Gain of chromosomal region 20q and loss of 18 discriminates between Lynch syndrome and familial colorectal cancer

Familial colorectal cancer type X: genetic profiles and phenotypic features

“…25,77 The limited data available regarding signaling pathways in FCCTX tumors indicate involvement of G proteincoupled signaling and candidate genes involved in proliferation and migration, for example, CDH26, SRC, and ASIP (located in chromosome 20q). 24,25 'PTGER1 (prostaglandin E receptor 1 (subtype EP1), 42 kDa)' is activated by COX-2/PGE-2 signaling that is overexpressed in 90% of sporadic colon carcinomas and is induced by hypoxia. 78,79 Another target that has shown to directly upregulate COX-2 expression is the 'HIST1H1A (histone cluster 1, H1a)', whose overexpression had been significantly associated with a shorter colorectal cancer-specific and overall survival.…”

“…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.…”

“…62,63 Gain of the 20q region has been specifically linked to FCCTX tumors and several candidate target genes such as 'GNAS (GNAS complex locus),' 'AURKA (aurora kinase A),' 'SRC (v-src avian sarcoma (Schmidt-Ruppin A-2) viral oncogene homolog),' 'TOP1 (topoisomerase (DNA) I),' 'NELFCD (negative elongation factor complex member C/D),' 'ADRM1 (adhesion regulating molecule 1),' 'ASIP (agouti signaling protein),' 'CDH26 (cadherin 26),' and 'HNF1A (HNF1 homeobox A)' reside herein (Figure 3). 24,62,63 GNAS promotes proliferation through activation of the Wnt and ERK1/2 MAPK signaling pathways. 64 Activating missense mutations in GNAS have been demonstrated in sporadic colorectal cancer, but the GNAS c.601G4T hot spot mutation could not be identified in a study of FCCTX tumors.…”

“…67 Loss of Familial colorectal cancer type X chromosome 18 is a common change in sporadic tumors as well as in FCCTX tumors and may be linked to downregulation of for example, 'SMAD2 (SMAD family member 2),' 'SMAD4 (SMAD family member 4),' 'DCC (deleted in colorectal carcinoma),' 'SERPINB5 (serpin peptidase inhibitor, clade B (ovalbumin), member 5),' and 'BCL2 (B-cell CLL/ lymphoma 2)' (Figure 3). 24,25 Frequent (32%) genome-wide copy neutral loss of heterozygosity and a low frequency (14%) of chromosomal losses have been demonstrated in FCCTX tumors that could indicate involvement of yet unidentified DNA repair mechanisms. 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.…”

Update on Hereditary Colorectal Cancer

“…Families meeting AC-I for Lynch syndrome, but not carrying deleterious alterations in MMR genes, nor MSI, are defined as having FCCTX (36), however, some studies have also included AC-II with microsatellite stable (MSS) tumors (36)(37)(38)(39)(40). CRCs in FCCTX families are diagnosed at a slightly older age compared to those with Lynch syndrome and the risk of extracolonic cancer is not more than that of the average-risk population (14).…”