A common variant of the MACC1 gene is significantly associated with overall survival in colorectal cancer patients

Abstract

BackgroundThe newly discovered metastasis-associated in colon cancer-1 (MACC1) gene is a key regulator of the HGF/MET pathway. Deregulation of HGF/MET signaling is reported as a prognostic marker for tumorigenesis, early stage invasion, and metastasis. High expression levels of MACC1 have been associated with colon cancer metastasis and reduced survival. Potential links between the genetic diversity of the MACC1 locus and overall survival are unknown. We therefore investigated the association between MACC1 tagging single nucleotide polymorphisms (SNPs) and overall survival in a large cohort of colorectal cancer patients.MethodsThe study included 318 subjects with histopathologically proven colorectal cancer at the Academic Teaching Hospital Feldkirch, Austria. Survival data were provided by the federal agency for statistics in Austria. Genomic DNA was isolated from formalin-fixed paraffin-embedded specimens; six tagging SNPs (rs1990172, rs3114446, rs10275612, rs3095007, rs3095009, and rs7780032), capturing most of the common variants of the MACC1 locus, were genotyped by SNaPshot assays.ResultsOver a mean follow up period of 5.3 (± 1.0) years, 94 deaths were recorded. Carriers of the G-allele of SNP rs1990172 showed a significantly decreased overall survival (additive HR = 1.38 [1.05-1.82]; p = 0.023). Multivariate analysis adjusted for age and UICC tumor stage confirmed this result (HR = 1.49 [1.12-1.98]; p = 0.007). Other investigated genetic variants of the MACC1 gene were not significantly associated with overall survival (p-values > 0.05).ConclusionsFor the first time, our study investigated the influence of MACC1 tagging polymorphisms on overall survival suggesting SNP rs1990172 as a predictor for reduced overall survival in colorectal cancer patients. Further studies will be required to validate our findings.

Single Nucleotide Polymorphisms in the Metastasis-associated in Colon Cancer-1 Gene Predict the Recurrence of Hepatocellular Carcinoma after Transplantation

“…In fact, these two SNPs are in strong linkage disequilibrium with each other (r 2 =0.858; http://www.hapmap.org). However, the substitution of leucine to serine at codon 515, fifth exon demonstrated no adverse effect on the structure or function of the MACC1 protein in silico analysis using software tools PolyPhen-2 and SIFT, respectively 18. Moreover, the exchange of leucine to serine in the MACC1 gene was also demonstrated no impact on expression level of MACC1 mRNA in the CRC in vitro experiments 19.…”

“…Moreover, the relationship between the single nucleotide polymorphisms (SNP) of MACC1 and OS or metastasis-free survival (MFS) of CRC patients has been detected 18,19. However, the effect of MACC1 SNPs on the clinical outcome of HCC has not been investigated yet.…”

Investigation of MACC1-AS1 gene mutations in colorectal cancer

“…Fakat bu SNP'ler ile MACC1 ifadesi arasında, metakronoz metastazda olduğu gibi yaş, cinsiyet, UICC-evreleri, tümör ve lenf nodu infiltrasyonu gibi klinik etkenlerle birlikte ilişki gözlenmemiştir (24). Lang ve arkadaşları (25), KRK'li hastalarda ölüm için artmuş risk ile MACC1'de yer alan SNP rs1990172 arasında pozitif ilişki bulmuştur. Genotiplenmiş SNP'ler rs3114446, rs10275612, rs3095007, rs3095009 ve rs7780032'nin genel sağkalımla ilişkili olmadığı görülmüştür (25).…”

“…Lang ve arkadaşları (25), KRK'li hastalarda ölüm için artmuş risk ile MACC1'de yer alan SNP rs1990172 arasında pozitif ilişki bulmuştur. Genotiplenmiş SNP'ler rs3114446, rs10275612, rs3095007, rs3095009 ve rs7780032'nin genel sağkalımla ilişkili olmadığı görülmüştür (25). Bu değişkenlerin hepsi kodlanmayan veya düzenleyici olmayan bölgelerde bulunmaktadır ve HapMap veri tabanında verilen işlevsel SNP'lerin hiçbiriyle yüksek bağlantı eşitsizliğinde (linkage disequilibrium) değildir (25).…”

“…Genotiplenmiş SNP'ler rs3114446, rs10275612, rs3095007, rs3095009 ve rs7780032'nin genel sağkalımla ilişkili olmadığı görülmüştür (25). Bu değişkenlerin hepsi kodlanmayan veya düzenleyici olmayan bölgelerde bulunmaktadır ve HapMap veri tabanında verilen işlevsel SNP'lerin hiçbiriyle yüksek bağlantı eşitsizliğinde (linkage disequilibrium) değildir (25). Çeşitli zararlı varsayılan SNP'ler MACC1 lokusunda bulunmaktadır: 390. noktada erken dur kodonunun oluşmasıyla bağlantılı olarak SNP rs2108292, 670 numaralı amino asit sonra okuma çerçevesinde kaymaya neden olan rs36106647 ve rs35043094 numaralı SNP'ler bilinmektedir (25).…”