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2.
Ned Tijdschr Geneeskd ; 1632019 May 31.
Artigo em Holandês | MEDLINE | ID: mdl-31187964

RESUMO

OBJECTIVE: This survey explores the degree of consensus amongst healthcare professionals for the support of cancer patients' lifestyle management, based on three questions posed to them: a) what do they know about the relation between lifestyle and cancer?; b) do they consider lifestyle support for cancer patients part of their professional role?; c) does their own lifestyle influence the lifestyle management consultations they may have with cancer patients? Design Survey study. METHOD: A digital questionnaire with questions concerning lifestyle and cancer was sent to 1550 healthcare professionals in and around Nijmegen. The questionnaire was filled out by 562 healthcare professionals (36% response rate), of whom 404 (72%) were involved in cancer patient care. This cohort of responders consisted of 170 medical specialists, 62 general practitioners, and 172 nurses and allied health professionals. RESULTS: Healthcare professionals acknowledge the influence of lifestyle on the development of cancer. Almost all healthcare professionals (98%) agree on the positive effects of a healthy lifestyle on the well-being of cancer patients. Approximately two-thirds of all responders believe that lifestyle support should 'usually' or 'always' form part of cancer care; about fifty percent report to implement this in clinical practice. Healthcare professionals require evidence-based knowledge concerning the relationship between lifestyle and cancer, patient information materials, and additional consultation time to support lifestyle management involving cancer patients. The healthcare professionals' own lifestyle appears to have an influence: in those responders who do not adhere to a healthy lifestyle themselves, lifestyle was also covered less in consultations. CONCLUSION: This explorative survey shows that lifestyle support of cancer patients is deemed an important topic amongst healthcare professionals.

3.
J Med Genet ; 56(9): 581-589, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31186341

RESUMO

BACKGROUND: The currently known breast cancer-associated single nucleotide polymorphisms (SNPs) are presently not used to guide clinical management. We explored whether a genetic test that incorporates a SNP-based polygenic risk score (PRS) is clinically meaningful in non-BRCA1/2 high-risk breast cancer families. METHODS: 101 non-BRCA1/2 high-risk breast cancer families were included; 323 cases and 262 unaffected female relatives were genotyped. The 161-SNP PRS was calculated and standardised to 327 population controls (sPRS). Association analysis was performed using a Cox-type random effect regression model adjusted by family history. Updated individualised breast cancer lifetime risk scores were derived by combining the Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm breast cancer lifetime risk with the effect of the sPRS. RESULTS: The mean sPRS for cases and their unaffected relatives was 0.70 (SD=0.9) and 0.53 (SD=0.9), respectively. A significant association was found between sPRS and breast cancer, HR=1.16, 95% CI 1.03 to 1.28, p=0.026. Addition of the sPRS to risk prediction based on family history alone changed screening recommendations in 11.5%, 14.7% and 19.8 % of the women according to breast screening guidelines from the USA (National Comprehensive Cancer Network), UK (National Institute for Health and Care Excellence and the Netherlands (Netherlands Comprehensive Cancer Organisation), respectively. CONCLUSION: Our results support the application of the PRS in risk prediction and clinical management of women from genetically unexplained breast cancer families.

4.
J Natl Cancer Inst ; 2019 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-31076742

RESUMO

BACKGROUND: Women with epithelial ovarian cancer (OC) have a higher chance to benefit from PARP inhibitor (PARPi) therapy if their tumor has a somatic or hereditary BRCA1/2 pathogenic variant. Current guidelines advise BRCA1/2 genetic predisposition testing for all OC patients, though this does not detect somatic variants. We assessed the feasibility of a workflow for universal tumor DNA BRCA1/2 testing of all newly diagnosed OC patients as prescreen for PARPi treatment and cancer predisposition testing. METHODS: Formalin fixed paraffin embedded (FFPE) tissue was obtained from OC patients in seven hospitals, immediately after diagnosis or primary surgery. DNA was extracted and universal tumor BRCA1/2 testing was then performed in a single site. Diagnostic yield, uptake, referral rates for genetic predisposition testing, and experiences of patients and gynecologists were evaluated. RESULTS: Tumor BRCA1/2 testing was performed for 315 (77.6%) of the 406 eligible OC samples, of which 305 (96.8%) were successful. In 51 of these patients pathogenic variants were detected (16.7%). Most patients (88.2%) went on to have a genetic predisposition test. BRCA1/2 pathogenic variants were shown to be hereditary in 56.8% and somatic in 43.2% patients. Participating gynecologists and patients were overwhelmingly positive about the workflow. CONCLUSIONS: Universal tumor BRCA1/2 testing in all newly diagnosed OC patients is feasible, effective and appreciated by patients and gynecologists. Because many variants cannot be detected in DNA from blood, testing tumor DNA as the first step can double the identification rate of patients who stand to benefit most from PARP inhibitors.

