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.<sup>[3]wikipedia


2 xia et al: described superbly the role of PALB2
"</sup> 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

SIAN JONES ET AL

"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. "

SOME AUTHORS ADD GALLBLADDER,MELANOMA AND GASTRIC CANCERS TO THIS SAD LITANY.
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6.RAD51

"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

RAD 51 KEEPS BAD ASSOCIATIONS, BROADENING THE DANGER!

" 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.<sup>[34]"WIKIPEDIA

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ON TOP OF ALL THIS 
YOU STILL HAVE 
- CDH1
- p53 MUTATIONS
- PTEN

OUR WORK IS CUT OUT TO TRAVEL THIS MAZE!</sup>

NOMENCLATURE OF GENES TO LOOK FOR IN TRIPLE NEGATIVE BREAST CANCER

One may try to determine whether a breast cancer has bad prognosis in order to determine whether chemotherapy should be given (MammaPrint, Oncotypr DX), but more importantly, I believe, is to focus on genes of good prognosis which include driver genes against which we dispose of an answer in our Arsenal.
Currently we dispose of
1. Chemotherapy that attacks DNA and Microfilament/Microtubules,  (first and second law of nature)
2. Immune Modulators such as Interferon
3. Antibody to Membrane Receptor (EGFR/VEGF) Avastin
4.  Inhibitor to T-cell driven immunity (CTLA4)
5.  Inhibitors to sub-membrane or first line driver Mutations KRAS, HRAS, or the RAS family
6.  Inhibitors to 2nd line driver Mutations (anti MEK)
7. Inhibitor to Tertiary line driver Mutations and Mitochondrial level inhibition (MTOR, Metformin)
8. Anti-proteasome or inhibitor to cellular protein degradation (Velcade)
9. Inhibitors at Nuclear lever Include Histone Deacethylator and Acyl transferase inhibitor, check point controller inhibitors,  anti-Centrosome metabolism and inhibitors of various promoters and transcription factors.

Other opportunities not included in this classification go to specific genes of proliferation, Amplification, differentiation and metastasis that have been brought forth as indicator of either response to chemotherapy or simply as "Good prognosis" genes.  These will include the BRCA since a response to PARP inhibitors and Cisplatin based combinations should be anticipated.

Multikinase inhibitors such as Dasatinib (SRC+ BCR/ABL but also STAT5) and Arsenic Trioxide should be included   
LBK1: could predict early disease (inhibitor controlling initiation of metastasis)
DDR2: could predict anti MEK sensitivity
MEKK-1 sensitivity to Cisplatin
TFF1-could predict sensitivity to estrogen despite negative Estrogen
DYRK2, favorable in lung cancer
 
c-JUN amplification and over expression of 8q23-24 could predict  response to interferon/Interleukin
EGFR, VEGF, ALK,  and other Driver Mutations would match those discussed By DR Kris in lung cancer.

(to be continued!)

BRCA 1,2  
BR=Breast   CA=cancer
Tumor suppressor gene which encodes a protein regulator of transcription gene involved with cell proliferation (once again it is a regulator that is involved!)

1. Prophylactic Bilateral mastectomy reduces the short term risk of Breast cancer, and overall risk by 90%
2.Adding Bilateral Salpingo-Oophorectomy decreases risk of Breast and Ovarian cancer.
3.BRCA1 high grade and Hormone Receptor Negative, majority are basal like subtype  (but also more Atypia and Medullary histology found here!
4.whereas BRCA2 are more likely receptor positive and of luminal subtype
5. Risk of contralateral breast cancer in those with the disease 50-60%
6.BRCA 2 increases risk of Gastric,bilary,gallbladderand pancreatic cancer also.
7. The 2 HITS Theory assumes that the first hit is to have the abnormality but with the protecting presence of the normal BRCA gene.  The second (environment factor) Hit knock out the normal BRCA to unleash the effect of the abormal BRCA1-100
IF YOU HAVE IT
1-Abide by strict surveillance protocol
2-Bilateral protective Mastectomy
3. Bilateral protective Oophorectomy
4. participation in preventive research drug (Tamoxifen,Raloxifen)

and know about possibility of insurance issues that may arise
SEE A GENETIC COUNSELOR PRIOR TO TESTING!