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Download jane-oiler | 2017-06-19 | General & 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). ID: 561055

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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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