TY - JOUR
T1 - Lack of APC somatic mutation is associated with early-onset colorectal cancer in African Americans
AU - Xicola, Rosa M.
AU - Manojlovic, Zarko
AU - Augustus, Gaius J.
AU - Kupfer, Sonia S.
AU - Emmadi, Rajyasree
AU - Alagiozian-Angelova, Victoria
AU - Triche, Tim
AU - Salhia, Bodour
AU - Carpten, John
AU - Llor, Xavier
AU - Ellis, Nathan A.
N1 - Funding Information:
National Institutes of Health (U01 CA153060 and P30 CA023074 to N.A.E.); American Cancer Society Illinois Division (223187 to X.L.); Cancer Biology Training T32 from the National Institute of Health (CA009213 to G.J.A.); Training Program in Investigative Gastroenterology T32 (DK007017 to R.M.X.). Internal funds from the Office of the Vice Chancellor of the University of Illinois at Chicago (to N.A.E. and X.L.)
Publisher Copyright:
© The Author(s) 2018. Published by Oxford University Press. All rights reserved.
PY - 2018/12/13
Y1 - 2018/12/13
N2 - African Americans (AAs) have higher incidence and mortality rates of colorectal cancer (CRC) compared with other US populations. They present with more right-sided, microsatellite stable disease and are diagnosed at earlier ages compared with non-Hispanic Whites (NHWs). To gain insight into these trends, we conducted exome sequencing (n = 45), copy number (n = 33) and methylation analysis (n = 11) of microsatellite stable AA CRCs. Results were compared with data from The Cancer Genome Atlas (TCGA). Two of the 45 tumors contained POLE mutations. In the remaining 43 tumors, only 27 (63%) contained loss-of-function mutations in APC compared with 80% of TCGA NHW CRCs. APC-mutation-negative CRCs were associated with an earlier onset of CRC (P = 0.01). They were also associated with lower overall mutation burden, fewer copy number variants and a DNA methylation signature that was distinct from the CpG island methylator phenotype characterized in microsatellite unstable disease. Three of the APC-mutation-negative CRCs had loss-of-function mutations in BCL9L. Mutations in driver genes identified by TCGA exome analysis were less frequent in AA CRC cases than TCGA NHWs. Genes that regulate the WNT signaling pathway, including SOX9, GATA6, TET1, GLIS1 and FAT1, were differentially hypermethylated in APC-mutation-negative CRCs, suggesting a novel mechanism for cancer development in these tumors. In summary, we have identified a subtype of CRC that is associated with younger age of diagnosis, lack of APC mutation, microsatellite and chromosome stability, lower mutation burden and distinctive methylation changes.
AB - African Americans (AAs) have higher incidence and mortality rates of colorectal cancer (CRC) compared with other US populations. They present with more right-sided, microsatellite stable disease and are diagnosed at earlier ages compared with non-Hispanic Whites (NHWs). To gain insight into these trends, we conducted exome sequencing (n = 45), copy number (n = 33) and methylation analysis (n = 11) of microsatellite stable AA CRCs. Results were compared with data from The Cancer Genome Atlas (TCGA). Two of the 45 tumors contained POLE mutations. In the remaining 43 tumors, only 27 (63%) contained loss-of-function mutations in APC compared with 80% of TCGA NHW CRCs. APC-mutation-negative CRCs were associated with an earlier onset of CRC (P = 0.01). They were also associated with lower overall mutation burden, fewer copy number variants and a DNA methylation signature that was distinct from the CpG island methylator phenotype characterized in microsatellite unstable disease. Three of the APC-mutation-negative CRCs had loss-of-function mutations in BCL9L. Mutations in driver genes identified by TCGA exome analysis were less frequent in AA CRC cases than TCGA NHWs. Genes that regulate the WNT signaling pathway, including SOX9, GATA6, TET1, GLIS1 and FAT1, were differentially hypermethylated in APC-mutation-negative CRCs, suggesting a novel mechanism for cancer development in these tumors. In summary, we have identified a subtype of CRC that is associated with younger age of diagnosis, lack of APC mutation, microsatellite and chromosome stability, lower mutation burden and distinctive methylation changes.
UR - http://www.scopus.com/inward/record.url?scp=85058612181&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85058612181&partnerID=8YFLogxK
U2 - 10.1093/carcin/bgy122
DO - 10.1093/carcin/bgy122
M3 - Article
C2 - 30239619
AN - SCOPUS:85058612181
VL - 39
SP - 1331
EP - 1341
JO - Carcinogenesis
JF - Carcinogenesis
SN - 0143-3334
IS - 11
ER -