Simultaneous analysis of multiple genes using next‐generation sequencing (NGS) technology has become widely available. Copy‐number variations (CNVs) in disease‐associated genes have emerged as a ...cause for several hereditary disorders. CNVs are, however, not routinely detected using NGS analysis. The aim of this study was to assess the diagnostic yield and the prevalence of CNVs using our panel of Hereditary Thoracic Aortic Disease (H‐TAD)‐associated genes. Eight hundred ten patients suspected of H‐TAD were analyzed by targeted NGS analysis of 21 H‐TAD associated genes. In addition, the eXome hidden Markov model (XHMM; an algorithm to identify CNVs in targeted NGS data) was used to detect CNVs in these genes. A pathogenic or likely pathogenic variant was found in 66 of 810 patients (8.1%). Of these 66 pathogenic or likely pathogenic variants, six (9.1%) were CNVs not detectable by routine NGS analysis. These CNVs were four intragenic (multi‐)exon deletions in MYLK, TGFB2, SMAD3, and PRKG1, respectively. In addition, a large duplication including NOTCH1 and a large deletion encompassing SCARF2 were detected. As confirmed by additional analyses, both CNVs indicated larger chromosomal abnormalities, which could explain the phenotype in both patients. Given the clinical relevance of the identification of a genetic cause, CNV analysis using a method such as XHMM should be incorporated into the clinical diagnostic care for H‐TAD patients.
The aim of this study was to assess the diagnostic yield and the prevalence of copy number variants in patients suspected of hereditary thoracic aortic disease (H‐TAD). A pathogenic or likely pathogenic variant was found in 66 of 810 patients (8.1%) and six out of these 66 likely pathogenic or pathogenic variants (9.1%) were copy number variants. Given the clinical relevance of identification of a genetic cause, copy number variant analysis should be incorporated into the clinical diagnostics of patients suspected of hereditary thoracic aortic disease.
Germline mutations in the Folliculin (
) tumor suppressor gene cause Birt-Hogg-Dubé (BHD) syndrome, a rare autosomal dominant disorder predisposing carriers to kidney tumors.
is a conserved, ...essential gene linked to diverse cellular processes but the mechanism by which
prevents kidney cancer remains unknown. Here, we show that disrupting
in human renal tubular epithelial cells (RPTEC/TERT1) activates TFE3, upregulating expression of its E-box targets, including RRAGD and GPNMB, without modifying mTORC1 activity. Surprisingly, the absence of FLCN or its binding partners FNIP1/FNIP2 induces interferon response genes independently of interferon. Mechanistically, FLCN loss promotes STAT2 recruitment to chromatin and slows cellular proliferation. Our integrated analysis identifies STAT1/2 signaling as a novel target of FLCN in renal cells and BHD tumors. STAT1/2 activation appears to counterbalance TFE3-directed hyper-proliferation and may influence immune responses. These findings shed light on unique roles of FLCN in human renal tumorigenesis and pinpoint candidate prognostic biomarkers.
Previously, it has been suggested that colorectal polyps and carcinomas might be associated with Birt-Hogg-Dubé syndrome. We aimed to compare the occurrence of colorectal neoplasms between Dutch ...patients with Birt-Hogg-Dubé syndrome and their relatives without Birt-Hogg-Dubé syndrome.
In all, 399 patients with a pathogenic FLCN mutation and 382 relatives without the familial FLCN mutation were included. Anonymous data on colon and rectum pathology was provided by PALGA: the Dutch Pathology Registry.
No significant difference in the percentage of individuals with a history of colorectal carcinoma was found between the two groups (3.6% vs 2.6%, p = 0.54). There was also no significant difference between the age at diagnosis, diameter, differentiation and location of the colorectal carcinomas. Significantly more individuals with Birt-Hogg-Dubé syndrome underwent removal of colorectal polyps (12.2% vs 6.3%, p = 0.005). However, there was no significant difference between the number of polyps per person, the histology, grade of dysplasia and location of the polyps.
Our data do not provide evidence for an increased risk for colorectal carcinoma in Birt-Hogg-Dubé syndrome, arguing against the need for colorectal surveillance. The difference in polyps might be due to a bias caused by a higher number of colonoscopies in patients with Birt-Hogg-Dubé syndrome.
Height, body mass index (BMI), and weight gain are associated with breast cancer risk in the general population. It is unclear whether these associations also exist for carriers of pathogenic ...variants in the BRCA1 or BRCA2 genes.
An international pooled cohort of 8091 BRCA1/2 variant carriers was used for retrospective and prospective analyses separately for premenopausal and postmenopausal women. Cox regression was used to estimate breast cancer risk associations with height, BMI, and weight change.
