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Thursday, 31 January 2013

Her2 Neu, BRCA1 or Telomere in Breast Cancer in JCP


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Original article: Molecular profile of ductal carcinoma in situ of the breast in BRCA1 and BRCA2 germline mutation carriers
  • P van der Groep,
  • P J van Diest,
  • F H Menko,
  • J Bart,
  • E G E de Vries,
  • E van der Wall
J Clin Pathol 2009;62:10 926-930 Published Online First: 18 June 2009 doi:10.1136/jcp.2009.065524

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

    http://jcp.bmj.com/content/62/10/926.abstract 

    Institute of Post Graduate Medical Education & Research, 244a AJC Bose Road, Kolkta-20, W.B, India
    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] "
    Authors
    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),
    References
    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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    Published 4 November 2009
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A casual role for Human Papilloma virus-16 for the Head and Neck Cancers word wide published in JCP


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Short report: Human papilloma virus in squamous carcinoma of the head and neck: a study of cases in south east Scotland
  • C E Anderson,
  • K M McLaren,
  • F Rae,
  • R J Sanderson,
  • K S Cuschieri
J Clin Pathol 2007;60:4 439-441 doi:10.1136/jcp.2005.033258

  1. A casual role for Human Papilloma virus-16 for the Head and Neck Cancers word wide-

    http://jcp.bmjjournals.com/content/60/4/439.abstract 

    Institute of Post Graduate Medical Education & Research ,244a AJC Bose Road, KOlkata-20, W.B, India
    A casual role for Human Papilloma virus-16 for the Head and Neck Cancers word wide-and role of HPV vaccine altering the carriage rate of oropharyngeal HPV16?
    Dear Editor
    Infection with Human Papilloma Virus (HPV) 16 and 18 mostly is well established for development of cervical cancers in pre and post menopausal women through out the world. Professor H. Zur Housen was awarded the Nobel Prize for medicine and physiology for establishing role of HPV in development of cancer in 2008 instead of HSV2. But a pathogenic role for this HPV in non ano- genital cancer has yet been unclear till now. Tobacco and alcohol is considered today as important etiological factor for Head and Neck Squamous cell cancers(HNSCC). Epidemiological and laboratory evidences howevver now suggest this conclusion that in addition to tobacco and alcohol, HPV may be also the causative agent for the head and neck SCC. In our Institute at IPGME&R, Kolkata-20, West Bengal, India, from Pathology department the major bulk of cancer are diagnosed in the male population in any year is HNSCC and more then 95% of these sufferers gives however history of either smoking cigarette or local made Bidi or chewing Pan Parag products for long periods. These people are usually older and middle aged male. What about those young people dignosed with HNSCC? As with cervical cancer HNSCC is today a world wide public health problem with more then 9-10 lacks population per year are diagnosed by the Histopathologists having HNSCC. High risk HPV like HPV16 or HPV18 is probably not necessary for development of HNSCC. In our laboratory, we carried a work for 2 years on Role of HPV 16 and HNSCC mostly in younger people particularly and found HPV type 16 DNA is present in primary[poorly differentiated] and in metastatic cell nucleus in high copy numbers frequently integrated and transcriptionaly active by ISH technique. We are not sure whether these findings is casual association of HPV16 with HNSCC or etiology. Researches over past several years had also shown a string and consistent association between high risk HPV and distinct subset of HNSCC . However in our study these HPV associated HNSCC are characterized clinically by their location within the laryngeal and palatal tonsil of oropharynx. Their poorly differentiated histopatholgy and their frequent occurrence in nonsmoking and young patients then in HNSCC not associated with HPV. The proportion of HNSCC that is associated with HPV may be greater in a nonsmoker. HPV positive cancer may also occur in smokers. However it is unclear whether elevated risk of HNSCC for contamination of HPV infection and tobacco addiction is synergistic or additive with HPV? Thus screening for HPV in oral cavity and development of oral PAP smear might lead to early diagnosis and treatment for HNSCC. The prevalence of oral HPV infection presently a pre-requisite for HPV associated HNSCC was around 7% in centers without cancer in the IARC study [1] Another possibility for prevention of HPV associated HNSCC lies in HPV vaccine as we consider. Systemic Immunization with a protective HPV16 vaccine will be highly effective no doubt in preventing persistence HPV 16 in female genital tract. It is however not known to us whether such a vaccine will also alter the carriage rate of oropharyngial HPV16 and HNSCC.