5.
Ned Tijdschr Geneeskd ; 1632019 May 20.
Artigo em Holandês | MEDLINE | ID: mdl-31140768

RESUMO

Genetic testing in patients with cancer; new developments About 5% of patients with cancer have a causative germline mutation. When a germline mutation is detected, this may have major implications for treatment and follow-up of the patient, as well as for relatives who are at risk of carrying the mutation. Increasingly, DNA-testing of tumor tissue is being performed to identify potential druggable targets, aiming at personalized medicine. Both germline testing and tissue testing may have consequences for the patient, for treatment and for family members. Currently there is a trend towards mainstreaming of genetic testing, which implies that treating physicians will increasingly be the ones to order DNA tests. This implies that they need to be aware of the (family) consequences and pitfalls of genetic testing. It calls for close collaboration between clinical genetics and regional treating physicians, and adequate referral of patients with abnormal DNA results and those with other clues for a genetic predisposition. The aim being optimal tailored treatment for each patient and adequate cancer prevention for their relatives.

6.
Am J Hum Genet ; 104(4): 758-766, 2019 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-30929739

RESUMO

By using exome sequencing and a gene matching approach, we identified de novo and inherited pathogenic variants in KDM3B in 14 unrelated individuals and three affected parents with varying degrees of intellectual disability (ID) or developmental delay (DD) and short stature. The individuals share additional phenotypic features that include feeding difficulties in infancy, joint hypermobility, and characteristic facial features such as a wide mouth, a pointed chin, long ears, and a low columella. Notably, two individuals developed cancer, acute myeloid leukemia and Hodgkin lymphoma, in childhood. KDM3B encodes for a histone demethylase and is involved in H3K9 demethylation, a crucial part of chromatin modification required for transcriptional regulation. We identified missense and truncating variants, suggesting that KDM3B haploinsufficiency is the underlying mechanism for this syndrome. By using a hybrid facial-recognition model, we show that individuals with a pathogenic variant in KDM3B have a facial gestalt, and that they show significant facial similarity compared to control individuals with ID. In conclusion, pathogenic variants in KDM3B cause a syndrome characterized by ID, short stature, and facial dysmorphism.

7.
Int J Cancer ; 145(4): 941-951, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-30694527

RESUMO

Two percent of patients with Wilms tumors have a positive family history. In many of these cases the genetic cause remains unresolved. By applying germline exome sequencing in two families with two affected individuals with Wilms tumors, we identified truncating mutations in TRIM28. Subsequent mutational screening of germline and tumor DNA of 269 children affected by Wilms tumor was performed, and revealed seven additional individuals with germline truncating mutations, and one individual with a somatic truncating mutation in TRIM28. TRIM28 encodes a complex scaffold protein involved in many different processes, including gene silencing, DNA repair and maintenance of genomic integrity. Expression studies on mRNA and protein level showed reduction of TRIM28, confirming a loss-of-function effect of the mutations identified. The tumors showed an epithelial-type histology that stained negative for TRIM28 by immunohistochemistry. The tumors were bilateral in six patients, and 10/11 tumors are accompanied by perilobar nephrogenic rests. Exome sequencing on eight tumor DNA samples from six individuals showed loss-of-heterozygosity (LOH) of the TRIM28-locus by mitotic recombination in seven tumors, suggesting that TRIM28 functions as a tumor suppressor gene in Wilms tumor development. Additionally, the tumors showed very few mutations in known Wilms tumor driver genes, suggesting that loss of TRIM28 is the main driver of tumorigenesis. In conclusion, we identified heterozygous germline truncating mutations in TRIM28 in 11 children with mainly epithelial-type Wilms tumors, which become homozygous in tumor tissue. These data establish TRIM28 as a novel Wilms tumor predisposition gene, acting as a tumor suppressor gene by LOH.

