Abstract
Higher risk of developing secondary cancer after human stem cell transplants from female donors.
Scientists from the Gordon & Leslie Diamond Health Care Centre (Canada) made a surprising discovery during research into second solid cancers after allogenic hematopoietic stem cell transplantation (allo-HSCT).
It was discovered that patients who received allo-HSCT for treatment of leukemia have a higher risk of developing secondary cancer, and surprisingly those who received stem cells from female donors appeared to have an increased risk than those who received stem cells from males donors.
The authors reviewed the case files of 926 patients who underwent allo-HSCT at the institution between 1985 and 2003. Results showed that a significant number of the recipients were suffering from leukemia as a secondary cancer. The review demonstrated that 28 patients developed 30 solid malignancies at a median of 6.8 years after allo-HSCT. Patients who receive allo-HSCT at advanced age also appeared more likely to develop leukemia following transplantation. Overall, the scientists found that the remaining patients faced a 2.3% risk of cancer over the course of 10 years, nearly twice the risk in the general population.
The risk of developing cancer over the course of 10 years was 4.6% in patients who received stem cells from a female donor, which is a notable increase from the 1.8% risk when treated with stem cells from a male donor.
This unexpected finding is a new observation and has not been reported previously. It is suggested by the authors that extensive follow up is required to fully assess the incidence and risk factors for the development of solid tumors, due to possible prolonged latency. This report may influence future stem cell treatments, indicating caution that HSCT may carry a cancer risk, and a higher one if the donor is female.
Donna Forrest of the British Columbia Cancer Agency (Canada), who led the research, suggests that the cells from female donors may differ in some way, making them disruptive when transplanted. This could lead to chronic inflammation, which results in a greater risk of cancer.
There is a growing need to understand what happens to transplanted stem cells due to their differentiation capabilities.
The findings are preliminary and the analysis did not control for confounding factors such as whether the donor patient smoked, was overweight, and their general health. It therefore remains unclear exactly how much the stem cell transplants contributed to the risk of second cancers.
Simon Cherry, a stem cell researcher at the University of California (USA), cautions that researchers should actively investigate the possible cancer risk to avoid any unexpected negative outcomes of future uses of stem cells. This could have a large impact on the current uses of stem cells for spinal cord injury, macular regeneration and heart failure.
Source: Gallagher G, Forrest DL: Leukemia/Bone Marrow Transplantation Program of British Columbia. Cancer (DOI: 10.1002/cncr.22375) (2006).
Novel gene biomarker in breast cancer
Scientists from the University of Rochester report that a novel gene could act as a new biomarker for breast cancer.
The gene C35 (C17orf37) was selected by representational difference analysis of tumor and normal human mammary cell lines. The gene is located on chromosome 17q12, 505 nucleotides from the 3′ end of the ERBB2 oncogene, which is a member of the epidermal growth factor receptor family of receptor tyrosine kinases, known to be expression in breast and ovarian tumors. The ERBB2 oncogene is an antigenic target for trastuzumab, which is administered under the trade name Herceptin®.
The gene is expressed in 32% of grade 1 infiltrating ductal carcinomas of the breast, which is the most common invasive breast cancer, accounting for 70% of all cancers. It is abundant at distant metastases and occurs in very low levels or is completely absent in normal breast tissue.
C35 is poised to be a successful biomarker and possibly a broad target for the development of new anticancer drugs. This study warrants further investigation into the relevance of C35 as a biomarker.
Source: Evans EE, Henn AD, Jonason A et al.: C35 (C17orf37) is a novel tumor biomarker abundantly expressed in breast cancer. Mol. Cancer Ther. 5(11), 2919–2930 (2006).
in brief…
Diesch CH, Holzgreve W, Hahn S et al.: Prenat. Diagn. 1, 26(13), 1267–1270 (2006)
Examines how plasma activin A concentrations before the onset of preeclampsia differ from the concentration in cell-free fetal DNA in maternal plasma. The correlation between the activin concentrations were analyzed using the spearman rank test. Plasma activin A levels were significantly higher in the preeclampsia samples, and the increase in concentration was observed prior to the onset of preeclampsia. The increase in activin A correlates significantly with the increased level of cell-free fetal DNA. The study suggested that circulatory activin A could be an independent biomarker for early indication and monitoring of preeclampsia.
