Increased frequency of 20q gain and copy‐neutral loss of heterozygosity in mismatch repair proficient familial colorectal carcinomas

Abstract

Many hereditary nonpolyposis colorectal cancers (CRCs) cannot be explained by Lynch syndrome. Other high penetrance genetic risk factors are likely to play a role in these mismatch repair (MMR)-proficient CRC families. Because genomic profiles of CRC tend to vary with CRC susceptibility syndromes, our aim is to analyze the genomic profile of MMR-proficient familial CRC to obtain insight into the biological basis of MMR-proficient familial CRC. We studied 30 MMR-proficient familial colorectal carcinomas, from 15 families, for genomic aberrations, including gains, physical losses, and copy-neutral loss of heterozygosity LOH (cnLOH) using SNP array comparative genomic hybridization. In addition, we performed somatic mutation analysis for KRAS, BRAF, PIK3CA and GNAS. The frequency of 20q gain (77%) is remarkably increased when compared with sporadic CRC, suggesting that 20q gain is involved in tumor progression of familial CRC. There is also a significant increase in the frequency of cnLOH and, as a consequence, a reduced frequency of physical loss compared with sporadic CRC. The most frequent aberrations observed included gains of 7p, 7q, 8q, 13q, 20p and 20q as well as physical losses of 17p, 18p and 18q. Most of these changes are also observed in sporadic CRC. Mutations in KRAS were identified in 37% of the MMRproficient CRCs, and mutations in BRAF were identified in 16%. No mutations were identified in PIK3CA or chromosome 20 candidate gene GNAS. We show that the patterns of chromosomal instability of MMR-proficient familial CRC are clearly distinct from those from sporadic CRC. Both the increased gain on chromosome 20 and the increased levels of cnLOH suggest the presence of yet undiscovered germline defects that can, in part, underlie the cancer risk in these families.

Familial colorectal cancer type X: genetic profiles and phenotypic features

“…42 Comparative genomic hybridization studies suggest that FCCTX tumors typically harbor 6-8 copy number alterations with recurrent gains of 7p, 7q, 8q, 13q, 20p, and 20q and losses of 17p, 18p, and 18q. 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.…”

“…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.…”

“…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. 63,65 An overexpression of the chromosome-associated gene AURKA has been correlated to aneuploidy, invasion, and progression of colorectal adenoma to carcinoma. 66 A candidate link also exists between gain of 20q and overexpression of ASIP, that could influence sensitivity to 5-fluorouracil.…”

“…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. 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

“…In particular, the frequency of 20q gain is remarkably increased when compared with sporadic colorectal cancer, suggesting that the 20q gain is involved in the genetic etiology of these mismatch repair-proficient familial colorectal cancers. 104 The finding that most of these genomic aberrations were also observed in sporadic colorectal cancer further suggests that familial and sporadic colorectal cancers could share genetic predisposition to a certain extent.…”