8.
Oncogene ; 38(19): 3743-3755, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30670777

RESUMO

PTEN hamartoma tumor syndrome (PHTS) is caused by inactivating germline PTEN mutations with subsequent activation of Akt-mTOR signaling, leading to an increased risk of developing thyroid carcinoma (TC). Activation of Akt-mTOR signaling is essential for innate immune cell activation and reprogramming of TC-induced macrophages. Here, we aim to assess the effect of PTEN mutations on innate immune cell function in PHTS patients, especially in the context of TC, using a unique ex vivo model. Monocyte-derived cytokine responses were assessed in 29 PHTS patients and 29 controls. To assess the functional profile of TC-induced-macrophages, a co-culture model with two TC cell lines was performed. Rapamycin, a lactate transport blocker and metformin were used as modulators of the Akt-mTOR pathway and cell metabolism. Monocytes from PHTS patients showed increased production of IL-6, TNF-α, IL-8 and MCP-1, and higher lactate production. After co-culture with TC cell lines, TC-induced macrophages showed significantly increased production of cytokines in both patients and controls, especially after co-culture with a PTEN-deficient TC cell line; these effects were abolished after use of rapamycin or a lactate transport blocker. Metformin blocked the production of anti-inflammatory cytokines. In conclusion, innate immune cells from PHTS patients have increased lactate production and a more proinflammatory phenotype, especially after co-culture with PTEN-deficient TC. Metformin promotes a proinflammatory phenotype by blocking anti-inflammatory cytokine response, whereas rapamycin reduces production of proinflammatory cytokines. This indicates that PHTS patients may benefit from treatment with mTOR blocking agents to limit the inflammatory response in the tumor microenvironment.

9.
Transl Oncol ; 12(2): 361-367, 2018 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-30504085

RESUMO

Carriers of a pathogenic germline mutations in the PTEN gene, a well-known tumor suppressor gene, are at increased risk of multiple benign and malignant tumors, e.g. breast, thyroid, endometrial and colon cancer. This is called PTEN Hamartomous Tumor Syndrome (PHTS). PHTS patients may also have an increased risk of immunological dysregulation, such as autoimmunity and immune deficiencies. The effects of PTEN on the immune system have been studied in murine knockout models demonstrating that loss of PTEN function leads to dysregulation of the immune response. This results in susceptibility to autoimmunity, impaired B cell class switching with subsequent hypogammaglobulinemia. Additionally, a decreased ability of dendritic cells to prime CD8+ T cells was observed, leading to impaired tumor eradication. Immune dysfunction in PHTS patients has not yet been extensively studied but might be a manageable contributing factor to the increased cancer risk in PHTS.

10.
Fam Cancer ; 2018 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-30302652

RESUMO

Approximately 27-36 million patients in Europe have one of the ~ 5.000-8.000 known rare diseases. These patients often do not receive the care they need or they have a substantial delay from diagnosis to treatment. In March 2017, twenty-four European Reference Networks (ERNs) were launched with the aim to improve the care for these patients through cross border healthcare, in a way that the medical knowledge and expertise travels across the borders, rather than the patients. It is expected that through the ERNs, European patients with a rare disease get access to expert care more often and more quickly, and that research and guideline development will be accelerated resulting in improved diagnostics and therapies. The ERN on Genetic Tumour Risk Syndromes (ERN GENTURIS) aims to improve the identification, genetic diagnostics, prevention of cancer, and treatment of European patients with a genetic predisposition for cancer. The ERN GENTURIS focuses on syndromes such as hereditary breast cancer, hereditary colorectal cancer and polyposis, neurofibromatosis and more rare syndromes e.g. PTEN Hamartoma Tumour Syndrome, Li Fraumeni Syndrome and hereditary diffuse gastric cancer.