Lyytinen H, Pukkala E, Ylikorkala O: Obstet. Gynecol. 108(6), 1354–1360 (2006).
Examines the long-term risk of breast cancer involved in use of estrogen-only therapy and ascertains whether risk varies by dose. Women over the age of 50 years using estrogen-only therapy (transdermal estradiol, oral estriol or vaginal estrogens) for at least 6 months were studied. Use of estradiol for 5 years or more, either orally or transdermally, was shown to result in 2–3 extra cases of breast cancer/1000 women. The risk was most prominent with doses greater than 1.9 mg/day orally.
Belosay A, Brodie AM, Njar VC et al.: Cancer Res. 1, 66(23),11485–11489 (2006).
Aromatase inhibitors are proving to be more effective than tamoxifen for postmenopausal estrogen receptor (ER)-positive breast cancer but resistence is a concern. Long-term letrozole cultured (LTLC) cells are not sensitive to growth inhibition by aromatase inhibitors. The study examined the effect of VN/14–1 on these cells and found that the drug effectively downregulated ERα, amplified in breast cancer (AIB)1, pMAPK, HER-2, cyclin D1, cyclindependent kinase 4, and Bcl2 and upregulated cytokeratins 8/18, Bad and Bax. This led to inhibition of LTLC cell growth with VN/14–1 treatment.
New ultrasound technique for breast cancer detection
A new ultrasound technique, elastography, is enabling doctors to diagnose breast cancer, and has proved to be so successful it could replace biopsies.
Elastography or real-time, free-hand elasticity imaging detects the changes that occur in soft tissue when it becomes tumorous, and enables identification of malignant lumps or lesions in the breast. The new research was presented at the Radiological Society of North America Annual Meeting, by Richard Barr Northeastern Ohio Universities College of Medicine (USA) and claims to be 100% effective.
In the study, 72 patients were evaluated with the new real-time, freehand elasticity image technique. A total of 56 benign and 16 malignant lesions were evaluated from 49 patients, based on the change in lesion size between the elasticity image and the fundamental image. Characteristic strain patterns in elasticity for each specific pathology were also identified to allow tissue characterization. The technique has high sensitivity and specificity for characterizing lesions in both benign and malignant tumors.
Researchers are hopeful that the stress and discomfort of invasive biopsies could be eliminated entirely. Over 1 million are performed each year in the USA alone. The technique would also lead to reduced healthcare costs as the new technique is said to cost US$ 100–200 per use.
The study requires further research on a larger scale to confirm the initial findings. Elastography may also have uses in prostate and thyroid cancer diagnosis and treatment.
Source: Barr R: Initial results of breast real-time elasticity imaging to characterize lesions. Radiological Society of North America Annual Meeting (CODE: LL-BR4218-B01).
Placental infection doubles risk of recurrence during second pregnancy
A total of 10% of women who have vaginal births with their first child will develop chorioamnionitis. These women have twice the risk of developing the infection again in a second pregnancy.
Chorioaminionitis, an infection that affects the placenta and surrounding membranes, can cause bleeding and widespread infection in the mother and the fetus. It is also believed that the type of bacteria involved may play a role in secondary infection. “Certain women could be colonized with bacteria that are more virulent and more likely to cause infection,” commented Vanessa Laibl, University of Texas Southwestern Medical Center (USA).
Longer labor, labor induction, long second stages of labor and use of medical equipment such as internal monitors also appeared to be factors present in those with the infection.
“Circumstances do play an important role,” noted Dr Laibl, who also added that “the women who got the infection the first time were still more prone to getting it in their second pregnancy.”
