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Thursday, 31 January 2013

Her2 Neu, BRCA1 or Telomere in Breast Cancer in JCP

  1. Her2 Neu, BRCA1 or Telomere in Breast Cancer? 

    Dear Editor,
    Elizabeth H Blackburn and Jack Szostak discovered that a unique DNA sequence in the telomeres protects chromosomes from degradation. Carol Greider and Elizabeth Blackburn identified telomerase, the enzyme that makes telomere DNA. These discoveries explained how the ends of the chromosomes are protected by the telomeres and that they are built by telomerase. If the telomeres are shortened, cells age. Conversely, if telomerase activity is high, telomere length is maintained, and cellular senescence is delayed. This is the case in cancer cells, which can be considered to have eternal life [1]. Cancer cells have the ability to divide infinitely and yet preserve their telomeres. How do they escape cellular senescence? One explanation became apparent with the finding that cancer cells often have increased telomerase activity [1] Telomeres, repeated sequences of DNA at the end of chromosomes, prevent degradation of genetic material. Each time chromosomes replicate a small amount of the DNA at both ends is lost, by an uncertain mechanism. Because human telomeres shorten at a much faster rate than many lower organisms, we do speculate that this telomere shortening probably has a beneficial effect for humans, namely mortality. The telomere hypothesis of aging postulates that as the telomeres naturally shorten during the lifetime of an individual, a signal or set of signals is given to the cells to cause the cells to cease growing (senesce). At birth, human telomeres are about 10,000 base pairs long, but by 100 years of age this telomere reduces to about 5,000 base pairs. Scientists discovered an important enzyme that can turn the telomere production on the DNA molecule "on" and "off." It's called telomerase. It seems that as we get older, the amount of telomerase in our cells decreases. Naturally, the exploration of this enzyme is now the focus of much investigation, but unfortunately the research is aimed at understanding how to turn telomeres "off" to limit the spread of "immortal" cancer cells. Telomerase is actually an enzyme (a catalytic protein) that is able to arrest or reverse this shortening process. Normally, telomerase is only used to increase the length of telomeres during the formation of sperm and perhaps eggs, thus ensuring that our offspring inherit long "young" telomeres to propagate the species. The telomere hypothesis of cancer is that the function of telomere shortening is to cause cells that have lost normal control over growth to senesce (i.e. stop growing) before being able to replicate enough times to become a tumor, thus decreasing the frequency of cancer. Immortal cells like cancer have an unfair advantage over normal human cells which are designed to senesce. But nature seems to have planned this human telomere shortening perhaps to prolong life by hindering the otherwise unchecked growth of non-immortal or benign tumors. Malignant, or immortal tumors can simply outlive the rest of the organism. Malignant cancer cells are being studied because they appear to have altered the shortening of telomeres by turning "on" the telomerase. Thus it appears that some cancers and aging are both connected with the biology of telomeres. So telomerase-inhibiting drugs would probably kill the cancer cells before much damage is done to normal cell
    Today reduction in mortality in breast cancer is due to early detection through screening by mammography. However at least 25% reduction in mortality could have been achieved due this screening procedure [early-stage pre menopausal breast cancer, for example, 10-year survival rates is today 68% for African Americans versus 77% for Caucasians]. Besides these there played other factors also and these are 1) systemic or improved systemic treatment with chemotherapy 2) adjuduvant therapies after surgery to eliminate micro metastasis like Her2 Nue antagonist Herpentine and to prevent recurrences. Women with steroid hormone receptor[ER+ or PR+] positive and negative cases are benefited by Cyclopshomide & methotraxate & 5 FU chemotherapeutic agents. More effective adjuduvant endocrine treatments are with variuous aromatase inhibitors like letrozole or anastrozole. Cases of breast cancers occur even when there is no family history or only a few cases in elderly relatives are known as sporadic breast cancer. Hereditary breast cancer is different from those of sporadic breast cancer .The increased risk of breast cancer for those with a family history may be caused by inherited factors (genes) like BRCA1 and BRCA2,[both the genes protects breast cells from developing cancer. Certain mutations