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    Published 6 October 2009 Professor Pranab kumar Bhattacharya MD(cal), FIC path(Ind.) , Professor of Pathology, In charge of Histopathology Unit, in charge Blood Bank &VCCTC, Cytogenetics. Institute of Post Graduate Medical Education & Research, 244a AJC Bose Road, Kolkta-20, West Bengal, India; **Mr. Ritwik Bhattacharya, B.Com(cal); ***Mr. Rupak Bhattacharya BSc(Cal)MSc(JU) of 7/51 purbapalli, Sodepur Dist 24 parganas(North) Kol- 110, West Bengal, India; ****Mrs Dahlia Mukherjee BA(hons) Swamiji Road, Habra N-24 parganas, W.B, India, *****Miss upasana Bhattacharya of Mahamyatala, Garia kol-86,Daughter of Prof. Bhattacharya**** Dr Debasis Bhattacharya Ms(cal) FRCS(eng). Associate Professor, dept. of Surgery IPGME&R, Dr. Tarun Mandal MBBS(cal) , Dr. Ananya Pal MD(PGT) Pathology Dept. Of Pathology Institute of Post Graduate Medical Education & Research, 244a AJC Bose Road, Kolkta-20, West Bengal, India 
  2. Reference
    1. Herrero R, Castellasaguex, Pawlita M etal “ Human Paplloma Virus and Oral Cancer, The international gency for Research on Cancer-a multicenter study J. Natl .cancer Institute 2003:95:1272-83
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Bone marrow Aspiration and Bone marrow Trephine biopsy studies are complementary to each other and in kolkata, West Bengal, Bone marrow Aspiration is most choicely investigation than trephine biopsy for Diagnosis and Follow up of common Hematological problem Published in Journal of Clinical Pathology


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Review: Pitfalls in obtaining and interpreting bone marrow aspirates: to err is human
  • Barbara J Bain,
  • Katharine Bailey
J Clin Pathol 2011;64:5 373-379 Published Online First: 4 February 2011 doi:10.1136/jcp.2010.080820


  3. Bone marrow Aspiration and Bone marrow Trephine biopsy studies are complementary to each other and in kolkata, West Bengal, Bone marrow Aspiration is most choicely investigation than trephine biopsy for Diagnosis and Follow up of common Hematological problems