11.
Acta Oncol ; : 1-7, 2018 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-30334464

RESUMO

BACKGROUND: Genetic testing is increasing in patients newly diagnosed with cancer. This study investigated the levels, course and predictors of cancer-related distress, defined as intrusion and avoidance, in women undergoing BRCA1/2 testing without pretest genetic counseling shortly after a diagnosis of breast or ovarian cancer. MATERIAL AND METHODS: Unselected for family history or age, 259 women with breast cancer and 50 women with ovarian cancer, underwent BRCA1/2 testing shortly after diagnosis. Cancer-related distress was measured with the Impact of Event Scale before and after genetic testing. In order to identify predictors of distress, the subscale scores were regressed on baseline predictor variables including sociodemographic and medical variables, perceived social support, and decisional conflict regarding genetic testing. RESULTS: The mean levels of intrusion and avoidance were in the moderate range both before and after genetic testing with a statistically significant decline during follow-up. Younger age, shorter time since diagnosis, lower levels of social support, and a diagnosis of ovarian cancer predicted higher levels of both intrusion and avoidance. In addition, higher levels of decisional conflict and living with a partner predicted higher levels of intrusion. CONCLUSIONS: Women having genetic testing shortly after a diagnosis of breast or ovarian cancer had a moderate mean level of cancer-related distress, which decreased with time. Health personnel offering genetic testing to newly diagnosed women with breast or ovarian cancer should be aware of the potential predictors for increased cancer-related distress identified in this study: younger age, less perceived social support, higher levels of decisional conflict regarding genetic testing, and living with a partner.

12.
Breast Cancer Res ; 20(1): 84, 2018 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-30075794

RESUMO

BACKGROUND: Breast magnetic resonance imaging (MRI) is the most sensitive imaging method for breast cancer detection and is therefore offered as a screening technique to women at increased risk of developing breast cancer. However, mammography is currently added from the age of 30 without proven benefits. The purpose of this study is to investigate the added cancer detection of mammography when breast MRI is available, focusing on the value in women with and without BRCA mutation, and in the age groups above and below 50 years. METHODS: This retrospective single-center study evaluated 6553 screening rounds in 2026 women at increased risk of breast cancer (1 January 2003 to 1 January 2014). Risk category (BRCA mutation versus others at increased risk of breast cancer), age at examination, recall, biopsy, and histopathological diagnosis were recorded. Cancer yield, false positive recall rate (FPR), and false positive biopsy rate (FPB) were calculated using generalized estimating equations for separate age categories (< 40, 40-50, 50-60, ≥ 60 years). Numbers of screens needed to detect an additional breast cancer with mammography (NSN) were calculated for the subgroups. RESULTS: Of a total of 125 screen-detected breast cancers, 112 were detected by MRI and 66 by mammography: 13 cancers were solely detected by mammography, including 8 cases of ductal carcinoma in situ. In BRCA mutation carriers, 3 of 61 cancers were detected only on mammography, while in other women 10 of 64 cases were detected with mammography alone. While 77% of mammography-detected-only cancers were detected in women ≥ 50 years of age, mammography also added more to the FPR in these women. Below 50 years the number of mammographic examinations needed to find an MRI-occult cancer was 1427. CONCLUSIONS: Mammography is of limited added value in terms of cancer detection when breast MRI is available for women of all ages who are at increased risk. While the benefit appears slightly larger in women over 50 years of age without BRCA mutation, there is also a substantial increase in false positive findings in these women.

