Activating germline mutations of the
MET
gene are associated with hereditary papillary renal cancer. This a very rare autosomal dominant condition, which is usually considered not to display a ...phenotype of multiple types of malignancy. However, this report describes the case of a man who has been affected with testicular teratoma, diffuse large B-cell lymphoma and multiple hepatic cysts, as well as multiple papillary renal cancers. There is good supporting evidence for roles of over-expression/activity of the HGF/MET ligand-receptor in development of these tumours, raising the possibility of other increased cancer risks associated with activating germline
MET
gene mutations.
Reliable estimates of cancer risk are critical for guiding management of BRCA1 and BRCA2 mutation carriers. The aims of this study were to derive penetrance estimates for breast cancer, ovarian ...cancer, and contralateral breast cancer in a prospective series of mutation carriers and to assess how these risks are modified by common breast cancer susceptibility alleles.
Prospective cancer risks were estimated using a cohort of 978 BRCA1 and 909 BRCA2 carriers from the United Kingdom. Nine hundred eighty-eight women had no breast or ovarian cancer diagnosis at baseline, 1509 women were unaffected by ovarian cancer, and 651 had been diagnosed with unilateral breast cancer. Cumulative risks were obtained using Kaplan-Meier estimates. Associations between cancer risk and covariables of interest were evaluated using Cox regression. All statistical tests were two-sided.
The average cumulative risks by age 70 years for BRCA1 carriers were estimated to be 60% (95% confidence interval CI = 44% to 75%) for breast cancer, 59% (95% CI = 43% to 76%) for ovarian cancer, and 83% (95% CI = 69% to 94%) for contralateral breast cancer. For BRCA2 carriers, the corresponding risks were 55% (95% CI = 41% to 70%) for breast cancer, 16.5% (95% CI = 7.5% to 34%) for ovarian cancer, and 62% (95% CI = 44% to 79.5%) for contralateral breast cancer. BRCA2 carriers in the highest tertile of risk, defined by the joint genotype distribution of seven single nucleotide polymorphisms associated with breast cancer risk, were at statistically significantly higher risk of developing breast cancer than those in the lowest tertile (hazard ratio = 4.1, 95% CI = 1.2 to 14.5; P = .02).
Prospective risk estimates confirm that BRCA1 and BRCA2 carriers are at high risk of developing breast, ovarian, and contralateral breast cancer. Our results confirm findings from retrospective studies that common breast cancer susceptibility alleles in combination are predictive of breast cancer risk for BRCA2 carriers.
BRCA1 and BRCA2 mutations have been associated with prostate cancer (PCa) risk but a wide range of risk estimates have been reported that are based on retrospective studies.
To estimate relative and ...absolute PCa risks associated with BRCA1/2 mutations and to assess risk modification by age, family history, and mutation location.
This was a prospective cohort study of male BRCA1 (n = 376) and BRCA2 carriers (n = 447) identified in clinical genetics centres in the UK and Ireland (median follow-up 5.9 and 5.3 yr, respectively).
Standardised incidence/mortality ratios (SIRs/SMRs) relative to population incidences or mortality rates, absolute risks, and hazard ratios (HRs) were estimated using cohort and survival analysis methods.
Sixteen BRCA1 and 26 BRCA2 carriers were diagnosed with PCa during follow-up. BRCA2 carriers had an SIR of 4.45 (95% confidence interval CI 2.99–6.61) and absolute PCa risk of 27% (95% CI 17–41%) and 60% (95% CI 43–78%) by ages 75 and 85 yr, respectively. For BRCA1 carriers, the overall SIR was 2.35 (95% CI 1.43–3.88); the corresponding SIR at age <65 yr was 3.57 (95% CI 1.68–7.58). However, the BRCA1 SIR varied between 0.74 and 2.83 in sensitivity analyses to assess potential screening effects. PCa risk for BRCA2 carriers increased with family history (HR per affected relative 1.68, 95% CI 0.99–2.85). BRCA2 mutations in the region bounded by positions c.2831 and c.6401 were associated with an SIR of 2.46 (95% CI 1.07–5.64) compared to population incidences, corresponding to lower PCa risk (HR 0.37, 95% CI 0.14–0.96) than for mutations outside the region. BRCA2 carriers had a stronger association with Gleason score ≥7 (SIR 5.07, 95% CI 3.20–8.02) than Gleason score ≤6 PCa (SIR 3.03, 95% CI 1.24–7.44), and a higher risk of death from PCa (SMR 3.85, 95% CI 1.44–10.3). Limitations include potential screening effects for these known mutation carriers; however, the BRCA2 results were robust to multiple sensitivity analyses.
The results substantiate PCa risk patterns indicated by retrospective analyses for BRCA2 carriers, including further evidence of association with aggressive PCa, and give some support for a weaker association in BRCA1 carriers.
In this study we followed unaffected men known to carry mutations in the BRCA1 and BRCA2 genes to investigate whether they are at higher risk of developing prostate cancer compared to the general population. We found that carriers of BRCA2 mutations have a high risk of developing prostate cancer, particularly more aggressive prostate cancer, and that this risk varies by family history of prostate cancer and the location of the mutation within the gene.
