Colorectal and Other Cancer Risks for Carriers and Noncarriers From Families With a DNA Mismatch Repair Gene Mutation: A Prospective Cohort Study

The University of Melbourne, Australia.
Journal of Clinical Oncology (Impact Factor: 18.43). 02/2012; 30(9):958-64. DOI: 10.1200/JCO.2011.39.5590
Source: PubMed

ABSTRACT To determine whether cancer risks for carriers and noncarriers from families with a mismatch repair (MMR) gene mutation are increased above the risks of the general population.
We prospectively followed a cohort of 446 unaffected carriers of an MMR gene mutation (MLH1, n = 161; MSH2, n = 222; MSH6, n = 47; and PMS2, n = 16) and 1,029 their unaffected relatives who did not carry a mutation every 5 years at recruitment centers of the Colon Cancer Family Registry. For comparison of cancer risk with the general population, we estimated country-, age-, and sex-specific standardized incidence ratios (SIRs) of cancer for carriers and noncarriers.
Over a median follow-up of 5 years, mutation carriers had an increased risk of colorectal cancer (CRC; SIR, 20.48; 95% CI, 11.71 to 33.27; P < .001), endometrial cancer (SIR, 30.62; 95% CI, 11.24 to 66.64; P < .001), ovarian cancer (SIR, 18.81; 95% CI, 3.88 to 54.95; P < .001), renal cancer (SIR, 11.22; 95% CI, 2.31 to 32.79; P < .001), pancreatic cancer (SIR, 10.68; 95% CI, 2.68 to 47.70; P = .001), gastric cancer (SIR, 9.78; 95% CI, 1.18 to 35.30; P = .009), urinary bladder cancer (SIR, 9.51; 95% CI, 1.15 to 34.37; P = .009), and female breast cancer (SIR, 3.95; 95% CI, 1.59 to 8.13; P = .001). We found no evidence of their noncarrier relatives having an increased risk of any cancer, including CRC (SIR, 1.02; 95% CI, 0.33 to 2.39; P = .97).
We confirmed that carriers of an MMR gene mutation were at increased risk of a wide variety of cancers, including some cancers not previously recognized as being a result of MMR mutations, and found no evidence of an increased risk of cancer for their noncarrier relatives.

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Available from: Graham G Giles, Aug 27, 2015
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    • "The mechanistic insights obtained by these studies did advance our understanding on how hereditary sequence variants in the minimal human MMR system affect the MMR function and hence predispose to the DNA instabilities linked to cancer predisposition. The list of cancer types where MMR malfunction has been observed expanded to include the most frequent hereditary predisposition to colorectal cancer along with increased risk for development of endometrial, ovarian, gastric, small bowel, urothelial, brain, hepatobiliary, pancreatic, bladder, kidney, prostate and breast cancers, and hematological malignances (Scott et al., 2001; Umar et al., 2004; Grindedal et al., 2009; van Oers et al., 2010; Wimmer and Kratz, 2010; Buerki et al., 2012; Win et al., 2012a,b; Vasen et al., 2013). The ability to predict cancer predisposition by analyzing the sequence variants for the MMR genes also contributed to better management of patients and their relatives and resulted in reduced mortality (Jarvinen et al., 2009). "
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    ABSTRACT: DNA is constantly under attack by a number of both exogenous and endogenous agents that challenge its integrity. Among the mechanisms that have evolved to counteract this deleterious action, mismatch repair (MMR) has specialized in removing DNA biosynthetic errors that occur when replicating the genome. Malfunction or inactivation of this system results in an increase in spontaneous mutability and a strong predisposition to tumor development. Besides this key corrective role, MMR proteins are involved in other pathways of DNA metabolism such as mitotic and meiotic recombination and processing of oxidative damage. Surprisingly, MMR is also required for certain mutagenic processes. The mutagenic MMR has beneficial consequences contributing to the generation of a vast repertoire of antibodies through class switch recombination and somatic hypermutation processes. However, this non-canonical mutagenic MMR also has detrimental effects; it promotes repeat expansions associated with neuromuscular and neurodegenerative diseases and may contribute to cancer/disease-related aberrant mutations and translocations. The reaction responsible for replication error correction has been the most thoroughly studied and it is the subject to numerous reviews. This review describes briefly the biochemistry of MMR and focuses primarily on the non-canonical MMR activities described in mammals as well as emerging research implicating interplay of MMR and chromatin.
    Frontiers in Genetics 08/2014; 5:287. DOI:10.3389/fgene.2014.00287
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    • "Lynch syndrome is caused by a germline mutation in one of four mismatch repair genes: MLH1, MSH2, MSH6 and the most recently discovered gene PMS2. People with Lynch syndrome have a high risk of colorectal and endometrial cancer (and also an increased risk of some other cancers including stomach, ovary, small intestine, biliary tract, and urinary tract cancers) with the risks varying depending on which gene is involved (Win et al. 2012). Here we discuss a family with a PMS2 mutation c.989-?_1144+?del (p.?) leading to a deletion of exon 10. "
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    ABSTRACT: We present a case where an apparently straightforward Lynch syndrome predictive genetic test of DNA from a blood sample from a woman yielded an unexpected result of X/Y chromosome imbalance. Furthermore, it demonstrates the complexities of genetic testing in people who have had bone marrow transplants. This highlights the potential for multiple ethical and counselling challenges, including the inadvertent testing of the donor. Good communication between clinics and laboratories is essential to overcome such challenges and to minimise the provision of false results.
    Journal of Genetic Counseling 08/2013; DOI:10.1007/s10897-013-9643-x · 1.75 Impact Factor
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    • "It participates in different cellular processes, including cell growth, the mitotic cycle, and oncogenic transformation [24]. MSH6 is a DNA mismatch repair protein that participates in the recognition of mismatched nucleotides prior to their repair [25]. Mutations in this gene have been associated with hereditary nonpolyposis colon cancer and endometrial cancer [26]. "
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    ABSTRACT: Only PTPN12, MSH6, and ZEB1 have significant miR-1279 binding sites among paralogous genes of human tyrosine phosphatase family, DNA mismatch repair family, and zinc finger family, respectively. All miRNA binding sites are located within CDSs of studied mRNAs. Nucleotide sequences of hsa-miR-1279 binding sites with mRNAs of human PTPN12, MSH6, and ZEB1 genes encode TKEQYE, EGSSDE, and GEKPYE oligopeptides, respectively. The conservation of miRNA binding sites encoding oligopeptides has been revealed. MRNAs of many paralogs of zinc finger gene family have from 1 to 12 binding sites coding the same GEKPYE hexapeptide. MRNAs of PTPN12, MSH6, and ZEB1 orthologous genes from different animal species have binding sites for hsa-miR-1279 which consist of homologous oligonucleotides encoding similar human oligopeptides TKEQYE, EGSSDE, and GEKPYE. MiR-548j, miR-548m, and miR-548d-5p have homologous binding sites in the mRNA of PTPN12 orthologous genes which encode PRTRSC, TEATDI, and STASAT oligopeptides, respectively. All regions of miRNA are important for binding with the mRNA.
    07/2013; 2013:902467. DOI:10.1155/2013/902467
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