13.
J Clin Oncol ; 36(29): 2961-2968, 2018 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-30161022

RESUMO

PURPOSE: Lynch syndrome due to pathogenic variants in the DNA mismatch repair genes MLH1, MSH2, and MSH6 is predominantly associated with colorectal and endometrial cancer, although extracolonic cancers have been described within the Lynch tumor spectrum. However, the age-specific cumulative risk (penetrance) of these cancers is still poorly defined for PMS2-associated Lynch syndrome. Using a large data set from a worldwide collaboration, our aim was to determine accurate penetrance measures of cancers for carriers of heterozygous pathogenic PMS2 variants. METHODS: A modified segregation analysis was conducted that incorporated both genotyped and nongenotyped relatives, with conditioning for ascertainment to estimates corrected for bias. Hazard ratios (HRs) and corresponding 95% CIs were estimated for each cancer site for mutation carriers compared with the general population, followed by estimation of penetrance. RESULTS: In total, 284 families consisting of 4,878 first- and second-degree family members were included in the analysis. PMS2 mutation carriers were at increased risk for colorectal cancer (cumulative risk to age 80 years of 13% [95% CI, 7.9% to 22%] for males and 12% [95% CI, 6.7% to 21%] for females) and endometrial cancer (13% [95% CI, 7.0%-24%]), compared with the general population (6.6%, 4.7%, and 2.4%, respectively). There was no clear evidence of an increased risk of ovarian, gastric, hepatobiliary, bladder, renal, brain, breast, prostate, or small bowel cancer. CONCLUSION: Heterozygous PMS2 mutation carriers were at small increased risk for colorectal and endometrial cancer but not for any other Lynch syndrome-associated cancer. This finding justifies that PMS2-specific screening protocols could be restricted to colonoscopies. The role of risk-reducing hysterectomy and bilateral salpingo-oophorectomy for PMS2 mutation carriers needs further discussion.

14.
Eur J Hum Genet ; 26(10): 1417-1423, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29904176

RESUMO

Constitutional MisMatch Repair Deficiency (CMMRD) is caused by homozygous or compound heterozygous germline variants in one of the mismatch repair (MMR) genes (MSH2, MSH6, PMS2, MLH1). This syndrome results in early onset colorectal cancer, leukemia and lymphoma, brain tumors and other malignancies. Children with CMMRD are at high risk of developing multiple cancers and cancer surveillance does not guarantee detection of cancer at a curable stage. The development of a preventive treatment strategy would be a major step forward. Long-term daily use of acetylsalicylic acid (ASA) has been shown to reduce cancer risk in individuals with Lynch syndrome (LS). LS is caused by heterozygous germline variants of MSH2, MSH6, PMS2 and MLH1 and characterized by an increased risk of developing colorectal and endometrial cancer at adult age. Here we discuss the potential use of ASA for cancer prevention in patients with CMMRD.

15.
Clin Cancer Res ; 24(7): 1594-1603, 2018 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-29351919

RESUMO

Purpose: In many children with cancer and characteristics suggestive of a genetic predisposition syndrome, the genetic cause is still unknown. We studied the yield of pathogenic mutations by applying whole-exome sequencing on a selected cohort of children with cancer.Experimental Design: To identify mutations in known and novel cancer-predisposing genes, we performed trio-based whole-exome sequencing on germline DNA of 40 selected children and their parents. These children were diagnosed with cancer and had at least one of the following features: (1) intellectual disability and/or congenital anomalies, (2) multiple malignancies, (3) family history of cancer, or (4) an adult type of cancer. We first analyzed the sequence data for germline mutations in 146 known cancer-predisposing genes. If no causative mutation was found, the analysis was extended to the whole exome.Results: Four patients carried causative mutations in a known cancer-predisposing gene: TP53 and DICER1 (n = 3). In another 4 patients, exome sequencing revealed mutations causing syndromes that might have contributed to the malignancy (EP300-based Rubinstein-Taybi syndrome, ARID1A-based Coffin-Siris syndrome, ACTB-based Baraitser-Winter syndrome, and EZH2-based Weaver syndrome). In addition, we identified two genes, KDM3B and TYK2, which are possibly involved in genetic cancer predisposition.Conclusions: In our selected cohort of patients, pathogenic germline mutations causative or likely causative of the cancer phenotype were found in 8 patients, and two possible novel cancer-predisposing genes were identified. Therewith, our study shows the added value of sequencing beyond a cancer gene panel in selected patients, to recognize childhood cancer predisposition. Clin Cancer Res; 24(7); 1594-603. ©2018 AACR.

