MLH1 PowerPoint Presentation, PPT - DocSlides

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MLH1 PowerPoint Presentation, PPT - DocSlides - & its role in Lynch Syndrome and sporadic colorectal cancers. By Annie Jin. Colorectal cancer (CRC) – 2. nd. leading cause of cancer death in the US. Approximately 50% of individuals with Lynch syndrome have mutations in MLH1 (mostly truncating mutations).

MLH1 PowerPoint Presentation, PPT - DocSlides

    Slide1

    MLH1 & its role in Lynch Syndrome and sporadic colorectal cancers

    By Annie Jin

    Slide2

    Colorectal cancer (CRC) – 2nd leading cause of cancer death in the US

    Slide3

    Approximately 50% of individuals with Lynch syndrome have mutations in MLH1 (mostly truncating mutations)

    Slide4

    Lynch syndrome is inherited in an autosomal dominant fashion

    Slide5

    Single base mismatches and insertion-deletion loops (IDLs) are recognized and repaired through Mammalian Mismatch Repair (MMR)

    Slide6

    Mammalian Mismatch Repair (MMR)

    Slide7

    MLH1 is an integral part of the heterodimer MutLα and allows the release of MMR proteins from DNA through its ATPase domain

    Slide8

    X-ray exposure at 10 weeks promoted tumorigenesis of gastrointestinal tumors (GIT) in MLH1-/- mice and accelerated the time to death

    Slide9

    Microsatellite instability (MSI) due to loss of MMR results in mutations in growth-regulatory genes

    Slide10

    The majority of MSI-high sporadic colon tumors are due to the inactivation MLH1 and most inactivations are due to MLH1 promoter hypermethylation

    Slide11

    Absence of MLH1 protein despite wild-type MLH1-coding sequences suggest silencing of MLH1 alleles in 4 MSI-positive sporadic tumor cell lines

    Slide12

    Loss of MLH1 expression is associated with methylation of the MLH1 gene promoter

    Slide13

    Summary of molecular pathways leading to development of CRC

    Slide14

    Treatment – Fluorouracil treatment (in addition to surgery)not advised in MSI-high stage II CRC patients

    Slide15

    Treatment (cont.)

    Slide16

    References

    Jang, E. and Chung, D. C. (2010). Hereditary Colon Cancer: Lynch Syndrome. 

    Gut and Liver

    , 4(2):151-160

    .

    Jovanovic

    J,

    Rønneberg

    JA,

    Tost

    J,

    Kristensen

    V. The epigenetics of breast cancer.

    Mol

    Oncol

    . 2010; 4(3):242-54.

    Kuismanen

    SA, Holmberg MT,

    Salovaara

    R, de la

    Chapelle

    A,

    Peltomäki

    P. Genetic and Epigenetic Modification of 

    MLH1

     Accounts for a Major Share of Microsatellite-Unstable Colorectal Cancers. 

    The American Journal of Pathology

    . 2000;156(5):1773-1779.

    Peltomaki

    P. Deficient DNA mismatch repair: a common etiologic factor for colon cancer. 

    Hum. Mol. Genet.

    , 

    10

    :

     735-740, 2001.

    Ribic

    CM, Sargent DJ, Moore MJ, et al. Tumor Microsatellite-Instability Status as a Predictor of Benefit from Fluorouracil-Based Adjuvant Chemotherapy for Colon Cancer. The New England journal of medicine. 2003;349(3):247-257. doi:10.1056/NEJMoa022289

    .

    Shokal

    U, Sharma PC. Implication of microsatellite instability in human gastric cancers. 

    The Indian Journal of Medical Research

    . 2012;135(5):599-613.

    Sinicrope

    , F. A. (2010). DNA mismatch repair and adjuvant chemotherapy in sporadic colon cancer.

    Nature Reviews. Clinical Oncology

    , 7(3), 174-7.

    doi:http

    ://dx.doi.org/10.1038/nrclinonc.2009.235

    Tokairin

    Y,

    Kakinuma

    S, Arai M, et al. Accelerated growth of intestinal

    tumours

    after radiation exposure in Mlh1-knockout mice: evaluation of the late effect of radiation on a mouse model of HNPCC. 

    International Journal of Experimental Pathology

    . 2006;87(2):89-99. doi:10.1111/j.0959-9673.2006.00464.x.

    Veigl

    ML,

    Kasturi

    L,

    Olechnowicz

    J, et al.

    Biallelic

    inactivation of 

    hMLH

    1 by epigenetic gene silencing, a novel mechanism causing human MSI cancers.

    Proceedings of the National Academy of Sciences of the United States of America

    . 1998;95(15):8698-8702

    .

    Slide17

    References (cont.)

    http://www.cancer.gov/cancertopics/pdq/treatment/colon/Patient/page2

    Gastroenterology

    , Vol. 119, No. 3, Randall W. Burt, Colon Cancer Screening, Pages 837-853, Copyright (2000

    )

    http://https://www.myriad.com/patients-families/disease-info/colon-cancer

    /

    http://

    www.cancer.gov/cancertopics/pdq/genetics/colorectal/HealthProfessional/page1

    http://www.niddk.nih.gov/about-niddk/staff-directory/intramural/peggy-hsieh/ResearchImages/HsiehLabImage2_3389_Scheme-for-DNA[1].png

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