in BRCA1 stop the gene working properly and therefore make it more likely that breast cancer will develop],or a combination of inherited factors and lifestyle like no breast feeding or unmarried women. Having an increased genetic risk by mutation of these two genes can lead to breast cancer developing even at an earlier age. BRCA1 and TP53 genes are of high penetrance genes for breast Cancers. Mutations in the rare high penetrance breast cancer predisposing genes are BRCA1 and BRCA2 and they account for 16 to 25% of the inherited component of breast cancers in the world scenario.This, in turn, can have an impact on raising your family. So is it today possible to do BRCA1 gene test for people that know they carry a specific mutation that predisposes them to suffer from breast cancer. It is a real fact that most Breast cancers develop sporadically and not related with a familial history or hereditary BRCA genes. It is thought that less than 5% of people those develop breast or bowel cancer do so because of an inherited fault. Unless there is a strong family history of breast cancer in you it is unlikely that your child will inherit a gene that increases the risk of developing cancer. So splicing off BRCA1 gene before embryo may be an advancement for medical technology [2]. Mutations in TP53, which at same time may cause the Li Fraumeni syndrome, STK11 gene causing Peutz Jeghers syndrome, and PTEN causing Cowden syndrome are however very uncommon sporadic causes of breast cancers of NOS type, as are mutations in CDH1, although these mutations may be highly penetrant for breast cancer The intermediate penetrance breast cancer susceptibility genes are mutations in ATM, CHEK2, BRIP1, BARD1, and PALB2. They can cause an increased odds ratio for breast cancer of 2 to 4. These genes are all involved in the same DNA repair pathways, but it is curious that they do not confer the high risk of breast cancer seen in women who carry mutations in BRCA1 and BRCA2. Also of great interest is that biallelic mutations in BRCA2, BRIP1, and PALB2 cause Fanconi anaemia subtypes FANC D, J, and N respectively, further indicating overlap in the functions of these genes. There are also good evidences now that there are up to eight polymorphisms, which are reproducibly found to influence breast cancer risk, particularly the FGFR2 gene. Carriers of two low risk rs2981582 alleles at the FGFR2 locus (frequency 38% of the population) have a relative risk of breast cancer of 0.83 compared with the general population, carriers of one high-risk and one low-risk allele (47%) have a relative risk of 1.05, and carriers of two high-risk alleles (14%) have a relative risk of 1.26
    Telomere crisis is also an important early event in the development of breast cancer. In the breast, cells in a milk-collecting duct occasionally proliferate excessively due to development of a regulatory defect and results usual ductal hyperplasia." The chromosomes in these growing cells lose a hundred or so base pairs of DNA every time they divide," ,because the usual DNA replication processes don't copy DNA all the way out to the ends of the chromosomes. This erodes the DNA sequences that interact with proteins to form structures called telomeres, which protect the chromosome ends. Eventually the DNA ends erode so much they can no longer protect the chromosomes. When this happens the chromosomes become unstable, and damage-control mechanisms kick in that kill the unstable cells. This process, known as "telomere crisis Cells in which telomerase is activated can then proliferate indefinitely to form the next stage of cancer, known as 'ductal carcinoma in situ.' The mean telomere length is found decreased from normal tissue to carcinoma in situ, and decreased even more in invasive cancers of breast. It was therefore proposed that breast cancer might be treated by eradicating telomerase. Several studies are underway in this area, including clinical trials evaluating vaccines directed against cells with elevated telomerase activity[1] "
    Professor Pranab kumar Bhattacharya MD(cal), FIC path(Ind.) Mr. Ritwik Bhattacharya, B.Com(cal) Mr. Rupak Bhattacharya BSc Mrs Dahlia Mukherjee BA (hons) Miss Upasana Bhattacharya of Mahamyatala, Dr. Debashis Bhattacharya Ms(cal) FRCS(Edin) Dr. Diptendra Narayan Sarkar Dr. Tarun Biswas MBBS(cal)- Dr. Satyaki Mitra MD(PGT) Dr. Avisnata Das MBBS(cal),
    1] Press Release on the 5 October 2009 “The Nobel Prize in Physiology or Medicine 2009â€� by The Nobel Assembly, consisting of at Karolinska Institutet, Sweden
    2] Response by Professor Pranab Kumar Bhattacharya Published by BMJ on 4th feb 20009 .for the BMJ case reports Blog unnatural selection by author Dean Jankens, published on 9th Jan 2009
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