16.
Cancer ; 124(5): 952-959, 2018 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-29315498

RESUMO

BACKGROUND: Risk-reducing salpingo-oophorectomy (RRSO) is recommended for BRCA1/2 mutation carriers because of their increased risk of ovarian carcinoma. Despite RRSO, metachronous peritoneal carcinomatosis occasionally is diagnosed. METHODS: The literature was searched for BRCA1/2 mutation carriers with peritoneal carcinomatosis after risk-reducing surgery. The authors were asked for additional data. Clinical and histopathological data were descriptively analyzed. Cases were compared with a single-institution control cohort. RESULTS: Of 36 cases, 86.1% concerned BRCA1 mutation carriers. The median age of the patients was 52 years (range, 30-71 years) at the time of risk-reducing surgery and 60 years (range, 37-75 years) at the time of diagnosis of peritoneal carcinomatosis. The median interval between the 2 events was 54.5 months (range, 11-292 months). Peritoneal carcinomatosis was mostly high-grade serous carcinoma. Histopathological details of the RRSO specimens were retrieved in 8 cases; 5 (62.5%) were found to have serous tubal intraepithelial carcinoma and 1 had epithelial atypia. Cases were older (P = .025) at the time of risk-reducing surgery and harbored more serous tubal intraepithelial carcinomas (P<.001) compared with women from the control cohort. CONCLUSIONS: Metachronous peritoneal carcinomatosis after risk-reducing surgery occurs predominantly in BRCA1 mutation carriers, usually within 5 years. Data have suggested that surgery at a younger age lowers the rates of peritoneal carcinomatosis. These data can be used in the gynecologic counseling of BRCA1/2 mutation carriers. RRSO should include complete salpingectomy. Detailed histopathological examination of specimens removed during RRSO is essential. Cancer 2018;124:952-9. © 2018 American Cancer Society.

17.
J Med Genet ; 55(10): 669-674, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29330337

RESUMO

BACKGROUND: In approximately 10% of all gastric cancer (GC) cases, a heritable cause is suspected. A subset of these cases have a causative germline CDH1 mutation; however, in most cases the cause remains unknown. Our objective was to assess to what extent these remaining cases may be explained by germline mutations in the novel candidate GC predisposing genes CTNNA1, MAP3K6 or MYD88. METHODS: We sequenced a large cohort of unexplained young and/or familial patients with GC (n=286) without a CDH1germline mutation for germline variants affecting CTNNA1, MAP3K6 and MYD88 using a targeted next-generation sequencing approach based on single-molecule molecular inversion probes. RESULTS: Predicted deleterious germline variants were not encountered in MYD88, but recurrently observed in CTNNA1 (n=2) and MAP3K6 (n=3) in our cohort of patients with GC. In contrast to deleterious variants in CTNNA1, deleterious variants in MAP3K6 also occur frequently in the general population. CONCLUSIONS: Based on our results MAP3K6 should no longer be considered a GC predisposition gene, whereas deleterious CTNNA1 variants are confirmed as an infrequent cause of GC susceptibility. Biallelic MYD88 germline mutations are at most a very rare cause of GC susceptibility as no additional cases were identified.

18.
Maturitas ; 108: 13-17, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29290209

RESUMO

OBJECTIVES: To reduce the risk of ovarian cancer, BRCA1/2 mutation carriers are advised to undergo salpingo-oophorectomy (RRSO) around the age of 40 years. This may induce severe climacteric symptoms, potentially lowering their quality of life. Personal positive resources such as physical fitness and self-compassion may help women to deal with these symptoms. We investigated the association of climacteric symptoms with self-compassion and physical fitness in oophorectomized BRCA1/2 mutation carriers. STUDY DESIGN: A cross-sectional study was conducted in 165 BRCA1/2 mutation carriers, aged 40-63 years, who underwent an RRSO at age 45 years or younger and at least 5 years previously. MAIN OUTCOME MEASURES: Climacteric symptoms were measured by the Greene Climacteric Scale. Self-compassion was rated using the Self-Compassion Scale-Short Form, and physical fitness using the Duke Activity Status Index. RESULTS: BRCA1/2 mutation carriers reported low levels of climacteric symptoms (mean 10.28 [SD 6.45], and being highly self-compassionate and physically fit. After adjustment for possible covariates, higher self-compassion (ß=-1.65, 95% CI -2.46, -0.84) and physical fitness (ß=-0.25, 95% CI -0.34, -0.16) were associated with fewer climacteric symptoms. Current smoking was independently associated with more climacteric symptoms (ß=2.66, 95% CI 0.26, 5.07). CONCLUSIONS: Being self-compassionate and physically fit were associated with fewer climacteric symptoms. Future research is needed to investigate the effect of training in self-compassion and physical fitness on climacteric symptoms in BRCA1/2 mutation carriers.


