RÉSUMÉ
BACKGROUND: Germline genetic testing, previously restricted to familial and young-onset breast cancer, is now offered increasingly broadly to patients with 'population-type' breast cancer in mainstream oncology clinics, with wide variation in the genes included. PATIENTS AND METHODS: Weighted meta-analysis was carried out for three population-based case-control studies (BRIDGES, CARRIERS and UK Biobank) comprising in total 101 397 women with breast cancer and 312 944 women without breast cancer, to quantify 37 putative breast cancer susceptibility genes (BCSGs) for the frequency of pathogenic variants (PVs) in unselected, 'population-type' breast cancer cases and their association with breast cancer and its subtypes. RESULTS: Meta-analysed odds ratios (ORs) and frequencies of PVs in 'population-type' breast cancer cases were generated for BRCA1 (OR 8.73, 95% confidence interval (CI) 7.47-10.20; 1 in 101), BRCA2 (OR 5.68, 95% CI 5.13-6.30; 1 in 68) and PALB2 (OR 4.30, 95% CI 3.68-5.03; 1 in 187). For both CHEK2 (OR 2.40, 95% CI 2.21-2.62; 1 in 73) and ATM (OR 2.16, 95% CI 1.93-2.41; 1 in 132) subgroup analysis showed a stronger association with oestrogen receptor-positive disease. The magnitude of association and frequency of PVs were low for RAD51C (OR 1.53, 95% CI 1.29-2.04; 1 in 913), RAD51D (OR 1.76, 95% CI 1.29-2.41; 1 in 1079) and BARD1 (OR 2.34, 95% CI 1.85-2.97; 1 in 672); frequencies and associations were higher when the analysis was restricted to triple-negative breast cancers. The PV frequency in 'population-type' breast cancer cases was very low for 'syndromic' BCSGs TP53 (1 in 1844), STK11 (1 in 11 525), CDH1 (1 in 2668), PTEN (1 in 3755) and NF1 (1 in 1470), with metrics of association also modest ranging from OR 3.62 (95% CI 1.98-6.61) for TP53 down to OR 1.60 (95% CI 0.48-5.30) for STK11. CONCLUSIONS: These metrics reflecting 'population-type' breast cancer will be informative in defining the appropriate gene set as we continue to expand to germline testing to an increasingly unselected group of breast cancer cases.
Sujet(s)
Tumeurs de la surrénale/génétique , Protocoles de polychimiothérapie antinéoplasique/usage thérapeutique , Phéochromocytome/traitement médicamenteux , Phéochromocytome/génétique , Succinate Dehydrogenase/génétique , Adolescent , Adulte , Sujet âgé , Enfant , Cyclophosphamide/usage thérapeutique , Dacarbazine/usage thérapeutique , Survie sans rechute , Femelle , Humains , Mâle , Adulte d'âge moyen , Mutation , Vincristine/usage thérapeutique , Jeune adulteRÉSUMÉ
Recent years have seen important advances in our understanding of the etiology, biology and genetics of kidney cancer. To summarize important achievements and identify prominent research questions that remain, a workshop was organized by IARC and the US NCI. A series of 'difficult questions' were formulated, which should be given future priority in the areas of population, genomic and clinical research.
Sujet(s)
Génomique , Tumeurs du rein/génétique , Recherche biomédicale , Humains , Tumeurs du rein/étiologie , Tumeurs du rein/anatomopathologieRÉSUMÉ
An inherited germline mutation in CDKN2A is the most common cause of familial atypical multiple mole melanoma (FAMMM) syndrome. Although it is well known that CDKN2A mutations confer an increased risk for melanoma and pancreatic carcinoma, the association with an increased risk for nerve sheath tumours and other tumour types is under-recognized. We report a family with a missense mutation (c.151-1G>C) at the acceptor splice site of intron 1 of CDKN2A, resulting in loss of function of both tumour suppressor proteins p16(INK) (4) and p14(ARF) . This mutation is associated with a clinical phenotype of FAMMM syndrome in which patients develop numerous benign and malignant mutations, brain tumours, sarcomas and other solid tumours, in addition to melanoma and dysplastic naevi. Our proband initially presented with multiple nerve sheath tumours, leading to diagnostic confusion with Neurofibromatosis type 1. Loss of p14 expression results in increased MDM2-mediated degradation of the tumour suppressor protein p53, and predisposes mutation carriers to multiple benign and malignant neoplasms. This article highlights the importance of considering CDKN2A mutations in patients with dysplastic naevi, melanoma and multiple nerve sheath tumours, specifically those with histological features of both neurofibromas and schwannomas. We also present a discussion of medical management for patients with this high-risk cancer susceptibility syndrome.
