Extracolonic features of familial adenomatous polyposis in patients with sporadic colorectal cancer

Abstract

Summary We have investigated the occurrence of attenuated extracolonic manifestations (AEMs) of familial adenomatous polyposis (FAP) in patients with non-polyposis colorectal cancer. In a prospective case-control study, we observed that significantly more colorectal cancer patients exhibited AEM 1985a, b; Houlston et al., 1992; Dunlop, 1983; Hunt et al., 1994). These features, congenital hypertrophy of the retinal pigment epithelium (CHRPE) and mandibular osteomas, occur in 90% and 75% respectively of patients with classical FAP (Utsunomiya and Nakamura, 1975;Bulow et al., 1984; Traboulsi et al., 1987;Berk et al., 1988;Chapman et al., 1989;Giardiello et al., 1991; Hodgson et al., 1994;Wallis et al., 1994). The finding of such extracolonic features in patients with non-FAP colorectal cancer is of considerable interest because of the central, and probably initiating, role of the gene for FAP (APC) in colorectal tumorigenesis. Constitutional and heterozygous mutation of the APC gene is responsible for the FAP syndrome (Groden et al., 1991; Nishishio et al., 1991;Nagase and Nakamura, 1993), while a high proportion of non-FAP colorectal adenomas and cancers have somatic APC mutations (Powell et al., 1992; Ichii et al., 1993; Nagasse and Nakamura, 1993). Inactivating APC mutations have also been noted in dysplastic aberrant crypt foci Smith et al., 1984), which are believed to be the very earliest histological manifestation of colorectal neoplasia.The available data suggest that the extracolonic manifestations of FAP, which we term attenuated extracholonic manifestations (AEMs), occur particularly in colorectal cancer patients with a family history of the disease (Sondergaard et al., 1985b; Houlston et al., 1992; Hunt et al., 1994). Thus we wished to determine whether there was any link with hereditary non-polyposis colorectal cancer (HNPCC), which is responsible for 2-5% of all colorectal cancer cases. HNPCC gene carriers develop few colorectal adenomas but are at high risk of colorectal cancer, particularly of the right colon, as well as other cancers Jass et al., 1994). Causative germline mutations in the DNA mismatch repair (MMR) genes hMSH2, hMLHI, hPMSJ and hPMS2 (Liu et al., 1996) have been identified in HNPCC families. Such mutations result in defective MMR (Parsons et al., 1993;Umar et al., 1994), manifest as instability of repetitive DNA in tumours (Ionov et al., 1993;Aaltonen et al., 1993;Thibodeau et al., 1993;Lothe et al., 1993;Aaltonen et al., 1994;Bhattacharyya et al., 1994;Liu et al., 1995a) (Traboulsi et al., 1987; Chapman et al., 1988;Berk et al., 1988; Giardello et al., 1991; Hodgson et al., 1994;Wallis et al., 1994). Because of the variety of CHRPE lesions, we devised a scoring system derived from the relative importance ascribed to each feature in previous FAP studies. Pigmented haloed lesions and lesions > 1 disc diameter scored 5: small lesions scored 1 and the total score for bilateral lesions was doubted.Posteroanterior, occlusal and pantomographic radiographic views of the mand...

APC mutations are associated with increased bone mineral density in patients with familial adenomatous polyposis

“…They are present in 46% to 93% of FAP patients, an incidence 4 to 20 times higher than in control groups (3% to 16%). (38)(39)(40) In keeping with previous studies, (2) osteomas were located predominantly in the upper and/or lower mandible in our patients, and their presence was positively correlated with the presence of teeth anomalies. (41,42) Patients with scintigraphic evidence of osteoma(s) were, on average, younger than those without osteomas, albeit nonstatistically significantly.…”

Congenital hypertrophy of the retinal pigment epithelium (CHRPE) in familial colorectal cancer

“…CHRPE is a congenital manifestation of APC gene mutations that is not age-dependent and hence could provide a useful marker of patients with a germline APC gene mutation [31]. This possibility has been addressed on a number of occasions and by different means with conflicting outcomes [9,16,[19][20][21][22].…”

“…Type D: Round, large and depigmented patients with sporadic CRC (8%; P = 0.01) or in people with no evidence of intestinal disease (12.5%; P = 0.04). Two years later, Dunlop et al [19] documented a higher frequency of CHRPE in patients with CRC than healthy controls (P < 0.02). They were unable to identify heritable APC mutations in the patients with CHRPE and raised the possibility that these patients had mosaicism for pathogenic APC mutations.…”

Common variation near CDKN1A, POLD3 and SHROOM2 influences colorectal cancer risk

“…Like GPR143, SHROOM2 regulates melanosome biogenesis and localisation in the retinal pigment epithelium 21 . Intriguingly, abnormal retinal pigmentation, similar to the congenital hypertrophy of retinal pigment epithelium (CHRPE) lesions that are a component of the familial adenomatous polyposis syndrome, has been previously been shown to be an extracolonic feature of non-FAP CRC 22,23 . To our knowledge, the relationship between Xp22.2 and CRC risk represents the first evidence for the role of X-chromosome variation in predisposition to a non-sex-specific cancer.…”

“…Indeed, rs5934683 genotype accounted for 55% of the variation in SHROOM2 expression. Exploring the relationship between SHROOM2 expression, rs5934683 risk genotype and CRC causation will be of considerable interest, not least because of the observations of an association between excess pigmented lesions in the retinal pigment epithelium and CRC 22,23 . There was no significant difference in the observed MAF of rs5934683 between female and male cases raising the possibility that skewed X-inactivation might underscore the associated CRC risk.…”