Risk-reducing salpingo-oophorectomy (RRSO) lowers mortality from ovarian/tubal and breast cancers among BRCA1/2 mutation carriers. Uncertainties persist regarding potential benefits of RRSO among ...high-risk noncarriers, optimal surgical age, and anatomic origin of clinically occult cancers detected at surgery. To address these topics, we analyzed surgical treatment arm results from Gynecologic Oncology Group Protocol-0199 (GOG-0199), the National Ovarian Cancer Prevention and Early Detection Study.
This analysis included asymptomatic high-risk women age ≥ 30 years who elected RRSO at enrollment. Women provided risk factor data and underwent preoperative cancer antigen 125 (CA-125) serum testing and transvaginal ultrasound (TVU). RRSO specimens were processed according to a standardized tissue processing protocol and underwent central pathology panel review. Research-based BRCA1/2 mutation testing was performed when a participant's mutation status was unknown at enrollment. Relationships between participant characteristics and diagnostic findings were assessed using univariable statistics and multivariable logistic regression.
Invasive or intraepithelial ovarian/tubal/peritoneal neoplasms were detected in 25 (2.6%) of 966 RRSOs (BRCA1 mutation carriers, 4.6%; BRCA2 carriers, 3.5%; and noncarriers, 0.5%; P < .001). In multivariable models, positive BRCA1/2 mutation status (P = .0056), postmenopausal status (P = .0023), and abnormal CA-125 levels and/or TVU examinations (P < .001) were associated with detection of clinically occult neoplasms at RRSO. For 387 women with negative BRCA1/2 mutation testing and normal CA-125 levels, findings at RRSO were benign.
Clinically occult cancer was detected among 2.6% of high-risk women undergoing RRSO. BRCA1/2 mutation, postmenopausal status, and abnormal preoperative CA-125 and/or TVU were associated with cancer detection at RRSO. These data can inform management decisions among women at high risk of ovarian/tubal cancer.
Young women who have been identified as carrying a deleterious mutation in BRCA1 or BRCA2 face a unique set of challenges related to managing cancer risk during a demographically-dense stage of life. ...They may struggle with decision-making in the absence of clear age-specific guidelines for medical management and because they have not yet fully developed the capacity to make life-altering decisions confidently. This study sought a patient-centered perspective on the dilemmas faced by 18-24 year olds who completed BRCA1/2 gene mutation testing prior to their 25(th) birthdays.
This study integrated qualitative data from three independent investigations of BRCA1/2-positive women recruited through cancer risk clinics, hospital-based research centers, and online organizations. All 32 participants were women aged 21-25 who tested positive for a BRCA1/2 gene mutation between 2 and 60 months prior to data collection. Investigators used techniques of grounded theory and interpretive description to conduct both within and cross-study analysis.
Participants expressed needs for (1) greater clarity in recommendations for screening and prevention before age 25, especially with consideration of early and regular exposure to radiation associated with mammography or to hormones used in birth control, and (2) ongoing contact with providers to discuss risk management protocols as they become available.
Health care needs during the young adult years evolve with the cognitive capacity to address abrupt and pressing change. Specific needs of women in this population include a desire to balance autonomous decision-making with supportive guidance, a need for clear, accurate and consistent medical recommendations. Optimally, these women are best cared for by a team of genetically-oriented providers as part of a sustained program of ongoing support, rather than seen in an episodic, crisis-driven fashion. A discussion of insurance issues and provider-patient cultural differences is presented.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Women at familial/genetic ovarian cancer risk often undergo screening despite unproven efficacy. Research suggests each woman has her own CA125 baseline; significant increases above this level may ...identify cancers earlier than standard 6- to 12-monthly CA125 > 35 U/mL.
Data from prospective Cancer Genetics Network and Gynecologic Oncology Group trials, which screened 3,692 women (13,080 woman-screening years) with a strong breast/ovarian cancer family history or
mutations, were combined to assess a novel screening strategy. Specifically, serum CA125 q3 months, evaluated using a risk of ovarian cancer algorithm (ROCA), detected significant increases above each subject's baseline, which triggered transvaginal ultrasound. Specificity and positive predictive value (PPV) were compared with levels derived from general population screening (specificity 90%, PPV 10%), and stage-at-detection was compared with historical high-risk controls.