Sujet(s)
Inhibiteur p18 de kinase cycline-dépendante/génétique , Mélanome/génétique , Mutation faux-sens/génétique , Tumeurs des gaines nerveuses/génétique , Tumeurs cutanées/génétique , Adolescent , Adulte , Sujet âgé , Inhibiteur p16 de kinase cycline-dépendante , Diagnostic différentiel , Femelle , Prédisposition génétique à une maladie/génétique , Humains , Introns/génétique , Mâle , Mélanome/diagnostic , Adulte d'âge moyen , Tumeurs des gaines nerveuses/diagnostic , Neurinome/diagnostic , Neurofibromatose de type 1/diagnostic , Pedigree , Sites d'épissage d'ARN/génétique , Tumeurs cutanées/diagnostic , Jeune adulte ,RÉSUMÉ
Elevated activity of the mitogen-activated protein kinase (MAPK) signaling cascade is found in the majority of human melanomas and is known to regulate proliferation, survival and invasion. Current targeted therapies focus on decreasing the activity of this pathway; however, we do not fully understand how these therapies impact tumor biology, especially given that melanoma is a heterogeneous disease. Using a three-dimensional (3D), collagen-embedded spheroid melanoma model, we observed that MEK and BRAF inhibitors can increase the invasive potential of â¼20% of human melanoma cell lines. The invasive cell lines displayed increased receptor tyrosine kinase (RTK) activity and activation of the Src/FAK/signal transducers and activators of transcription-3 (STAT3) signaling axis, also associated with increased cell-to-cell adhesion and cadherin engagement following MEK inhibition. Targeting various RTKs, Src, FAK and STAT3 with small molecule inhibitors in combination with a MEK inhibitor prevented the invasive phenotype, but only STAT3 inhibition caused cell death in the 3D context. We further show that STAT3 signaling is induced in BRAF-inhibitor-resistant cells. Our findings suggest that MEK and BRAF inhibitors can induce STAT3 signaling, causing potential adverse effects such as increased invasion. We also provide the rationale for the combined targeting of the MAPK pathway along with inhibitors of RTKs, SRC or STAT3 to counteract STAT3-mediated resistance phenotypes.
Sujet(s)
Régulation de l'expression des gènes tumoraux , Mélanome/métabolisme , Mitogen-Activated Protein Kinases/antagonistes et inhibiteurs , Facteur de transcription STAT-3/métabolisme , Tumeurs cutanées/métabolisme , Cadhérines/métabolisme , Adhérence cellulaire , Lignée cellulaire tumorale , Survie cellulaire , Analyse de mutations d'ADN , Résistance aux médicaments antinéoplasiques , Humains , Invasion tumorale , Protéines proto-oncogènes B-raf/métabolisme , Transduction du signal , Peau/anatomopathologieRÉSUMÉ
Adult stem cells are multipotent and persist in small numbers in adult tissues throughout the lifespan of an organism. Unlike differentiated cells, adult stem cells are intrinsically resistant to senescence. It is unclear how adult stem cells in solid organs respond to oncogenic stimulation and whether these cells have a role in tumor initiation. We report here that expression of BRAF(V600E) in human neural crest progenitor cells (hNCPCs) did not induce growth arrest as seen in human melanocytes, but instead, increased their cell proliferation capacity. These cells (hNCPCs(V600E)) acquired anchorage-independent growth ability and were weakly tumorigenic in vivo. Unlike in human melanocytes, BRAF(V600E) expression in hNCPCs did not induce p16(INK4a) expression. BRAF(V600E) induced elevated expression of CDK2, CDK4, MITF and EST1/2 protein in hNCPCs, and also induced melanocytic differentiation of these cells. Furthermore, overexpression of MITF in hNCPCs(V600E) dramatically increased their tumorigenicity and resulted in fully transformed tumor cells. These findings indicate that hNCPCs are susceptible to BRAF(V600E)-induced transformation, and MITF potentiates the oncogenic effect of BRAF(V600E) in these progenitor cells. These results suggest that the hNCPCs are potential targets for BRAF(V600E)-induced melanocytic tumor formation.