Male BRCA2 mutation carriers have a high risk of developing prostate cancer, particularly high-grade disease. However, the risk is heterogeneous and varies with family history and the location of the mutation within the gene. BRCA1 mutations may have a similar but weaker association.
Candidate predictive biomarkers for irinotecan and oxaliplatin were assessed in 1,628 patients in Fluorouracil, Oxaliplatin, CPT-11: Use and Sequencing (FOCUS), a large randomized trial of ...fluorouracil alone compared with fluorouracil and irinotecan and compared with fluorouracil and oxaliplatin in advanced colorectal cancer.
The candidate biomarkers were: tumor immunohistochemistry for MLH1/MSH2, p53, topoisomerase-1 (Topo1), excision repair cross-complementing gene 1 (ERCC1), O-6-methylguanine-DNA-methyltranserase (MGMT), and cyclooxygenase 2 (COX2); germline DNA polymorphisms in GSTP1, ABCB1, XRCC1, ERCC2, and UGT1A1. These were screened in more than 750 patients for interaction with benefit from irinotecan or oxaliplatin; two markers (Topo1 and MLH1/MSH2) met criteria to be taken forward for analysis in the full population. Primary end points were progression-free survival (PFS) and overall survival.
One thousand three hundred thirteen patients (81%) were assessable for Topo1 immunohistochemistry (low, < 10%; moderate, 10% to 50%; or high, > 50% tumor nuclei). In patients with low Topo1, PFS was not improved by the addition of either irinotecan (hazard ratio HR, 0.98; 95% CI, 0.78 to 1.22) or oxaliplatin (HR, 0.85; 95% CI, 0.68 to 1.07); conversely, patients with moderate/high Topo1 benefited from the addition of either drug (HR, 0.48 to 0.70 in all categories; interaction P = .005; overall, P = .001 for irinotecan; P = .05 for oxaliplatin). High Topo1 was associated with a major overall survival benefit with first-line combination chemotherapy (HR, 0.60; median benefit, 5.3 months); patients with moderate or low Topo1 did not benefit (HR, 0.92 and 1.09, respectively; interaction P = .005). MLH1/MSH2 did not show significant interaction with treatment, although the low rate of loss (4.4%) limits the power of the study for this biomarker.
Topo1 immunohistochemistry identified subpopulations that did or did not benefit from irinotecan, and possibly also from oxaliplatin. If verified independently, this information will contribute to the individualization of treatment for colorectal cancer.
Von Hippel-Lindau (VHL) disease is an inherited tumour predisposition syndrome and a paradigm for the importance of early diagnosis and surveillance. However, there is limited information on the ..."real world" management of VHL disease.
A national audit of VHL disease in the United Kingdom.
VHL disease was managed mostly via specialist clinics coordinated through regional clinical genetics services (but frequently involving additional specialties). Over the study period, 19 genetic centres saw 842 individuals (393 males, 449 females) with a clinical and/or molecular diagnosis of VHL disease and 74 individuals (35 male, 39 female) with a prior risk of 50% (affected parent). All centres offered retinal, central nervous system and abdominal surveillance to affected individuals and at-risk relatives though surveillance details differed between centres (but complied with international recommendations). Renal lesions detected on the first surveillance scan were, on average, larger than those detected during subsequent scans and the larger the diameter at detection the greater the likelihood of early intervention.
In a state-funded health care system individuals with a rare inherited cancer predisposition syndrome are generally able to access appropriate surveillance and patient management is improved compared to historical data. The "real world" data from this study will inform the future development of VHL management protocols.
Predicting efficacy and toxicity could potentially allow individualization of cancer therapy. We investigated putative pharmacogenetic markers of chemotherapy toxicity in a large randomized trial.
...Patients were randomly assigned to different sequences of chemotherapy for advanced colorectal cancer. First-line therapy was fluorouracil (FU), irinotecan/FU (IrFU) or oxaliplatin/FU (OxFU). Patients allocated first-line FU had planned second-line irinotecan alone, IrFU, or OxFU. The primary toxicity outcome measure was toxicity-induced delay or dose reduction; the secondary outcome was Common Terminology Criteria of Adverse Events grade >or= 3 toxicity. DNA was analyzed in 1,188 patients; 1,036 were assessable for the primary outcome, including 688 treated with FU, 270 with IrFU (first or second line), 280 with OxFU (first or second line), 184 with irinotecan alone, and 454 with any irinotecan-containing regimen. Ten polymorphisms were assessed: thymidylate synthase-enhancer region (TYMS-ER), thymidylate synthase 1494 (TYMS-1494), dihydropyrimidine dehydrogenase (DPYD), methylenetetrahydrofolate reductase (MTHFR), mutL homolog 1 (MLH1), UDP glucuronyltransferase (UGT1A1), ATP-binding cassette group B gene 1 (ABCB1), x-ray cross-complementing group 1 (XRCC1), glutathione-S-transferase P1 (GSTP1), and excision repair cross-complementing gene 2 (ERCC2). Results Using the primary outcome measure, no polymorphism was significantly associated (P < .01) with the toxicity of any regimen or with the difference in toxicity of IrFU or OxFU versus FU alone. Trends (of doubtful significance) were seen for associations of XRCC1, ERCC2, and GSTP1 with toxicity during irinotecan regimens: XRCC1, primary end point, any irinotecan-containing regimen (P = .045); ERCC2, secondary end point, irinotecan alone (P = .003); GSTP1, secondary end point; IrFU (P = .039); and irinotecan alone (P = .05). There was no evidence of association of UGT1A1*28 with irinotecan toxicity.