Specificity for ultrasound referral was 92% versus 90% (
= 0.0001), and PPV was 4.6% versus 10% (
> 0.10). Eighteen of 19 malignant ovarian neoplasms prevalent = 4, incident = 6, risk-reducing salpingo-oophorectomy (RRSO) = 9 were detected via screening or RRSO. Among incident cases (which best reflect long-term screening performance), three of six invasive cancers were early-stage (I/II; 50% vs. 10% historical
controls;
= 0.016). Six of nine RRSO-related cases were stage I. ROCA flagged three of six (50%) incident cases before CA125 exceeded 35 U/mL. Eight of nine patients with stages 0/I/II ovarian cancer were alive at last follow-up (median 6 years).
For screened women at familial/genetic ovarian cancer risk, ROCA q3 months had better early-stage sensitivity at high specificity, and low yet possibly acceptable PPV compared with CA125 > 35 U/mL q6/q12 months, warranting further larger cohort evaluation.
.
Myotonic dystrophy type I (DM1) is an autosomal dominant multisystem disorder characterized by myotonia and muscle weakness. Type 2 diabetes (T2D) and cancer have been shown to be part of the DM1 ...phenotype. Metformin, a well‐established agent for the management of T2D, is thought to have cancer‐preventive effects in the general population. In our study, we aimed to assess the association between T2D, metformin use and the risk of cancer in DM1 patients. We identified a cohort of 913 DM1 patients and an age‐, sex‐ and clinic‐matched cohort of 12,318 DM1‐free controls from the UK Clinical Practice Research Datalink, a large primary care records database. We used Cox regression models to assess cancer risk in T2D patients who were metformin users or nonusers compared to patients without T2D. Separate analyses were conducted for DM1 patients and controls. T2D was more prevalent in DM1 than in controls (8% vs. 3%, p < 0.0001). DM1 patients with T2D, compared to those without T2D, were more likely to develop cancer (hazard ratio HR = 3.60, 95% confidence interval CI = 1.18–10.97; p = 0.02), but not if they were treated with metformin (HR = 0.43, 95% CI = 0.06–3.35; p = 0.42). Among controls, we observed no significant associations between T2D and cancer risk in either users or nonusers of Metformin (HR = 1.28, 95% CI = 0.91–1.79; p = 0.16 and HR = 1.13, 95% CI = 0.72–1.79; p = 0.59, respectively). These results show an association between T2D and cancer risk in DM1 patients and may provide new insights into the possible benefits of Metformin use in DM1.
What's new?
Recent evidence suggests that myotonic dystrophy type I (DM1), an inherited nucleotide repeat disorder, is a cancer predisposition syndrome. However, the underlying pathological mechanisms and cancer‐predisposing risk factors remain unknown. Here, type 2 diabetes (T2D) and metformin were investigated for potential associations with cancer risk in DM1 patients. T2D was found to be more prevalent in DM1 patients than controls. DM1 patients with T2D were at increased risk of developing cancer. By contrast, cancer risk was not elevated in DM1‐T2D patients taking metformin. Further investigation of metformin use and cancer in DM1 patients could yield important insights into DM1‐related cancer prevention.
BRCA1, a well-known tumor suppressor with multiple interacting partners, is predicted to have diverse biological functions. However, so far its only well-established role is in the repair of damaged ...DNA and cell cycle regulation. In this regard, the etiopathological study of low-penetrant variants of BRCA1 provides an opportunity to uncover its other physiologically important functions. Using this rationale, we studied the R1699Q variant of BRCA1, a potentially moderate-risk variant, and found that it does not impair DNA damage repair but abrogates the repression of microRNA-155 (miR-155), a bona fide oncomir. Mechanistically, we found that BRCA1 epigenetically represses miR-155 expression via its association with HDAC2, which deacetylates histones H2A and H3 on the miR-155 promoter. We show that overexpression of miR-155 accelerates but the knockdown of miR-155 attenuates the growth of tumor cell lines in vivo. Our findings demonstrate a new mode of tumor suppression by BRCA1 and suggest that miR-155 is a potential therapeutic target for BRCA1-deficient tumors.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
ABSTRACT
