Minerva Elements Records

Permanent URI for this collection

Search Results

Now showing 1 - 2 of 2
  • Item
    Thumbnail Image
    Are the common genetic variants associated with colorectal cancer risk for DNA mismatch repair gene mutation carriers?
    Win, AK ; Hopper, JL ; Buchanan, DD ; Young, JP ; Tenesa, A ; Dowty, JG ; Giles, GG ; Goldblatt, J ; Winship, I ; Boussioutas, A ; Young, GP ; Parry, S ; Baron, JA ; Duggan, D ; Gallinger, S ; Newcomb, PA ; Haile, RW ; Le Marchand, L ; Lindor, NM ; Jenkins, MA (ELSEVIER SCI LTD, 2013-05)
    BACKGROUND: Genome-wide association studies have identified at least 15 independent common genetic variants associated with colorectal cancer (CRC) risk. The aim of this study was to investigate whether 11 of these variants are associated with CRC risk for carriers of germline mutations in DNA mismatch repair (MMR) genes. METHODS: A total of 927 MMR gene mutation carriers (360 MLH1, 442 MSH2, 85 MSH6 and 40 PMS2) from 315 families enrolled in the Colon Cancer Family Registry, were genotyped for the single nucleotide polymorphisms (SNPs): rs16892766 (8q23.3), rs6983267 (8q24.21), rs719725 (9p24), rs10795668 (10p14), rs3802842 (11q23.1), rs4444235 (14q22.2), rs4779584 (15q13.3), rs9929218 (16q22.1), rs4939827 (18q21.1), rs10411210 (19q13.1) and rs961253 (20p12.3). We used a weighted Cox regression to estimate CRC risk for homozygous and heterozygous carriers of the risk allele compared with homozygous non-carriers as well as for an additive per allele model (on the log scale). RESULTS: Over a total of 40,978 person-years observation, 426 (46%) carriers were diagnosed with CRC at a mean age of 44.3 years. For all carriers combined, we found no evidence of an association between CRC risk and the total number of risk alleles (hazard ratio [HR] per risk allele=0.97, 95% confidence interval [CI]=0.88-1.07, p=0.52). CONCLUSIONS: We found no evidence that the SNPs associated with CRC in the general population are modifiers of the risk for MMR gene mutation carriers overall, and therefore any evidence of proven clinical utility in Lynch syndrome.
  • Item
    Thumbnail Image
    Cancer Risks for MLH1 and MSH2 Mutation Carriers
    Dowty, JG ; Win, AK ; Buchanan, DD ; Lindor, NM ; Macrae, FA ; Clendenning, M ; Antill, YC ; Thibodeau, SN ; Casey, G ; Gallinger, S ; Le Marchand, L ; Newcomb, PA ; Haile, RW ; Young, GP ; James, PA ; Giles, GG ; Gunawardena, SR ; Leggett, BA ; Gattas, M ; Boussioutas, A ; Ahnen, DJ ; Baron, JA ; Parry, S ; Goldblatt, J ; Young, JP ; Hopper, JL ; Jenkins, MA (WILEY, 2013-03)
    We studied 17,576 members of 166 MLH1 and 224 MSH2 mutation-carrying families from the Colon Cancer Family Registry. Average cumulative risks of colorectal cancer (CRC), endometrial cancer (EC), and other cancers for carriers were estimated using modified segregation analysis conditioned on ascertainment criteria. Heterogeneity in risks was investigated using a polygenic risk modifier. Average CRC cumulative risks at the age of 70 years (95% confidence intervals) for MLH1 and MSH2 mutation carriers, respectively, were estimated to be 34% (25%-50%) and 47% (36%-60%) for male carriers and 36% (25%-51%) and 37% (27%-50%) for female carriers. Corresponding EC risks were 18% (9.1%-34%) and 30% (18%-45%). A high level of CRC risk heterogeneity was observed (P < 0.001), with cumulative risks at the age of 70 years estimated to follow U-shaped distributions. For example, 17% of male MSH2 mutation carriers have estimated lifetime risks of 0%-10% and 18% have risks of 90%-100%. Therefore, average risks are similar for the two genes but there is so much individual variation about the average that large proportions of carriers have either very low or very high lifetime cancer risks. Our estimates of CRC and EC cumulative risks for MLH1 and MSH2 mutation carriers are the most precise currently available.