Abstract Objectives Women at increased genetic risk of ovarian cancer (OC) are recommended to have risk-reducing salpingo-oophorectomy (RRSO) after completion of reproductive planning. Effective ...screening has not been established, and novel screening modalities are being evaluated. Methods Participants chose either RRSO or a novel OC screening regimen (OCS) as their risk management option, and provided demographic and other data on BRCA mutation status, cancer worry, perceived intervention risks/benefits, perceived cancer risk, and quality-of-life at enrollment. We performed univariate and multivariate analyses to evaluate factors influencing decision between RRSO and OCS. Results Of 2287 participants enrolled, 904 (40%) chose RRSO and 1383 (60%) chose OCS. Compared with participants choosing OCS, participants choosing RRSO were older (p < 0.0001), more likely to carry deleterious BRCA1 / 2 mutations (p < 0.0001), perceive RRSO as effective, be more concerned about surgical harms and OCS limitations, and report higher perceived OC risk and OC-related worry. OCS participants were more likely to perceive screening as effective, be more concerned about menopausal symptoms, infertility, and loss of femininity, and report better overall quality-of-life. Twenty-four percent of participants believed they would definitely develop OC, and half estimated their lifetime OC risk as > 50%, both higher than objective risk estimates. Conclusions Cancer worry, BRCA1 / 2 mutation status, and perceived intervention-related risks and benefits were associated with choosing between RRSO and OCS. Efforts to promote individualized, evidence-based, shared medical decision-making among high-risk women facing management choices should focus on conveying accurate OC risk estimates, clarifying the current understanding of intervention-related benefits and limitations, and addressing OC worry.
Li-Fraumeni syndrome (LFS) is associated with germline
mutations and a very high lifetime cancer risk. Algorithms that assess a patient's risk of inherited cancer predisposition are often used in ...clinical counseling. The existing LFS criteria have limitations, suggesting the need for an advanced prediction tool to support clinical decision making for
mutation testing and LFS management.
Based on a Mendelian model, LFSPRO estimates
mutation probability through the Elston-Stewart algorithm and consequently estimates future risk of cancer. With independent datasets of 1,353 tested individuals from 867 families, we evaluated the prediction performance of LFSPRO.
LFSPRO accurately predicted
mutation carriers in a pediatric sarcoma cohort from MD Anderson Cancer Center in the United States, the observed to expected ratio (OE) = 1.35 (95% confidence interval, 0.99-1.80); area under the receiver operating characteristic curve (AUC) = 0.85 (0.75-0.93); a population-based sarcoma cohort from the International Sarcoma Kindred Study in Australia, OE = 1.62 (1.03-2.55); AUC = 0.67 (0.54-0.79); and the NCI LFS study cohort, OE = 1.28 (1.17-1.39); AUC = 0.82 (0.78-0.86). LFSPRO also showed higher sensitivity and specificity than the classic LFS and Chompret criteria. LFSPRO is freely available through the R packages LFSPRO and BayesMendel.
LFSPRO shows good performance in predicting
mutations in individuals and families in varied situations.
LFSPRO is more broadly applicable than the current clinical criteria and may improve clinical management for individuals and families with LFS.
.
Age is one of the most important risk factors for the development of breast cancer. Nearly a third of all breast cancer cases occur in older women (aged ≥70 years), with most cases being oestrogen ...receptor-positive (ER+). Such tumours are often indolent and unlikely to be the ultimate cause of death for older women, particularly when considering other comorbidities. This Review focuses on unique clinical considerations for screening, detection, and treatment regimens for older women who develop ER+ breast cancers—specifically, we focus on recent trends for de-implementation of screening, staging, surgery, and adjuvant therapies along the continuum of care. Additionally, we also review emerging basic and translational research that will further uncover the unique underlying biology of these tumours, which develop in the context of systemic age-related inflammation and changing hormone profiles. With prevailing trends of clinical de-implementation, new insights into mechanistic biology might provide an opportunity for precision medicine approaches to treat patients with well tolerated, low-toxicity agents to extend patients’ lives with a higher quality of life, prevent tumour recurrences, and reduce cancer-related burdens.
Objective: Female BRCA1/2 mutation carriers are at increased risk of breast and ovarian cancer. Annual breast and semiannual ovarian cancer screening is recommended for early detection, which ...frequently leads to false-positive test results (FPTR). FPTR may influence cancer risk perceptions and worry, which in turn may affect an individual's decision to undergo risk-reducing bilateral salpingo-oophorectomy (RRSO) or risk-reducing bilateral mastectomy (RRBM). The purpose of this study was to examine: (a) the effect of false-positive breast and ovarian cancer screening test results on perceived cancer risk and cancer worry, and (b) the joint effects of FPTR, risk perceptions, and worry on the choice of risk-reducing surgery among BRCA1/2 mutation carriers undergoing an intensive cancer screening protocol. Method: BRCA1/2 mutation carriers (N = 170) reported cancer risk perceptions and cancer worry during a prospective 4-year screening protocol (2001-2007) at the U.S. National Cancer Institute. FPTR and risk-reducing surgeries were objectively recorded. Results: FPTR at baseline were associated with transient elevations in worry; cumulative FPTR across the entire study were not associated with opting for risk-reducing surgery. However, cancer-specific worry was a strong predictor of surgery (RRSO: OR = 6.15; RRBM: OR = 4.27). Conclusions: In women at inherited risk of breast and ovarian cancer, FPTR were not associated with large increases in cancer risk perception, cancer worry, or increased uptake of risk-reducing surgery. However, cancer-specific worry was an independent predictor of uptake of risk-reducing surgery and warrants consideration when counseling high-risk women regarding risk-reducing interventions.