Sujet(s)
Cellules souches adultes/métabolisme , Transformation cellulaire néoplasique/génétique , Crête neurale/anatomopathologie , Cellules souches neurales/métabolisme , Protéines proto-oncogènes B-raf/génétique , Peau/anatomopathologie , Cellules souches adultes/anatomopathologie , Animaux , Prolifération cellulaire , Transformation cellulaire néoplasique/métabolisme , Transformation cellulaire néoplasique/anatomopathologie , Cellules cultivées , Variations de nombre de copies de segment d'ADN , Femelle , Expression des gènes , Humains , Mâle , Mélanome/génétique , Mélanome/métabolisme , Mélanome/anatomopathologie , Souris de lignée NOD , Souris SCID , Facteur de transcription associé à la microphtalmie/génétique , Mutation faux-sens , Transplantation tumorale , Cellules souches neurales/anatomopathologie , Phénotype , Protéines proto-oncogènes B-raf/métabolisme , Charge tumoraleRÉSUMÉ
BACKGROUND: The variable penetrance of breast cancer in BRCA1/2 mutation carriers suggests that other genetic or environmental factors modify breast cancer risk. Two genes of special interest are prohibitin (PHB) and methylene-tetrahydrofolate reductase (MTHFR), both of which are important either directly or indirectly in maintaining genomic integrity. METHODS: To evaluate the potential role of genetic variants within PHB and MTHFR in breast and ovarian cancer risk, 4102 BRCA1 and 2093 BRCA2 mutation carriers, and 6211 BRCA1 and 2902 BRCA2 carriers from the Consortium of Investigators of Modifiers of BRCA1 and BRCA2 (CIMBA) were genotyped for the PHB 1630 C>T (rs6917) polymorphism and the MTHFR 677 C>T (rs1801133) polymorphism, respectively. RESULTS: There was no evidence of association between the PHB 1630 C>T and MTHFR 677 C>T polymorphisms with either disease for BRCA1 or BRCA2 mutation carriers when breast and ovarian cancer associations were evaluated separately. Analysis that evaluated associations for breast and ovarian cancer simultaneously showed some evidence that BRCA1 mutation carriers who had the rare homozygote genotype (TT) of the PHB 1630 C>T polymorphism were at increased risk of both breast and ovarian cancer (HR 1.50, 95%CI 1.10-2.04 and HR 2.16, 95%CI 1.24-3.76, respectively). However, there was no evidence of association under a multiplicative model for the effect of each minor allele. CONCLUSION: The PHB 1630TT genotype may modify breast and ovarian cancer risks in BRCA1 mutation carriers. This association need to be evaluated in larger series of BRCA1 mutation carriers.
Sujet(s)
Tumeurs du sein/génétique , Gène BRCA1 , Gène BRCA2 , Methylenetetrahydrofolate reductase (NADPH2)/génétique , Tumeurs de l'ovaire/génétique , Polymorphisme génétique , Protéines de répression/génétique , Femelle , Prédisposition génétique à une maladie , Hétérozygote , Humains , Mutation , Prohibitines , RisqueRÉSUMÉ
In patients with malignant pheochromocytoma and paraganglioma, 131I-MIBG radiotherapy can achieve an objective response rate of 30-50% with the dose limiting toxicity being hematologic. Patients with disseminated disease, who also have a few index bulky or symptomatic lesions, may benefit from the addition of targeted external beam radiotherapy alone or in combination with systemic 131I-MIBG. The records of patients with malignant paraganglioma who were treated with external beam radiotherapy at the University of Pennsylvania from February 1973 to February 2011 were reviewed in an institutional review board approved retrospective study. Of the 17 patients with tumors in the thorax, abdomen, or pelvis, 76% had local control or clinically significant symptomatic relief for at least 1 year or until death. As expected, the predominant toxicity was due to irradiation of tumor-adjacent normal tissues without clinically significant hematologic toxicity. Due to widespread systemic metastases with areas of bulky, symptomatic tumor, 5 of the 17 patients were treated with sequential 131I-MIBG (2 mCi/kg per treatment) and external beam radiotherapy to 9 sites. In these patients, all areas that were irradiated with external beam radiotherapy showed durable objective response despite all patients eventually experiencing out-of-field systemic progression requiring other treatment. Four of these patients remain alive with excellent performance status 16, 18, 23, and 24 months after external beam radiotherapy. External beam radiotherapy can be highly effective in local management of malignant paraganglioma and can be used in conjunction with 131I-MIBG due to nonoverlapping toxicities with excellent control of locally bulky tumors.
