Familial colorectal cancer type X syndrome: two distinct molecular entities?

Abstract

In a fraction of families fulfilling the Amsterdam criteria for hereditary non-polyposis colorectal cancer, colorectal cancers are microsatellite stable and DNA mismatch repair gene (MMR) mutations are not found. These families were designated as familial colorectal cancer type X (FCCTX). We aimed to characterise a group of FCCTX families defined by the Amsterdam criteria and MSS tumours at clinical and molecular level. Twenty-four tumours from 15 FCCTX families were analysed for loss of known tumour suppressor gene (TSG) loci (APC, TP53, SMAD4 and DCC), MGMT and MMR genes promoter methylation, and also APC and KRAS somatic mutations. FCCTX families presented specific clinical features: absence of endometrial tumours, high adenoma/carcinoma ratio (1.91) and prevalence of rectal cancers (13/27, 48%). New molecular features were found: the majority of FCCTX tumours (13/18; 72%) presented TSG loss. TSG loss positive tumours presented frequent APC and KRAS somatic mutations and MGMT methylation [10/13 (77%), 7/13 (54%) and 6/11 (54%), respectively]. In TSG loss negative tumours (5/18; 28%), the same molecular events were found in 2/5 (40%), 2/5 (40%) and 1/3 (33%) tumours, respectively. Transition mutations in KRAS were more frequent among MGMT methylated tumours than in unmethylated [5/8 (63%) vs. 1/10 (10%), P = 0.03]. Although sharing similar clinical features, at least two different molecular entities should exist among FCCTX families, one whose tumours present frequent TSG loss, APC and KRAS somatic mutations, and MGMT promoter methylation, and a second, lesser predominant, with no evidence of TSG loss and rarely presenting promoter methylation.

Epidemioclinical Feature of Early-Onset Colorectal Cancer at-Risk for Lynch Syndrome in Central Iran

“…A significant portion of these families would be likely excluded from the Lynch Syndrome after molecular analyses. These cases are usually associated to other hereditary cancer syndromes, a fact that has been confirmed by different studies (Lindor, 2009;Francisco et al, 2011;Dominguez-Valentin et al, 2015).…”

Familial colorectal cancer type X: genetic profiles and phenotypic features

“…4,16,19,21 Some studies of FCCTX have also included AC2 families with MMR-stable tumors. [22][23][24][25] The FCCTX subset is a major cause of hereditary colorectal cancer, although it remains a weakly defined and sparsely investigated subgroup of hereditary colorectal cancer. A better understanding of hereditary colorectal cancer may provide important clues to disease-predisposition and could contribute to molecular diagnostics, improved risk stratification, and targeted therapeutic strategies.…”

“…Age at onset shows considerable interfamily as well as intrafamily variability with colorectal cancer diagnosed at a higher mean age (mean 57.3 years) in FCCTX than in Lynch syndrome (mean 49.7 years; Figure 1). 16,22,[29][30][31][32] The FCCTX tumor spectrum is predominated by colorectal cancer and does, in contrast to Lynch syndrome, not show any increased risk of extracolonic cancers. 16,33,34 Colorectal cancers linked to FCCTX are left sided in 70% of the cases.…”

“…63,68 Mutations in several cancer-related genes such as 'TP53 (tumor protein p53),' 'KRAS (Kirsten rat sarcoma viral oncogene homolog),' 'BRAF (v-raf murine sarcoma viral oncogene homolog B),' APC, 'MGMT (O-6-methylguanine-DNA methyltransferase),' and 'CTNNB1 (catenin (cadherin-associated protein), b1, 88 kDa)' divide FCCTX tumors into two major groups; one-third of the tumors that are characterized by stable genotypes with few genetic changes retained membranous b-catenin expression and infrequent TP53 mutations, and two-thirds of the tumors with frequent loss of tumor suppressor gene loci such as APC, TP53, SMAD4, and DCC, somatic methylation of APC, KRAS, and MGMT, and nuclear translocation of b-catenin. 22,69 These genetic subsets have been suggested to differ in clinical presentation; genetically simple tumors predominantly develop in the proximal colon and develop at a lower (mean 54 years) age, whereas the genetically complex tumors more often develop in the distal colon and are diagnosed at a higher (mean 59 years) age.…”

Gene discovery in familial cancer syndromes by exome sequencing: prospects for the elucidation of familial colorectal cancer type X

“…[78][79][80][81] In a study that investigated 25 families with truncating mutations in MLH1 or MSH2, and 16 families that fulfilled the Amsterdam Criteria but lacked mutations in these genes, major clinical differences in age of onset, tumor spectrum, tumor localization, and tumor progression were found. 81 These differences included an earlier age of onset for colorectal cancer and other tumors, and more synchronous and metachronous colorectal and extra-colonic tumors in the group with mutations in MLH1 or MSH2.…”