Alfred knudson and the two hit hypothesis
In this article, I reviewed Knudson's famous "two-hit" hypothesis of tumor suppression
Explanation slides Knudsons 2 Hit Hypothesis
APC is often cited as a prime example of a tumor suppressor gene. Truncating germline and somatic mutations (or, infrequently, allelic loss) occur in tumors in FAP (familial adenomatous polyposis). Most sporadic colorectal cancers also have two APC mutations1. Clues from attenuated polyposis2, 3, 4, missense germline variants with mild disease5, 6 and the somatic mutation cluster region (codons 1,250−1,450)1, 7, 8 indicate, however, that APC mutations might not result in simple loss of protein function. We have found that FAP patients with germline APC mutations within a small region (codons 1,194−1,392 at most) mainly show allelic loss in their colorectal adenomas, in contrast to other FAP patients, whose 'second hits' tend to occur by truncating mutations in the mutation cluster region. Our results indicate that different APC mutations provide cells with different selective advantages, with mutations close to codon 1,300 providing the greatest advantage. Allelic loss is selected strongly in cells with one mutation near codon 1,300. A different germline−somatic APC mutation association exists in FAP desmoids. APC is not, therefore, a classical tumor suppressor. Our findings also indicate a new mechanism for disease severity: if a broader spectrum of mutations is selected in tumors, the somatic mutation rate is effectively higher and more tumors grow.
This leaves only a non-functioning copy of the TSG, andthe individual goes on to develop cancer.Copy neutral LOH can be biologically equivalent to the secondhit in the Knudson hypothesis. Othernames for copy neutral LOH in tumor cells are acquired or gene conversion.
Explanation slides Knudsons 2 Hit Hypothesis ..
Retinoblastoma Gene ( RB Gene)
First discovered Tumor suppressor gene
Retinoblastoma: is a childhood tumor with inactivation of this gene.
Knudson’s two-hit hypothesis
Two mutations ( hits) involving both the alleles of TSG ( here RB gene) is a basic requisite for the development of tumor
Retinoblastoma can occur as hereditary or sporadic form
Explanation for the same is given by Knudson’s two-hit hypothesis
RB protein– product of RB gene
Key role in regulation of the cell cycle
“Governor” of the cell cycle
So, How does RB gets inactivated ?OrHow does the Antiproliferative activity of RB is nullified?
Our lab subsequently used the Knudson two-hit hypothesis of tumorigenesis to provide the first evidence that the also functions as a tumor suppressor (). Since IGF2R is imprinted (i.e. one copy of the gene silenced by DNA methylation), this finding thrusted me into the rapidly growing research field of . Interestingly, I had the honor of finally meeting Dr. Knudson almost a decade later in Stockholm, Sweden at the 2004 Nobel Symposium on epigenetics entitled, . I will greatly miss these pioneering scientists upon whose shoulders I stood.
Term Essays: ALFRED knudson two hit hypothesis to …
ALFRED KNUDSON TWO HIT HYPOTHESIS
Tumor Suppressor Genes: RB Gene, Knudson’s Two Hit Hypothesis
Explanation for the same is given by Knudson’s two-hit hypothesis ..
Consistent with the Knudson “Two-Hit” Hypothesis
Explanation slides Knudsons 2 Hit Hypothesis on …
fig002frb: Knudson’s two-hit hypothesis for …
Knudson’s Two hit Hypothesis;
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