HP occurring proximal to the sigmoid colon (of which at least two are greater than 10 mm in diameter).
- One HP occurring proximal to the sigmoid colon in an individual who has at least one first-degree relative with hyperplastic polyposis.
- Greater than 30 HPs distributed throughout the colon.
These WHO criteria are based on expert opinion; there is no known susceptibility gene or genomic region that has been reproducibly linked to this disorder, so genetic diagnosis is not possible. Although the vast majority of cases of HPPS lack a family history of HPs, approximately half of HPPS cases have a positive family history for CRC.[377,378] Several studies show that the prevalence of colorectal adenocarcinoma in patients with formally defined criteria for HPPS is 50% or more.[379,380,381,382,383]
Only one study to date has linked a germline mutation with HPPS. In a recent study of 38 patients with more than 20 HPs, a large (>1 cm) HP, or HPs in the proximal colon, molecular alterations were sought in the base-excision repair genes MBD4 and MYH. One patient was found to have biallelic MYH mutations, and thus was diagnosed with MYH-associated polyposis. No pathogenic mutations were detected in MBD4 among 27 patients tested. However, six patients had single nucleotide polymorphisms of uncertain significance. Only two patients had a known family history of HPPS, and ten of the 38 patients developed CRC. This series presumably included patients with sporadic HPs mixed in with other patients who may have HPPS.
In a cohort of 40 HPPS patients, defined as having more than five HPs or more than three HPs, two of which were larger than 1 cm in diameter, one patient was found to have a germline mutation in the EPHB2 gene (D861N). The patient had serrated adenomas and more than 100 HPs in her colon at age 58 years, and her mother died of colon cancer at age 36 years. EPHB2 germline mutations were not found in 100 additional patients with a personal history of CRC or in 200 population-matched healthy control patients.