Sujet(s)
3-Iodobenzyl-guanidine/usage thérapeutique , Tumeurs de la surrénale/radiothérapie , Radio-isotopes de l'iode/usage thérapeutique , Paragangliome/radiothérapie , Phéochromocytome/radiothérapie , Adulte , Association thérapeutique , Femelle , Humains , Mâle , Études rétrospectives , Jeune adulteRÉSUMÉ
Risk-reducing salpingo-oophorectomy (RRSO) significantly reduces the risk of ovarian cancer and breast cancer in pre-menopausal women with BRCA1 and BRCA2 (B1/2) mutations. Despite its clear benefits, little is known about non-cancer endpoints in this population. Medical records were examined in 226 B1/2 mutation carriers, who had previously undergone RRSO with a focus on bone health as well as the frequency of hypertension, hyperlipidemia, coronary artery disease (CAD), myocardial infarction (MI), diabetes, hypothyroidism and depression. From the medical records, DEXA scans, medications and medical conditions were recorded. Of the 226 patient records examined, 16% (36/226) had hypertension, 17% (39/226) hyperlipidemia, 2% (5/226) CAD or MI, 2% (4/226) diabetes, 13% (29/226) hypothyroidism and 14% (31/226) depression. DEXA results were available in 152 women. Of those DEXA scans, 71% (108/152) were abnormal (57% osteopenia and 14% osteoporosis). Among women who underwent RRSO prior to age 50, 71% (62/88) had osteopenia/osteoporosis. Although there was no difference in osteopenia/osteoporosis in women with RRSO prior to age 50 compared to those RRSO > 50, the age at follow up in these two groups differs greatly (mean age 44.7 vs. 60.6), suggesting that both current age and age at RRSO contribute to bone health assessment. In summary, here, we report the prevalence of non-cancer endpoints in a cohort of B1/2 mutation carriers and note a particularly high rate of osteopenia and osteoporosis in B1/2 with breast cancer undergoing RRSO prior to 50. Despite the risk reduction RRSO offers, attention should be paid to non-cancer endpoints, particularly bone health, in this population.
Sujet(s)
Protéine BRCA1/génétique , Protéine BRCA2/génétique , Maladies osseuses métaboliques/étiologie , Tumeurs du sein/génétique , Ostéoporose/étiologie , Tumeurs de l'ovaire/génétique , Ovariectomie , Complications postopératoires , Adulte , Sujet âgé , Sujet âgé de 80 ans ou plus , Maladies osseuses métaboliques/diagnostic , Tumeurs du sein/complications , Tumeurs du sein/chirurgie , Maladie des artères coronaires/diagnostic , Maladie des artères coronaires/étiologie , Dépression/diagnostic , Dépression/étiologie , Diabète/diagnostic , Diabète/étiologie , Femelle , Études de suivi , Hétérozygote , Humains , Hyperlipidémies/diagnostic , Hyperlipidémies/étiologie , Hypertension artérielle/diagnostic , Hypertension artérielle/étiologie , Hypothyroïdie/diagnostic , Hypothyroïdie/étiologie , Dossiers médicaux , Adulte d'âge moyen , Mutation/génétique , Infarctus du myocarde/diagnostic , Infarctus du myocarde/étiologie , Ostéoporose/diagnostic , Tumeurs de l'ovaire/complications , Tumeurs de l'ovaire/chirurgie , Pronostic , Études rétrospectives , Comportement de réduction des risquesRÉSUMÉ
BACKGROUND: Single-nucleotide polymorphisms (SNPs) in genes involved in DNA repair are good candidates to be tested as phenotypic modifiers for carriers of mutations in the high-risk susceptibility genes BRCA1 and BRCA2. The base excision repair (BER) pathway could be particularly interesting given the relation of synthetic lethality that exists between one of the components of the pathway, PARP1, and both BRCA1 and BRCA2. In this study, we have evaluated the XRCC1 gene that participates in the BER pathway, as phenotypic modifier of BRCA1 and BRCA2. METHODS: Three common SNPs in the gene, c.-77C>T (rs3213245) p.Arg280His (rs25489) and p.Gln399Arg (rs25487) were analysed in a series of 701 BRCA1 and 576 BRCA2 mutation carriers. RESULTS: An association was observed between p.Arg280His-rs25489 and breast cancer risk for BRCA2 mutation carriers, with rare homozygotes at increased risk relative to common homozygotes (hazard ratio: 22.3, 95% confidence interval: 14.3-34, P<0.001). This association was further tested in a second series of 4480 BRCA1 and 3016 BRCA2 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1 and BRCA2. CONCLUSIONS AND INTERPRETATION: No evidence of association was found when the larger series was analysed which lead us to conclude that none of the three SNPs are significant modifiers of breast cancer risk for mutation carriers.