Reply to m.j. Mourits et Al Sherman, Mark E; Piedmonte, Marion; Mai, Phuong L ...
Journal of clinical oncology,
2015-May-01, 2015-05-01, 20150501, Letnik:
33, Številka:
13
Journal Article
Hematopoietic stem cell (HSC) function is regulated by activation of receptor tyrosine kinases (RTKs). Receptor protein tyrosine phosphatases (PTPs) counterbalance RTK signaling; however, the ...functions of receptor PTPs in HSCs remain incompletely understood. We found that a receptor PTP, PTPσ, was substantially overexpressed in mouse and human HSCs compared with more mature hematopoietic cells. Competitive transplantation of bone marrow cells from PTPσ-deficient mice revealed that the loss of PTPσ substantially increased long-term HSC-repopulating capacity compared with BM cells from control mice. While HSCs from PTPσ-deficient mice had no apparent alterations in cell-cycle status, apoptosis, or homing capacity, these HSCs exhibited increased levels of activated RAC1, a RhoGTPase that regulates HSC engraftment capacity. shRNA-mediated silencing of PTPσ also increased activated RAC1 levels in wild-type HSCs. Functionally, PTPσ-deficient BM cells displayed increased cobblestone area-forming cell (CAFC) capacity and augmented transendothelial migration capacity, which was abrogated by RAC inhibition. Specific selection of human cord blood CD34⁺CD38⁻CD45RA⁻lin⁻ PTPσ⁻ cells substantially increased the repopulating capacity of human HSCs compared with CD34⁺CD38⁻CD45RA⁻lin⁻ cells and CD34⁺CD38⁻CD45RA⁻lin⁻PTPσ⁺ cells. Our results demonstrate that PTPσ regulates HSC functional capacity via RAC1 inhibition and suggest that selecting for PTPσ-negative human HSCs may be an effective strategy for enriching human HSCs for transplantation.
This study presents findings of a mixed-method descriptive exploration of the role of friends and spirituality/religiosity in easing the burden of families with the rare inherited disorder, ...Li-Fraumeni Syndrome (LFS). LFS is caused by germline mutations in the
TP53
gene and is associated with very high lifetime risk of developing one or more malignancies. During the first clinical visit we assessed several types of social support among a subset of study participants (
N
= 66) using an established interactive research tool called the Colored Eco-Genetic Relationship Map (CEGRM). We performed both quantitative and qualitative analyses of social relationships with LFS family members and close non-kin. Distress scores (
N
= 59) were mostly low normal, with some outliers. We found that reported friendships varied widely, that the friendships were often deep and enduring, and were important sources of informational, tangible, emotional and spiritual support. Confidantes tended to be best friends and/or spouses. Organized religion was important in selected families, typically from mainstream traditions. However, a number of people identified themselves as “spiritual” and reported spiritual and humanist explorations. Our results shed preliminary light on how some people in families with LFS cope in the face of tremendous medical, social and emotional challenges.
The recognition that a significant fraction of what historically has been classified as ovarian cancer is, in fact, a malignancy that arises in the fallopian tube mucosa comprises a paradigm shift in ...our understanding of these neoplasms. New etiologic and management opportunities have been created by this insight, both for women at increased genetic risk of ovarian cancer by virtue of being BRCA1/2 mutation carriers and, perhaps, for women in the general population as well.
Familial testicular germ cell tumours Kratz, Christian P., MD; Mai, Phuong L., MD; Greene, Mark H., MD
Best Practice & Research Clinical Endocrinology & Metabolism,
06/2010, Letnik:
24, Številka:
3
Journal Article
Recenzirano
Odprti dostop
This article defines familial testicular germ cell tumours (FTGCTs) as testicular germ cell tumours (TGCTs) diagnosed in at least two blood relatives, a situation which occurs in 1–2% of all cases of ...TGCT. Brothers and fathers of TGCT patients have an 8–10- and 4–6-fold increased risk of TGCT, respectively, and an even higher elevated risk of TGCT in twin brothers of men with TGCT has been observed, suggesting that genetic elements play an important role in these tumours. Nevertheless, previous linkage studies with multiple FTGCT families did not uncover any high-penetrance genes and it has been concluded that the combined effects of multiple common alleles, each conferring a modest risk, might underlie FTGCT. In agreement with this assumption, recent candidate gene-association analyses have identified the chromosome Y gr/gr deletion and mutations in the PDE11A gene as genetic modifiers of FTGCT risk. Moreover, two genome-wide association studies of predominantly sporadic but also familial cases of TGCT have identified three additional susceptibility loci, KITLG , SPRY4 and BAK1 . Notably, all five loci are involved in the biology of primordial germ cells, representing the cell of origin of TGCT, suggesting that the tumours arise as a result of disturbed testicular development.
PDF
