Hi Mona

repairing DNA is the best way for the cell to prevent apparition of mutations that could lead by positive cellular pressure to cancer cell lines (I mean that one "important" mutation will give one clone that will derive to cancer). it works fine until cells are exceeded...therefore you'll understand that such genes are important, but other genes as kinases, receptors...are also sensible to variants in the cancer development.

fred

Hi Fred,

We recently studied one of the most frequantely SNPs in XRCC1 gene. XRCC1 gene is one of the genes that has important role in the base excision repair (BER) pathway, one of pathways that repair most of the DNA damages. Unfortunately we didn’t find this SNP in the cancer under study in fact in many studies this gene is not associated with this cancer. This makes me wonder why? Although it is extremely important gene for DNA repair!

Hi Mona

genes are not alone, maybe the SNP will have an impact on other genes in the pathway. but, is it a real SNP or a variant with protein impact (mis or non-sense..)?

fred

Hi Mona,

Rightly so, for some of the genes this depends on the gene function in respect of the specific cells. In respect of mutations in DNA repair genes, it is the case that some are associated with specific cancer and not anther. This because, cancer results from accumulation of mutations in cells where the cell's DNA repair system is not able to effectively correct and furthermore, those cells are able to evade the programmed cell death system that is to kill cells that have accumulated damages to their genomes. Therefore, if there are mutations in the genes related to DNA repair systems in a cell, although other mutations may accumulate in those cells, this may not lead to cancer because a function programmed cell death system will ensure that these cell will be killed before they get transformed to malignancy.

In other words cancer results as a combination of mutations in specific genes, associated genes (tumor suppressor genes etc.), evasion of cell cycles control, and evasion of programmed cell death. so some mutation in DNA repiar system that are not associated with any of the other limitation, cancer may not develop.

Mona:

As you know, XRCC1 is a scaffolding protein that is important in the recruitment of BER factors to DNA lesions. Its mutation can affect BER efficiency in cells. Even though the SNP you're studying is not significantly associated with the cancer you're studying, it may be associated with other diseases. For example, a SNP in XRCC1 has been shown to be associated with the autoimmune lupus (reviewed by our lab).

There are other questions that need to be known about your specific SNP. Does this mutation lead to a functional effect? Does the SNP lead to a missense or nonsense mutation, and/or can it potentially be important for regulating gene expression of XRCC1? 

Hopefully this helps. 

Rithy

http://www.sciencedirect.com/science/article/pii/S1568786417302203

'So why mutations in DNA repair genes are associated with specific cancer and not the other?'

I think that's  because DNA repair enzymes usually repair specific DNA lesions. Loss of a DNA repair enzyme is  likely to cause a type of cancer related to that specific type of DNA lesion. For example, it's well known mutations in NER genes are associated with skin cancer but not other types of cancers. That's because NER is important for repairing UV damage, which is the initiating DNA damage for skin cancer.

Hope it's helpful!

Peng 

The DNA damage may be lethal and therefore the cells fail to make it to a cancerous state. There may also be another repair mechanism which is currently unknown which repairs the damaged DNA. Secondly, the SNPs under study may be that of non-coding areas of the gene.