Sujet(s)
Tumeurs du sein/génétique , Carcinomes/génétique , Protéines de liaison à l'ADN/physiologie , Épistasie/physiologie , Gène BRCA1 , Gène BRCA2 , Adolescent , Adulte , Sujet âgé , Sujet âgé de 80 ans ou plus , Tumeurs du sein/épidémiologie , Carcinomes/épidémiologie , Protéines de liaison à l'ADN/génétique , Femelle , Groupes de discussion , Gène BRCA1/physiologie , Gène BRCA2/physiologie , Prédisposition génétique à une maladie , Hétérozygote , Humains , Adulte d'âge moyen , Phénotype , Polymorphisme de nucléotide simple , Protéine-1 de complémentation croisée de la réparation des lésions induites par les rayons X , Jeune adulteRÉSUMÉ
Genetic testing for BRCA1 and BRCA2 mutations in family members of individuals with known deleterious mutations can distinguish between patients at high risk of disease and those who are not. Some studies have suggested that individuals testing negative for known familial mutations (true negatives), may still have a higher risk of breast cancer (BC) than the general population. We have examined a prospectively followed cohort of true negative women in the US. Subjects were close relatives of known BRCA1 and BRCA2 mutation carriers who had undergone genetic testing, were negative for the known familial mutation, and were unaffected at the time of genetic testing. Standardized incidence ratios (SIR) and 95% confidence intervals (CI) were calculated using SEER incidence rates. Among 375 true negatives, two invasive and two in situ BC and no ovarian cancers were diagnosed with mean follow up of 4.9 years (total of 1,962 person years).Four invasive BC were expected, whereas two were observed, for an age-adjusted SIR of 0.52 (95% CI 0.13-2.09). We observed more cases of in situ BC (n = 2) than were expected (n = 0.9; SIR = 2.30; 95% CI 0.57-9.19).There were no cases of ovarian cancer observed; 0.4 case was expected. In this prospective study of women who were unaffected at the time of genetic testing and who were negative for the known familial mutation in BRCA1/2, no excess risk of invasive BC was observed. Our data suggest that such women in the US should adhere to population based guidelines for breast cancer screening.
Sujet(s)
Protéine BRCA1/génétique , Protéine BRCA2/génétique , Marqueurs biologiques tumoraux/génétique , Tumeurs du sein/génétique , Régulation de l'expression des gènes tumoraux , Dépistage génétique , Mutation , Adulte , Protéines régulatrices de l'apoptose , Tumeurs du sein/épidémiologie , Tumeurs du sein/anatomopathologie , Femelle , Prédisposition génétique à une maladie , Adhésion aux directives , Humains , Incidence , Adulte d'âge moyen , Invasion tumorale , Pedigree , Phénotype , Guides de bonnes pratiques cliniques comme sujet , Valeur prédictive des tests , Études prospectives , Appréciation des risques , Facteurs de risque , Facteurs temps , États-Unis/épidémiologieRÉSUMÉ
BACKGROUND: In this study we aimed to evaluate the role of a SNP in intron 1 of the ERCC4 gene (rs744154), previously reported to be associated with a reduced risk of breast cancer in the general population, as a breast cancer risk modifier in BRCA1 and BRCA2 mutation carriers. METHODS: We have genotyped rs744154 in 9408 BRCA1 and 5632 BRCA2 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) and assessed its association with breast cancer risk using a retrospective weighted cohort approach. RESULTS: We found no evidence of association with breast cancer risk for BRCA1 (per-allele HR: 0.98, 95% CI: 0.93-1.04, P = 0.5) or BRCA2 (per-allele HR: 0.97, 95% CI: 0.89-1.06, P = 0.5) mutation carriers. CONCLUSION: This SNP is not a significant modifier of breast cancer risk for mutation carriers, though weak associations cannot be ruled out.