    http://jcp.bmj.com/content/64/5/373/reply#jclinpath_el_4834 

    • Professor Pranab kumar Bhattacharya- MD(cal) FIC Path(Ind),, Presently Professor & Head of Dept. of Pathology,
    • **. Rupak Bhattacharya , **Ritwik Bhattacharya ,** Soumyak Bhattacharya of 7/51 Purbapalli, Sodepur, Dist 24 parganas(north) ,Kolkata-110,W.B, India*Miss Upasana Bhattacharya* Mrs. Dalia Mukherjee* ; ***. Tridib Mandal *** Biplab Gayen ; ***Tarun BiswasRIO, Medical college, kolkata, C.R Avenue, Kolkata-73, W.B, India-
    The Hematologists(Pathologists trained in hematology) of kolkata, West Bengal( in private setup tertiary care hospitals or in diagnostic laboratories or in Govt. set up secondary or tertiary care teaching hospitals) are being mostly trained with performing, interpretation, evaluation and diagnosis of common hematological problems, requiring Bone Marrow studies, by Bone Marrow aspiration(for diagnostic and follow up after any therapy) than by Bone Marrow Trephine biopsy, unless there is1) failed aspirate due to no marrow fragments in conditions when there is Marrow fibrosis or Marrow aplasia or 2) when there is suspected Pathology in Bone or 3) Marrow is cellular but poor aspiration happens due to tightly packed marrow. In Kolkata the interpretation and reporting of Bone Marrow aspiration is usually done by consultant pathologists trained specially in hematology division in a laboratory or in a teaching hospital Pathology dept set up. A very few centers[ one or two] are there in kolkata in the medical colleges where there are post doctoral trainees in hematology who also perform and report Bone marrow aspiration mainly and occasionally by trephine biopsy.
    We authors consider however that there are till many advantages of performing and reporting Bone Marrow aspiration then reporting Bone Marrow Trephine biopsy, some of them can be summarized as follows • The Marrow aspiration needles are less costly, supplied and easily available in the kolkata market, in each &every laboratories and can be easily sterilized then islam or Jamshedi needles for marrow trephine biopsy ** the procedure can be repeated if and when necessary *** Multiple numbers of slides can be drawn from a single aspirate and may be used thus for special stain, cyto-chemistry and immuno histochemistry when necessary **** Report can be handed over to patient by 24 hours in most cases unless special stains or immunostains are asked for.***** Cytogenetic studies including flow cytometry can be performed with aspirated materials******The technique and interpretation can be percolated even at secondary health care level where there is a trained pathologists(at district and sub divisional level hospitals or diagnostic laboratories) and thus necessary treatment can be given earlier by General physicians or primary care physicians. • However there remain recognized problems with Bone Marrow aspiration studies 1) That the aspirated material often becomes diluted with much aspirated blood and in that case it is wiser to suck off blood before making smears with a blotting paper edge 2) the smear drawn by the trainee Post doctorals may not be equally enough thin and spreaded and clumping of many cells at some patchy areas of the slide 3) Marrow material may be drawn inadequate for interpretation 4) while Interpretation of cases and diagnosis are given erythriod hyperplasia particularly in children-the underlying diseases is not well described and many reports realy are such 5) When there is suspected focal lesion –in the bone marrow itself marrow aspiration can miss diagnosis 6) suspected &focal bone marrow fibrosis 7) when there is need to study the bone marrow architecture or bone structure or bone marrow blood vessels, Bone marrow aspiration may not be adequate study • Besides there may be many indications for performing Bone marrow Trephine biopsy like in Aplastic anemia; Myelofibrosis; MDS; Hairy cell leukemia; smoldering Multiple Myeloma; Early Multiple Myeloma Granulomatous lesions in Marrow [ may be from bacterial, viral, rickettsial, fungi, parasitic and sarcoidosis]; Osteopatheis. hypocellular MDS and investigation of suspected MDS or MDS with fibrosis; investigation for suspected amylodosis in cases of Multiple Myeloma ; Hypoplastic acute leukemia; AML M7; After Bone marrow transplant assessments; in CML for sub-typing the disease or to detect early blast crisis and to assess marrow fibrosis; for staging of Hodgkin disease(Bone marrow involvement is(2-32%) diagnosis and staging of small cell tumors of childhood; investigations for unexplained luekoerythroblastic blood picture and trephine biopsy can diagnose occult or micro metastasis if any or necrosis of bone marrow when there is infraction of bone which are missed or become difficult to diagnose by Bone Marrow aspiration studies. • The problem of trephine biopsy is that needles( Islam or jamshidi or westermann-jensen) needles are not available in every laboratories even at tertiary care teaching hospitals Pathology department and disposable needles are very costly for patient* it is always necessary to carry out aspiration at same time** Requires tissue processing set up with fixation facility {microwave fixation is better then10% buffered formalin or zinker fixative as often requires immuno stain as style] and decalcification fluid and making paraffin or resin blocks *** Training for interpretation and evaluation of Trephine biopsy is not adequate; Adequacy of length of Marrow tissues often not obtained (25% shrinkage is natural for fixation and at least 5-6 trabecular space is required for interpretation as per authors] and there remains also word of cautions for patients with coagulation disorders, liver failure and in patients with thrombocytopenia{< 1.5 lack/cumm] • Finally Bone Marrow aspiration and Bone Marrow trephine biopsy are complementary to each other as per authors at least if aspirations are not done then bone marrow imprint should be seen before evaluating Trephine biopsy.

    Conflict of Interest:

    None declared
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    Published 17 February 2011
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