Tag Archives: mutations

Types of Mutations

Genetic Mutations

Types of mutations

·    Point mutations (substitution), deletion, insertion, frameshift mutation

·    Trinucleotide repeat expansion (eg. fragile X syndrome is an expansion of the FMR1 gene)

·    Mutations to non-coding sequence of DNA (eg. to binding sites of transcription factors)

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Lymphoma Mutations

Lymphoma Mutations

Mantle cell lymphoma mutation:

cyclin D1 translocation [t(11;14]

Follicular lymphoma mutation:

translocation of bcl-2 to IgH heavy chain of immunoglobulin[t(14;18)]

Chronic Myelogenous Leukemia (CML) mutation:

creation of fusion protein bcr-abl from translocation [t(9;22)]

References:

Robbins Basic Pathology 7th ed, edited by Vinay Kumar, Ramzi S. Cotran, and Stanley J. Robbins, 873 pp, Philadelphia, Pa, Sounders, 2003.

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DNA Mutations

DNA Mutations

Mutation of DNA Molecules

Mutations of DNA molecules can occur through many ways. The most common are listed below:

Base substitutions occuring during DNA replication

Base changes due to chemical instability of the base and the N-glycosidic bond

Alterations on the DNA from external factors, such as chemicals and environmental agents that induce DNA breakdown

DNA Molecule Alterations

Incorrect DNA bases in one strand that are unable to form hydrogen bonds with the opposite corresponding base in the other strand. This can occur there two ways, through replication error such as with tautomeric shifts and through deamination of bases, such as cytosine to uracil.

Missing bases through depurination through alkylating agents

Altered bases such as through thymine dimers

Single-strand breaks termed Nicks. There can occur spontaneously, through Dnases or through ionizing radiation. DNA ligases can often repair these.

Double-strand breaks in which two single strand breaks occur in a small region of the DNA

Cross-linking of DNA strands. This occurs across strands and is caused by agents such as mitomycin C and nitrite ions. The DNA duplex cannot unwind subsequently to be cross-linked at such sites.

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Hereditary Nonpolyposis Colorectal Cancer Syndrome


Hereditary Nonpolyposis Colorectal Cancer (HNPCC) Syndrome

 

Hereditary Nonpolyposis Colorectal Cancer (HNPCC) Syndrome, also known as Lynch syndrome, is a rare colorectal syndrome that can lead to cancer of the colon.

Hereditary Nonpolyposis Colorectal Cancer Syndrome Inheritance pattern
- autosomal dominant
- syndromal patients have only one functional allele and cancer occurs through loss of heterozygosity (LOH)
- mutations occur in mismatch repair genes (MLH1, MSH 2, MSH6, PMS 1, PMS 2)
- mutations lead to microsatellite instability which are mostly repeats in intronic regions

What to look for?

- you can look for the loss of the genes themselves

- you can look at particular microsatellite loci and see how many have instability
- 0/5 – stable
- 1/5 – low frequency instability
- 2 or greater/5  – high frequency of instability – MSI-H
- microsatellite instability is NOT specific to HNPCC, as it is seen in 10-15 % of sporadic colorectal carcinomas. Sporadic tumors arise in older patients who lack a family history. The activity of the mismatch repair genes in sporadic tumors is lost through hypermethylation

Diagnostic criteria is through the Amsterdam II criteria

Clinical presentation

- development of multiple cancers at an early age, including cancer of the colon, endometrium, renal pelvis and ureter, small bowel, ovary, brain, hepatobiliary tract and sebaceous tumors 

Muir -Torre Syndrome

- sebaceous tumors along with HNPCC type of internal malignancy

Turcot Syndrome

- tumors of the CNS (usually gliobalstomas) and multiple colorectal tumors

Gross Appearance

- predilection for right colon and cecum all the way to the transverse colon
- usually polypoid in appearnace rather than diffuse

 

Microscopic Appearance

- sporadic tumors have the same features as tumors associated with HNPCC

- proximally located mucinous type of colorectal adenocarcinomas +/- tumor infiltrating lymphocytes

- proximally located, poorly differentiated medullary or undifferentiated colorectal adenocarcinomas – these are well circumscribed and lacking abundant desmoplastic stroma and may contain tumor infiltrating lymphocytes

- adenomas – many have a villous morphology and high grade dysplasia, with rapid progression to carcinoma

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