Sujet(s)
Protéines de liaison à l'ADN/génétique , Gène BRCA1 , Gène BRCA2 , Hétérozygote , Mutation , Polymorphisme de nucléotide simple , Études de cohortes , Femelle , Humains , Études rétrospectivesRÉSUMÉ
BACKGROUND: The TP53 pathway, in which TP53 and its negative regulator MDM2 are the central elements, has an important role in carcinogenesis, particularly in BRCA1- and BRCA2-mediated carcinogenesis. A single nucleotide polymorphism (SNP) in the promoter region of MDM2 (309T>G, rs2279744) and a coding SNP of TP53 (Arg72Pro, rs1042522) have been shown to be of functional significance. METHODS: To investigate whether these SNPs modify breast cancer risk for BRCA1 and BRCA2 mutation carriers, we pooled genotype data on the TP53 Arg72Pro SNP in 7011 mutation carriers and on the MDM2 309T>G SNP in 2222 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Data were analysed using a Cox proportional hazards model within a retrospective likelihood framework. RESULTS: No association was found between these SNPs and breast cancer risk for BRCA1 (TP53: per-allele hazard ratio (HR)=1.01, 95% confidence interval (CI): 0.93-1.10, P(trend)=0.77; MDM2: HR=0.96, 95%CI: 0.84-1.09, P(trend)=0.54) or for BRCA2 mutation carriers (TP53: HR=0.99, 95%CI: 0.87-1.12, P(trend)=0.83; MDM2: HR=0.98, 95%CI: 0.80-1.21, P(trend)=0.88). We also evaluated the potential combined effects of both SNPs on breast cancer risk, however, none of their combined genotypes showed any evidence of association. CONCLUSION: There was no evidence that TP53 Arg72Pro or MDM2 309T>G, either singly or in combination, influence breast cancer risk in BRCA1 or BRCA2 mutation carriers.
Sujet(s)
Tumeurs du sein/génétique , Gène BRCA1 , Gène BRCA2 , Gènes p53 , Prédisposition génétique à une maladie , Mutation , Polymorphisme de nucléotide simple , Protéines proto-oncogènes c-mdm2/génétique , Tumeurs du sein/étiologie , Femelle , Hétérozygote , Humains , Facteurs de risqueRÉSUMÉ
Annual MRI screening is recommended as an adjunct to mammography for BRCA1 and BRCA2 mutation carriers. Prophylactic oophorectomy has been shown to decrease breast cancer risk in BRCA1/2 mutation carriers. Here, we aimed to examine the combined effects of MRI and oophorectomy. For this purpose, 93 BRCA1/2 mutation carriers were screened with yearly mammograms and yearly MRI scans. Study endpoints were defined as date of breast cancer diagnosis, date of prophylactic mastectomy, or date of most recent contact. Of 93 women, with a median age of 47, 80 (86%) had prophylactic oophorectomy. Fifty-one women (55%) had BRCA1 mutations. A total of 283 MRI scans were performed. Eleven breast cancers (9 invasive, 2 ductal carcinoma in situ) were detected in 93 women (12%) with a median follow-up of 3.2 years (incidence 40 per 1,000 person-years). Six cancers were first detected on MRI, three were first detected by mammogram, and two were "interval cancers." All breast cancers occurred in BRCA1 mutation carriers (incidence 67 per 1,000 person-years). Apart from BRCA1 vs. BRCA2 mutation status, there were no other significant predictors of breast cancer incidence. Most invasive breast cancers were estrogen receptor negative (7 of 9) and lymph node negative (7 of 9). There have been no systemic recurrences with a median follow-up of 19 months after cancer diagnosis. Finally, it was concluded that all breast cancers occurred in BRCA1 mutation carriers, in most cases despite oophorectomy. These data suggest that surveillance and prevention strategies may have different outcomes in BRCA1 and BRCA2 mutation carriers.