Assuntos
Empatia , Menopausa/fisiologia , Ovariectomia , Aptidão Física , Adulto , Estudos Transversais , Feminino , Genes BRCA1 , Genes BRCA2 , Humanos , Pessoa de Meia-Idade , Mutação , Neoplasias Ovarianas/prevenção & controle , Qualidade de Vida , Risco
19.
J Pathol ; 244(2): 135-142, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29105096

RESUMO

It is now well established that germline genomic aberrations can underlie high-penetrant familial polyposis and colorectal cancer syndromes, but a genetic cause has not yet been found for the major proportion of patients with polyposis. Since next-generation sequencing has become widely accessible, several novel, but rare, high-penetrant risk factors for adenomatous polyposis have been identified, all operating in pathways responsible for genomic maintenance and DNA repair. One of these is the base excision repair pathway. In addition to the well-established role of the DNA glycosylase gene MUTYH, biallelic mutations in which predispose to MUTYH-associated polyposis, a second DNA glycosylase gene, NTHL1, has recently been associated with adenomatous polyposis and a high colorectal cancer risk. Both recessive polyposis syndromes are associated with increased risks for several other cancer types as well, but the spectrum of benign and malignant tumours in individuals with biallelic NTHL1 mutations was shown to be broader; hence the name NTHL1-associated tumour syndrome. Colorectal tumours encountered in patients with these syndromes show unique, clearly distinct mutational signatures that may facilitate the identification of these syndromes. On the basis of the prevalence of pathogenic MUTYH and NTHL1 variants in the normal population, we estimate that the frequency of the novel NTHL1-associated tumour syndrome is five times lower than that of MUTYH-associated polyposis. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

20.
Health Expect ; 21(3): 659-667, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29281161

RESUMO

BACKGROUND: BRCA1/2 mutation carriers' choice between risk-reducing salpingo-oophorectomy (RRSO) and salpingectomy with delayed oophorectomy is very complex. Aim was to develop a patient decision aid that combines evidence with patient preferences to facilitate decision making. DESIGN: Systematic development of a patient decision aid in an iterative process of prototype development, alpha testing by patients and clinicians and revisions using International Patient Decision Aid Standards (IPDAS) quality criteria. Information was based on the available literature and current guidelines. A multidisciplinary steering group supervised the process. SETTING AND PARTICIPANTS: Pre-menopausal BRCA1/2 mutation carriers choosing between RRSO and salpingectomy with delayed oophorectomy in Family Cancer Clinics in the Netherlands. MAIN OUTCOME MEASURES: IPDAS quality criteria, relevance, usability, clarity. RESULTS: The patient decision aid underwent four rounds of alpha testing and revisions. Finally, two paper decision aids were developed: one for BRCA1 and one for BRCA2. They both contained a general introduction, three chapters and a step-by-step plan containing a personal value clarification worksheet. During alpha testing, risk communication and information about premature menopause and hormone therapy were the most revised items. The patient decision aids fulfil 37 of 43 (86%) IPDAS criteria for content and development process. DISCUSSION AND CONCLUSIONS: Both BRCA1/2 mutation carriers and professionals are willing to use or offer the developed patient decision aids for risk-reducing surgery. The patient decision aids have been found clear, balanced and comprehensible. Future testing among patients facing the decision should point out its effectiveness in improving decision making.

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