These results do not support the routine clinical use of the evaluated polymorphisms, including UGT1A1*28. Further investigation of XRCC1, ERCC2, and GSTP1 as potential predictors of irinotecan toxicity is warranted.
DICER1 syndrome is a rare genetic disorder that predisposes to a wide spectrum of tumors. Developing surveillance protocols for this syndrome is challenging because uncertainty exists about the ...clinical efficacy of surveillance, and appraisal of potential benefits and harms vary. In addition, there is increasing evidence that germline
DICER1
pathogenic variants are associated with lower penetrance for cancer than previously assumed. To address these issues and to harmonize DICER1 syndrome surveillance programs within Europe, the Host Genome Working Group of the European branch of the International Society of Pediatric Oncology (SIOPE HGWG) and Clinical Guideline Working Group of the CanGene-CanVar project in the United Kingdom reviewed current surveillance strategies and evaluated additional relevant literature. Consensus was achieved for a new surveillance protocol and information leaflet that informs patients about potential symptoms of
DICER1
-associated tumors. The surveillance protocol comprises a minimum program and an extended version for consideration. The key recommendations of the minimum program are: annual clinical examination from birth to age 20 years, six-monthly chest X-ray and renal ultrasound from birth to age 6 years, and thyroid ultrasound every 3 years from age 8 to age 40 years. The surveillance program for consideration comprises additional surveillance procedures, and recommendations for
DICER1
pathogenic variant carriers outside the ages of the surveillance interval. Patients have to be supported in choosing the surveillance program that best meets their needs. Prospective evaluation of the efficacy and patient perspectives of proposed surveillance recommendations is required to expand the evidence base for DICER1 surveillance protocols.
The National Institute of health and Care Excellence issued guidelines on familial breast cancer screening in 2004. Such guidelines should be uniformly implemented to ensure that members of the same ...family with the same level of risk, but living in different areas, have the same access to screening. We assessed uptake by creating a short, six question online survey designed to assess compliance in each regional area. We used this to conduct a survey of all 22 regional genetics services. There was a 100% response to the survey allowing a complete map to be created. The devolved nations had near complete compliance with the sole exception of SW Scotland, but in England the picture was fragmented with regions representing a combined population of 26.6 million (48%) not implementing the full NICE recommendations. Fifteen years after the publication of the original guidelines, major inequity in provision for screening still occurs and a postcode lottery exists for the management of women from families with a history of breast cancer. We estimate that up to 73 preventable breast cancer deaths occur each year due to the current inequity of access. It may be time to consider alternative funding and implementation models to ensure consistent access across the country.
We report a case of breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) occurring in a 53-year-old female with Li Fraumeni syndrome (LFS) with a prior history of breast cancer. We ...present the clinical features, investigation, and management of this patient and potential mechanisms that could explain the increasing association of BIA-ALCL and LFS.
ABSTRACT
Targeted hybridization enrichment prior to next‐generation sequencing is a widespread method for characterizing sequence variation in a research setting, and is being adopted by diagnostic ...laboratories. However, the number of variants identified can overwhelm clinical laboratories with strict time constraints, the final interpretation of likely pathogenicity being a particular bottleneck. To address this, we have developed an approach in which, after automatic variant calling on a standard unix pipeline, subsequent variant filtering is performed interactively, using AgileExomeFilter and AgilePindelFilter (http://dna.leeds.ac.uk/agile), tools designed for clinical scientists with standard desktop computers. To demonstrate the method's diagnostic efficacy, we tested 128 patients using (1) a targeted capture of 36 cancer‐predisposing genes or (2) whole‐exome capture for diagnosis of the genetically heterogeneous disorder primary ciliary dyskinesia (PCD). In the cancer cohort, complete concordance with previous diagnostic data was achieved across 793 variant genotypes. A high yield (42%) was also achieved for exome‐based PCD diagnosis, underscoring the scalability of our method. Simple adjustments to the variant filtering parameters further allowed the identification of a homozygous truncating mutation in a presumptive new PCD gene, DNAH8. These tools should allow diagnostic laboratories to expand their testing portfolios flexibly, using a standard set of reagents and techniques.
We present two programs, AgileExomeFilter and AgilePindelFilter, which enable clinical scientists to rapidly and efficiently filter variants from next generation sequencing data. Using these tools a high diagnostic yield (42%) was obtained in a cohort of 24 primary ciliary dyskinesia (PCD) patients that underwent targeted exome analysis. Autozygosity mapping in the mutation negative cases revealed a homozygous truncating mutation in DNAH8, a presumptive new PCD gene.
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