Sujet(s)
Tumeurs du sein/génétique , Tumeurs du sein/prévention et contrôle , Gène BRCA1 , Gène BRCA2 , Dépistage de masse/méthodes , Adulte , Tumeurs du sein/épidémiologie , Femelle , Prédisposition génétique à une maladie , Hétérozygote , Humains , Incidence , Imagerie par résonance magnétique , Mammographie , Adulte d'âge moyen , Mutation , OvariectomieSujet(s)
Kystes/génétique , Mutation avec décalage du cadre de lecture/génétique , Maladies pulmonaires/génétique , Pneumothorax/génétique , Protéines proto-oncogènes/génétique , Dermatoses papulosquameuses/génétique , Protéines suppresseurs de tumeurs/génétique , Adulte , Humains , Mâle , Pneumothorax/imagerie diagnostique , Radiographie , SyndromeRÉSUMÉ
A majority of malignant melanomas harbor an oncogenic mutation in either BRAF or NRAS. If BRAF and NRAS transform melanoma cells by a similar mechanism, then additional genetic aberrations would be similar (or random). Alternatively, distinct mutation-associated changes would suggest the existence of unique cooperating requirements for each mutation group. We first analyzed a panel of 52 melanoma cell lines (n = 35, 11, 6 for BRAF*, NRAS*, and BRAF/NRAS(wt/wt), respectively) by array-based comparative genomic hybridization for unique alterations that associate with each mutation subgroup. Subsequently, those DNA copy number changes that correlated with a mutation subgroup were used to predict the mutation status of an independent panel of 43 tumors (n = 17, 13, 13 for BRAF*, NRAS*, and BRAF/NRAS(wt/wt), respectively). BRAF mutant tumors were classified with a high rate of success (74.4%, P = 0.002), whereas NRAS mutants were not significantly distinguished from wild types (26/43, P = 0.12). Copy number gains of 7q32.1-36.3, 5p15.31, 8q21.11, and 8q24.11 were most strongly associated with BRAF* tumors and cell lines, as were losses of 11q24.2-24.3. BRAF* melanomas appear to be associated with a specific profile of DNA copy number aberrations that is distinct from those found in NRAS* and BRAF/NRAS(wt/wt) tumors. These findings suggest that although both BRAF and NRAS appear to function along the same signal transduction pathway, each may have different requirements for cooperating oncogenic events. The genetic loci that make up this profile may harbor therapeutic targets specific for tumors with BRAF mutations.
Sujet(s)
Aberrations des chromosomes , Dosage génique , Gènes ras , Mélanome/génétique , Protéines proto-oncogènes B-raf/génétique , Lignée cellulaire tumorale , Loi du khi-deux , Humains , Mutation , Hybridation d'acides nucléiques , Séquençage par oligonucléotides en batterie , Transduction du signalRÉSUMÉ
Here, we identify a panel of melanoma lines with non-V600E mutations in BRAF. These G469E- and D594G-mutated melanomas were found to exhibit constitutive levels of phospho-extracellular signal-regulated kinase (pERK) and low levels of phospho-mitogen-activated protein kinase/ERK kinase (pMEK) and were resistant to MEK inhibition. Upon treatment with the CRAF inhibitor sorafenib, these lines underwent apoptosis and associated with mitochondrial depolarization and relocalization of apoptosis-inducing factor, whereas the BRAF-V600E-mutated melanomas did not. Studies have shown low-activity mutants of BRAF (G469E/D594G) instead signal through CRAF. Unlike BRAF, CRAF directly regulates apoptosis through mitochondrial localization where it binds to Bcl-2 and phosphorylates BAD. The CRAF inhibitor sorafenib was found to induce a time-dependent reduction in both BAD phosphorylation and Bcl-2 expression in the D594G/G469E lines only. Knockdown of CRAF using a lentiviral shRNA suppressed both Bcl-2 expression and induced apoptosis in the D594G melanoma line but not in a V600E-mutated line. Finally, we showed in a series of xenograft studies that sorafenib was more potent at reducing the growth of tumors with the D594G mutation than those with the V600E mutation. In summary, we have identified a group of melanomas with low-activity BRAF mutations that are reliant upon CRAF-mediated survival activity.
