Showing posts with label PTEN. Show all posts
Showing posts with label PTEN. Show all posts

Friday, November 8, 2013

Genes in Breast CANCERS

1.Variants in the PALB2 gene are associated with an increased risk of developing breast cancer [5] and PALB2-deficient cells are sensitive to PARP inhibitors. [4]
PALB2 was recently identified as a susceptibility gene for familial pancreatic cancer by scientists at the Sol Goldman Pancreatic Cancer Research Center at Johns Hopkins. This has paved for the way for developing a new gene test for families where pancreatic cancer occurs in multiple family members.[6] Tests for PALB2 have been developed by Ambry Genetics [7]and Myriad Genetics[8] that are now available through a genetic counselor.
Biallelic mutations in PALB2 (also known as FANCN), similar to biallelic BRCA2 mutations, cause Fanconi anemia.[3]wikipedia

2 xia et al: described superbly the role of PALB2
" the identification of PALB2, a BRCA2 binding protein. PALB2 colocalizes with BRCA2 in nuclear foci, promotes its localization and stability in key nuclear structures (e.g., chromatin and nuclear matrix), and enables its recombinational repair and checkpoint functions. In addition, multiple, germline BRCA2 missense mutations identified in breast cancer patients but of heretofore unknown biological/clinical consequence appear to disrupt PALB2 binding and disable BRCA2 HR/DSBR function. Thus, PALB2 licenses key cellular biochemical properties of BRCA2 and ensures its tumor suppression function."

3. And has mentioned hematologic complication is not very far!

" Fanconi anemia is a rare, recessive, chromosomal instability disorder characterized by growth retardation, congenital malformations, progressive bone marrow failure, cancer predisposition and cellular hypersensitivity to DNA cross-linking agents1. The syndrome is genetically heterogeneous with 12 complementation groups currently recognized, 11 of which have been attributed to distinct genes: FANCA (FA-A), FANCB (FA-B), FANCC (FA-C), BRCA2 (FA-D1), FANCD2 (FA-D2), FANCE (FA-E), FANCF (FA-F), FANCG (FA-G), BRIP1 (FA-J), FANCL (FA-L) and FANCM (FA-M)2, 3." Sarah Reid et al....

4. And the devastation does not stop to Fanconi and Breast cancer!

ERKKO et al:

"These results indicate that PALB2 is a breast cancer susceptibility gene that, in a suitably mutant form, may also contribute to familial prostate cancer development." in a Finnish population


"the role of PALB2 as a susceptibility gene for pancreatic cancer. PALB2 mutations have been previously reported in patients with familial breast cancer, and the PALB2 protein is a binding partner for BRCA2. "



"In humans, RAD51 is a 339-amino acid protein that plays a major role in homologous recombination of DNA during double strand break repair. In this process, an ATP dependent DNA strand exchange takes place in which a template strand invades base-paired strands of homologous DNA molecules. RAD51 is involved in the search for homology and strand pairing stages of the process.
Unlike other proteins involved in DNA metabolism, the RecA/Rad51 family forms a helical nucleoprotein filament on DNA.[2]
This protein can interact with the ssDNA-binding protein RPA, BRCA2, PALB2[3] and RAD52."WIKIPEDIA


" RAD51 has been shown to interact with BRE,[12] RAD54B,[13] Ataxia telangiectasia mutated,[14] BRCC3,[12] BARD1,[12] BRCA2,[12][15][16][17][18][19][20][21][6][22][23][24][25] UBE2I,[26][27] Abl gene,[14] BRCA1,[12][24][28][29] ATRX,[13][30] RAD52,[14] DMC1,[31] P53[12][32][33] and Bloom syndrome protein.[34]"WIKIPEDIA

- CDH1


Tuesday, October 29, 2013

Progress in Genome studies: case in point the DIGITAL PCR.

If what they promise is real, we are entering an important phase where not only we can count mutations,  but can also try to determine levels of gene amplifications  that are secondary, versus those that are in response or a consequence of upstream genes normally amplified or amplified because they are mutated!

" Next-generation sequencing technology has transformed cancer genomics, but faces the challenge of genome and transcriptome heterogeneity inherent to any tumor sample. One strategy for capturing the complex landscape of mutational processes, clonal evolution/amplification and tissue invasion is the application of digital PCR, which enables the identification and precise quantitation of individual mutations - including those present at a very low frequency."(Biomedcentral)

This new technology will open new evaluations of gene quantities as to their meaning and trigger!  It will allow also to detect levels of suppression of a normal gene when it is found in an unexpected amount.  We know for example that in many lung cancers PTEN is suppressed.  Whether  this is a primary happening or secondary can be further debated.  In Ovarian cancer DAB2 is suppressed. ("The down-regulation of DAB2 may play an important role in ovarian carcinogenesis. This gene was initially named DOC2 (for Differentially expressed in Ovarian Cancer) and is distinct from the DOC2A and DOC2B genes (for double C2-like domains, alpha and beta).[3]

 Most of these suppressions are the result of an amplification of an upstream gene or an overexpression of an inhibitory protein.  When it comes to DAB2, it is important to report that this gives the cancerous process some teeth and bad prognosis.  Indeed, the suppression of DOC2 gives the tumor ways of escaping proliferation control by the cancerous cell by activating E3 (removing by unbiquitilation of the inhibitor of the inhibitor of E3).  This new technology will allow direct quantification of the 2 inhibitors or the E3 for that matter.  It may also clarify how Velcade works in relation to the 3 compounds!

Thursday, August 22, 2013

Processes of cancerization

One of the most intriguing steps in the neoplastic transformation is determining the actual event that led to its occurrence. We all have the perception that because of what we ingest unfortunately on a continuous basis (medications or foods we like - man clings to habits) something will get either amplified or suppressed.  Certain amplifications can be deleterious or beneficial depending of where they occur or what gene is involved.  It is apparent that involvement of "wild genes" (those with multiple interactions with others, including genes involved in shaping the body) are more likely to lead to malignant transformation (ie. the Androgen gene, FYN,Grb2, MTIF, etc).  Secondly, knocking out break to proliferation (P53, Rb1, PTEN, and the many CDK) seems also to be a prelude to a neoplastic transformation.   Alteration in "switch" genes (SOS) and molecules intermediary to various cellular/membrane events can also trigger a persistent stimulation or suppression that could affect cellular processes enough to upset a balance.  Chronic hypoxia has emerged to be a potent neoplastic process inducer....(to be continued)

Friday, March 8, 2013


1.NF1 Mutation is upstream from
and MTOR
But NF-1 is Mutated in Melanoma
can infusion of protein resulting from NF-1 be used to strengthen effect of MTOR inhibitor and BRAF inhibitor by maintaining these pathways open!

2.  Discriminating Redundancy in cellular language
same gene base corresponding to same Amino Acid
same receptors at membrane being sensitive by different stimuli
but when it comes to the RAS, nature and intensity need to matter and this also a function of tissue involved!
some time however the nature of the stimulus is more important particularly inside the cell where ie HP90 seems to stimulate more the CoN to achieve PTEN suppression. And you know that CoM stimulation raise Bcl2 level...we will say more in our upcoming article of langaue of the cell as it pertains to pathways!

3. PTEN is repressed by low expression of gene or mislocalization (reported PNUTS 'role) at Nuclear level or both?