Germline (inherited) gene mutations and bladder cancer

5 months 3 weeks ago - 5 months 3 weeks ago #61953 by joea73
It is not a new news, but for those who are wondering if your bladder cancers can be inherited may find this study educating.

Once I was explained by a research scientist on bladder cancers that bladder cancers were not inheritable, but it seems that is not always the case.   Memorial Sloan Kettering (MSK) Cancer Center in NY published the result of their  clinical study finding influences of  germline gene mutations (inherited) on bladder cancers.   80 (14%)  of 586 patients were found to have pathogenic/likely pathogenic (P/LP) germline mutations.  The rest (86%) had somatic ( acquired after birth) mutations.  Patients with (P/LP) germline gene mutations were further investigated in detail.   Most germline mutations involved DNA damage repair genes. Proteins encoded by DNA damage repair genes are involved in repairing DNA damages which are caused by errors during DNA replications or by external sources such as UV light, radiation, reactive oxygens, etc..  As it is known that every day  about 1 million cells go though DNA replications to divide into two new cells, and DNA replication error (DNA damage) happens in once in every 100,000 DNA replications, every day 10 DNA damages occur.  So, it is crucial that DNA damage repair proteins in our body are functioning properly and that requires appropriate DNA damage repair genes are not mutated.  This study found mutations in 22 inherited  DNA damage repair genes  and 3 inherited tumor suppressor genes in patients with bladder cancers and upper tract cancers.   A key finding is that gene mutations known as DNA mismatching error repair (MMR) genes, which are known  strongly associated with colorectal cancers, have strong association with upper tract cancers (ureter and renal pelvis) but not so much bladder cancers.   Similar findings were reported by a  2015 study in Sweden  and a 2010 study in Netherland.   In this study by MSK,  Only 2 cases in bladder cancer were identified with MMR gene mutations whereas 10 cases in upper tract cancers were identified with MMR gene mutations.   Considering that clinically only 10% of urothelial cancers are upper tract cancers and 90% are bladder cancers, it is intriguing to find out that patients with MMR gene mutations had 5 times upper tract cancers than bladder cancers.     Yet, I understand that the wall structure of upper tract, i.e. ureter is exactly the same the structure of bladder, which comprised of urothelial tissue (Ta), connective tissue (T1), muscle tissue (T2), etc.  So, I do not understand MMR gene mutations affect more to upper tract cancers than bladder cancers.  I have not been able to find yet any study or article to explain it.    I will try to send a question to the team of MSK to find it out.    Also,  mutated BRAC genes well known as inheritable and cause breast cancers were also identified in high numbers urothelial cancers in this study, but contrary to MMR genes, 15 bladder cancers were found and only 2 upper tract cancers were found with BRAC1,2mutaed genes.   I will also ask possible reasons to MSK.    One thing we can take home from the findings of the study is that if someone is diagnosed with Lynch Syndrome and bladder cancer,  I think it is a good idea to ask urologist to check upper tracts carefully because the study found higher incidents of upper tract cancers with Lynch syndrome (mutations on DNA mismatching error repair genes) than bladder cancers.    

Below are the findings.   

463 patients had bladder cancer and 117 patients had upper tract cancers.
80(14%) of 586 patients had P/LP germline mutations.
25 P/LP germline mutations were identified.   Below the list.   B indicates 2 -8 cases found in bladder cancer, b indicates 1 case found in bladder cancer, U indicates 2-6 cases found in Upper tract cancer and u indicates 1 case found in upper tract cancer

Mismatch-repair (MMR) genes identified  which is  often associated with Lynch Syndrome 
MSH2, b,U
MSH5     U
 When these genes are mutated, enzymes , DNA mismatched pair cannot be located for repair

Other DNA damage repair genes identified
BRCA2,  B,u
BRCA1   B,u
As the name BRCA (BRest CAncer genes) suggest, BRCAs are well known for associated with breast cancers and ovarian cancers.   Angelia Jolie  decided to have a double mastectomy to reduce her chances of getting breast cancers because she carried  mutated BRCA1 gene.   

CHEK2    B,u     
MUTYH   B,u     
ERCC3    B,u
ERCC2    B 
NBN       B
RAD50   B
ATM       b,u
BLM        b
BARD1    b
RAD51C  b
BRIP1      u
PALB2    u
MRE11A b

OTHRES   These genes are considered as Tumor suppressor genes.  
APC       B, U  APC counteracts proliferation, facilitate apoptosis, suppress tumor progression.  The study found APC mutation in high number cancers equally in bladder cancer and upper tract cancers.
FH         B,u
SDHA    b
TP53     b   TP53 mutation is often found up to 50% of MIBC.  There was only one case in bladder cancer.  I did not know the mutation of TP53 gene can be inherited,  Mr. Google says somatic mutations (after birth) in the TP53 gene are one of the most frequent alternation in human cancers, and germline mutations are the underlining cause of Li-Fraument syndrome. Most mutations are single-base substitutions distributed throughout the coding sequence.  
BAP1    b
MITF     b

The study by MSK, published in 2020 in  American Society of Clinical Oncology Journal
Cancer Susceptibility Mutations in Patients With Urothelial Malignancies

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