Sujet(s)
Apoptose , Résistance aux médicaments antinéoplasiques/génétique , Mélanome/enzymologie , Protéines proto-oncogènes B-raf/génétique , Protéines proto-oncogènes c-raf/antagonistes et inhibiteurs , Apoptose/génétique , Benzènesulfonates/pharmacologie , Lignée cellulaire tumorale , Techniques de knock-down de gènes , Acide glutamique/génétique , Acide glutamique/métabolisme , Humains , Mélanome/génétique , Mitogen-Activated Protein Kinase Kinases/métabolisme , Mutation , Nicotinamide/analogues et dérivés , Phénylurées , Inhibiteurs de protéines kinases/pharmacologie , Protéines proto-oncogènes c-raf/génétique , Pyridines/pharmacologie , Petit ARN interférent/génétique , Transduction du signal , Sorafénib , Valine/génétique , Valine/métabolismeRÉSUMÉ
INTRODUCTION: Risk-reducing salpingo-oophorectomy (RRSO) reduces the risk of developing ovarian and breast cancer in BRCA 1 and BRCA 2 (BRCA1/2) mutation carriers. The short-term use of hormone replacement therapy (HRT) after RRSO may relieve menopausal symptoms and does not appear to affect the breast cancer risk reduction gained by RRSO. Multiple factors may influence decisions regarding whether or not total abdominal hysterectomy (TAH) is done at the time of RRSO, whether HRT is elected after surgery, and if so, which type of HRT is selected. Our investigation has been to examine factors associated with TAH and HRT use and to determine if the choice of TAH at the time of RRSO and the type of HRT that was chosen has changed since the report of data from the Women's Health Initiative (WHI) in 2002, which showed that the relative risk for breast cancer is higher in subjects who used combined estrogen-progestin HRT compared with those who used estrogen alone. METHODS: We identified 73 female BRCA1/2 mutation carriers who were known to have undergone RRSO between 1/1972 and 11/2005 who had no history of breast or ovarian cancer at the time of the surgery. Information regarding whether or not TAH was done in addition to RRSO, the type of HRT, and the subsequent diagnosis of breast cancer was collected. RESULTS: Of 73 unaffected BRCA1/2 carriers known to have had RRSO, 40 (40/73, 55%) also underwent TAH. Thirty-three of 73 (33/73, 45%) began HRT following RRSO. Of 33 HRT users, 17 (17/33, 52%) used estrogen only and 14 (14/33, 42%) used combined hormonal therapy. There was no difference in use of HRT in women with TAH (17/40, 43%) vs. those without (16/33, 48%) (P = 0.6). There was no difference in the proportion of women who underwent TAH before and after the WHI report in 2002. Use of HRT, most notably combined estrogen-progestin HRT, appears to have declined since 2002, although this result did not reach statistical significance. CONCLUSION: In this single institution study, the majority of BRCA1/2 mutation carriers undergoing RRSO also underwent TAH, and a substantial number took HRT. TAH did not increase the likelihood of taking HRT compared to RRSO alone.
Sujet(s)
Tumeurs du sein/prévention et contrôle , Trompes utérines/chirurgie , Hormonothérapie substitutive/statistiques et données numériques , Hystérectomie/statistiques et données numériques , Tumeurs de l'ovaire/prévention et contrôle , Ovariectomie , Tumeurs du sein/génétique , Femelle , Gène BRCA1 , Gène BRCA2 , Prédisposition génétique à une maladie , Hétérozygote , Humains , Mutation , Tumeurs de l'ovaire/génétiqueRÉSUMÉ
Five breast cancer subtypes have been described in sporadic breast cancer (SBC) using expression arrays: basal-like, ERBB2, normal breast-like, luminal A and B. These molecular subtypes show different genomic aberration patterns (GAPs). Recently, our group described these breast cancer subtypes in 50 non-BRCA1/2 familial tumors using immunohistochemistry assays. We extended this study to the other classes of familial breast cancer (FBC), including 62 tumors (18 BRCA1, 16 BRCA2 and 28 non-BRCA1/2), with the same panel of 25 immunohistochemical (IHC) markers and histological grade obtaining a similar classification. We combined these data with results generated by a 1 Mb BAC array-based CGH study to evaluate the genomic aberrations of each group. We found that BRCA1-related tumors are preferentially basal-like, whereas non-BRCA1/2 familial tumors are mainly luminal A subtype. We described distinct GAPs related to each IHC subtype. Basal tumors had a greater number of gains/losses, while luminal B tumors had more high-level DNA amplifications. Our data are similar to those obtained in SBC studies, highlighting the existence of distinct genetic pathways of tumor evolution, common to both SBC and FBC.
Sujet(s)
Tumeurs du sein/classification , Tumeurs du sein/génétique , Aberrations des chromosomes , Analyse de profil d'expression de gènes , Adulte , Marqueurs biologiques tumoraux/métabolisme , Tumeurs du sein/métabolisme , Chromosomes humains de la paire 8 , Analyse de regroupements , Famille , Femelle , Amplification de gène , Régulation de l'expression des gènes tumoraux , Fréquence d'allèle , Gène BRCA1 , Gène BRCA2 , Hétérogénéité génétique , Humains , Immunohistochimie , Mâle , Adulte d'âge moyen , Séquençage par oligonucléotides en batterieRÉSUMÉ
The loss of tumour phospho-extracellular responsive kinase (pERK) positivity is the major treatment biomarker for mitogen-activated protein kinase/extracellular responsive kinase (MEK) inhibitors. Here, we demonstrate that there is a poor correlation between pERK inhibition and the anti-proliferative effects of MEK inhibitors in melanoma cells. We suggest that Ki67 is a better biomarker for future clinical studies.