Introduction: Recent studies have provided evidence that patients with myotonic dystrophy (DM) are at excess risk of cancer. However, inconsistencies regarding affected anatomic sites ...persist. Methods: We performed a meta‐analysis of cancer risk in DM, searching among studies published between January 1, 1990 and December 31, 2016. Eligible studies were full reports of DM cohorts with site‐specific risks. Results: The analysis included 5 studies, comprising 2,779 patients. Risk estimates for cancers of the endometrium and cutaneous melanoma were reported in all studies. The pooled standardized incidence ratio (pSIRs) for endometrial cancer was 7.48 (95% confidence interval CI 4.72–11.8) and for cutaneous melanoma was 2.45 (95% CI 1.31–4.58). Among cancers reported in 4 of 5 studies, elevated risks were observed for thyroid (pSIR = 8.52, 95% CI 3.62–20.1), ovarian (pSIR = 5.56, 95% CI 2.99–10.3), testicular (pSIR = 5.95, 95% CI 2.34–15.1), and colorectal (pSIR = 2.2, 95% CI 1.39–3.49) cancers. Discussion: Our data refine the DM cancer phenotype, which may guide patient clinical management and inform plans for molecular investigations to understand DM‐related carcinogenesis. Muscle Nerve 58: 517–522, 2018
The international Testicular Cancer Consortium (TECAC) combined five published genome-wide association studies of testicular germ cell tumor (TGCT; 3,558 cases and 13,970 controls) to identify new ...susceptibility loci. We conducted a fixed-effects meta-analysis, including, to our knowledge, the first analysis of the X chromosome. Eight new loci mapping to 2q14.2, 3q26.2, 4q35.2, 7q36.3, 10q26.13, 15q21.3, 15q22.31, and Xq28 achieved genome-wide significance (P < 5 × 10
). Most loci harbor biologically plausible candidate genes. We refined previously reported associations at 9p24.3 and 19p12 by identifying one and three additional independent SNPs, respectively. In aggregate, the 39 independent markers identified to date explain 37% of father-to-son familial risk, 8% of which can be attributed to the 12 new signals reported here. Our findings substantially increase the number of known TGCT susceptibility alleles, move the field closer to a comprehensive understanding of the underlying genetic architecture of TGCT, and provide further clues to the etiology of TGCT.
Risk-reducing salpingo-oophorectomy (RRSO) is the most definitive surgical intervention for ovarian cancer risk reduction among BRCA1/2 mutation carriers. For women who have completed child-bearing ...but who are not ready for RRSO, bilateral salpingectomy with ovarian retention (BSOR) might serve as a temporary measure while definitive risk-reducing surgery is being contemplated. Here we summarize recent insights into the pathogenesis of hereditary ovarian cancer that might provide a basis for consideration of the proposed BSOR management strategy and outline the evidence for and against this potential risk-reducing intervention. Based on the evidence, we suggest that there may be sufficient merit in this proposed intervention to consider evaluating it formally, perhaps through an intergroup-based clinical trial. In the meanwhile, we believe that BSOR should be considered an investigational risk management option of unproven clinical usefulness, particularly because delay in bilateral oophorectomy theoretically could reduce the protective effect against breast cancer that has been documented in women who have undergone RRSO.
Recent studies show that patients with myotonic dystrophy (DM) have an increased risk of specific malignancies, but estimates of absolute cancer risk accounting for competing events are lacking. ...Using the Swedish Patient Registry, we identified 1,081 patients with an inpatient and/or outpatient diagnosis of DM between 1987 and 2007. Date and cause of death and date of cancer diagnosis were extracted from the Swedish Cause of Death and Cancer Registries. We calculated non-parametric estimates of absolute cancer risk and cancer mortality accounting for the high non-cancer competing mortality associated with DM. Absolute cancer risk after DM diagnosis was 1.6% (95% CI=0.4-4%), 5% (95% CI=3-9%) and 9% (95% CI=6-13%) at ages 40, 50 and 60 years, respectively. Females had a higher absolute risk of all cancers combined than males: 9% (95% CI=4-14), and 13% (95% CI=9-20) vs. 2% (95%CI= 0.7-6) and 4% (95%CI=2-8) by ages 50 and 60 years, respectively) and developed cancer at younger ages (median age =51 years, range=22-74 vs. 57, range=43-84, respectively, p=0.02). Cancer deaths accounted for 10% of all deaths, with an absolute cancer mortality risk of 2% (95%CI=1-4.5%), 4% (95%CI=2-6%), and 6% (95%CI=4-9%) by ages 50, 60, and 70 years, respectively. No gender difference in cancer-specific mortality was observed (p=0.6). In conclusion, cancer significantly contributes to morbidity and mortality in DM patients, even after accounting for high competing DM mortality from non-neoplastic causes. It is important to apply population-appropriate, validated cancer screening strategies in DM patients.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
PDF