Source: Laibl VR, Sheffield JS, Roberts S et al.: Recurrence of clinical chorioamnionitis in subsequent pregnancies Obstet. Gynecol. 108(6), 1493–1497 (2006).
BRCA gene mutations are more frequent in general population that first thought
Scientists analyzed the population of BRCA1 and BRCA2 mutation frequencies and cancer penetrance in a study conducted in Ontario (Canada).
The research involved screening for germline BRCA mutations in 1171 women who were diagnosed with ovarian cancer in Ontario between 1995 and 1999. The incidence of cancer was also studied in 8680 of the women's first-degree relatives, to prove the genetic link.
It was found that around 1% of the general population in Ontario carried BRCA mutation, which is now thought not only to be related to increased risk of breast cancer but also to testicular and pancreatic cancer. Screening involved testing for common variants of the gene, and protein truncation testing of long exons. Denaturing gradient gel electrophoresis was used for the remainder of BRCA1 and denaturing high-performance liquid chromatography for the remainder of BRCA2.
BRCA1 and BRCA2 mutations may be more frequent in the general population than previously thought and may be associated with various types of cancers.
The study published in the Journal of the National Cancer Institute reported that 13.2% of the participants had mutations present in either of the BRCA genes. Further analysis revealed that BRCA1 mutations were linked to an 11-fold increase in female breast cancer, a 17-fold increase in testicular cancer and a 21-fold increase in ovarian cancer. The population allele frequencies and relative risks were derived by using the regression results by an extension of Saunders–Begg methods.
The study also pinpointed the location of individual mutations within the BRCA gene regions and calculated the associated risk. Mutations outside of the ovarian cancer cluster region (OCCR) on BRCA2 lead to an increased risk in breast cancer development, compared with mutations found in the OCCR region.
Source: Risch HA, McLaughlin JR, Cole DE et al.: Population BRCA1 and mutation frequencies and cancer penetrances: a kin–cohort study in Ontario, Canada J. Natl Cancer Inst. 98(23) 1694–1706 (2006).
Lung cancer may be overdiagnosed in women
The 92nd Scientific Assembly and Annual Meeting of the Radiological Society of North America has revealed that 27% of lung cancers in women over a 5-year period are ‘overdiagnosed.’
The study from the Mayo clinic looked at computed topography (CT) scans of 61 lung cancers from 1520 regularly screened participants. Size, appearance, histology and staging were investigated.
Out of the 61 tumors, 48 of the tumors were imaged on more than one CT scan, and were assessed. Volume doubling times for the 48 tumors were greater than 400 days in the case of 13 of the 48 tumors, and 85% of these cases were in women.
All the tumors appeared to be operable, and this led to the conclusion that the women were overdiagnosed.
Source: RSNA 92nd Scientific Assembly and Annual Meeting. 29 November (2006 (Abstract SSK04-01).
Abortion pill may help prevent breast cancer
The antiprogesterone drug mifepristone may help to prevent breast cancer in a mouse model.
The drug works by blocking progesterone receptors in the uterus, thus competitively inhibiting endogenous progesterone.
Progesterone is required for the maintenance of implantation of the fertilized egg in the womb. The drug is speculated to be able to prevent the growth of mammary breast tumors by also inhibiting progesterone present in breast tissue cells.
“We found that progesterone plays a role in the development of breast cancer by encouraging the proliferation of mammary cells that carry a breast cancer gene,” reported Eva Lee, lead author of the study.
Mifepristone could be effective in women with a genetic disposition to cancer carrying the mutated BRCA1 gene. Women who have the BRCA1 gene have a more than 50% chance of developing breast or ovarian cancer over the age of 70 years. To date the studies on mice have been promising but experts warn that scientists are still a long way from recommending mifepristone as a treatment for breast cancer in humans.
Source: Poole AJ, Li Y, Kim Y et al.: Prevention of BRCA1-mediated mammary tumorigenesis in mice by a progesterone antagonist. Science 314, 1467–1470 (2006).
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