In the retrospective analysis, taller height was associated with risk of premenopausal breast cancer for BRCA2 variant carriers (HR 1.20 per 10 cm increase, 95% CI 1.04-1.38). Higher young-adult BMI was associated with lower premenopausal breast cancer risk for both BRCA1 (HR 0.75 per 5 kg/m
, 95% CI 0.66-0.84) and BRCA2 (HR 0.76, 95% CI 0.65-0.89) variant carriers in the retrospective analysis, with consistent, though not statistically significant, findings from the prospective analysis. In the prospective analysis, higher BMI and adult weight gain were associated with higher postmenopausal breast cancer risk for BRCA1 carriers (HR 1.20 per 5 kg/m
, 95% CI 1.02-1.42; and HR 1.10 per 5 kg weight gain, 95% CI 1.01-1.19, respectively).
Anthropometric measures are associated with breast cancer risk for BRCA1 and BRCA2 variant carriers, with relative risk estimates that are generally consistent with those for women from the general population.
Background
We present a family consisting of a father and his two children with an exceptional phenotype of childhood renal cell carcinoma and brain tumors. Extensive genetic testing revealed two ...inherited tumor predisposition syndromes in all three family members: Birt‐Hogg‐Dubé syndrome and Li‐Fraumeni syndrome. The corresponding genes (FLCN and TP53) are both located on the short arm of chromosome 17.
Methods
We describe the phenotype and performed single nucleotide polymorphism (SNP)‐based loss of heterozygosity (LOH) analysis of the tumors.
Results
All examined tumors showed somatic loss of the wild‐type alleles of both FLCN and TP53.
Conclusions
We hypothesize that a synergistic effect of both mutations caused the unusual phenotype of childhood renal cell carcinoma in this family. This family emphasizes the importance of further genetic testing if a tumor develops at an unexpected young age in an inherited cancer predisposition syndrome.
We describe a family with both Birt‐Hogg‐Dubé syndrome and Li‐Fraumeni syndrome, causing an exceptional phenotype of childhood renal cell carcinoma and brain tumors. All examined tumors showed somatic loss of the wild‐type alleles of FLCN and TP53, which are both located on chromosome 17p.
Germline BRCA1/2-associated epithelial ovarian cancer has been associated with better progression-free survival and overall survival than sporadic epithelial ovarian cancer, but conclusive data are ...lacking. We matched 389 BRCA1-associated and 123 BRCA2-associated epithelial ovarian cancer patients 1:1 to sporadic epithelial ovarian cancer patients on year of birth, year of diagnosis, and FIGO stage ( = IIB). Germline DNA test was performed before or after epithelial ovarian cancer diagnosis. All patients received chemotherapy. We used Cox proportional hazards models to estimate the associations between mutation status (BRCA1 or BRCA2 versus sporadic) and progression-free survival and overall survival. To investigate whether DNA testing after epithelial ovarian cancer diagnosis resulted in survival bias, we performed additional analyses limited to BRCA1/2-associated epithelial ovarian cancer patients with a DNA test result before cancer diagnosis (n = 73 BRCA1; n = 9 BRCA2) and their matched sporadic controls. The median follow-up was 4.4 years (range 0.1-30.1). During the first three years after epithelial ovarian cancer diagnosis, progression-free survival was better for BRCA1 (HR 0.88, 95% CI 0.74-1.04) and BRCA2 (HR 0.58, 95% CI 0.41-0.81) patients than for sporadic patients. Overall survival was better during the first six years after epithelial ovarian cancer for BRCA1 (HR 0.7, 95% CI 0.58-0.84) and BRCA2 (HR 0.41, 95% CI 0.29-0.59) patients. After surviving these years, survival benefits disappeared or were in favor of the sporadic patients. For epithelial ovarian cancer patients who received chemotherapy, we confirmed survival benefit for BRCA1 and BRCA2 germline pathogenic variant carriers. This may indicate higher sensitivity to chemotherapy, both in first line treatment and in the recurrent setting. The observed benefit appears to be limited to a relatively short period after epithelial ovarian cancer diagnosis.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The publication by Balsamo and colleagues describes a patient with Birt-Hogg-Dubé syndrome and hyperplastic polyposis throughout the gastro-intestinal tract. We question whether the diagnosis of BHD ...in this patient was justified. Using the previously proposed diagnostic criteria for establishing the diagnosis of BHD as a guideline, we systematically describe our concerns. In our opinion, the patient described by Balsamo and colleagues does not meet any of the proposed major and minor criteria for the diagnosis of Birt-Hogg-Dubé syndrome. Therefore, we believe that it is not justified to suggest a possible association between hyperplastic polyposis and Birt-Hogg-Dubé syndrome based on this patient, even though a higher risk for colorectal polyposis in Birt-Hogg-Dubé syndrome has not been excluded so far.
Birt-Hogg-Dubé syndrome is associated with an increased risk for renal cell carcinoma. Surveillance is recommended, but the optimal imaging method and screening interval remain to be defined. The ...main aim of our study was to evaluate the outcomes of RCC surveillance to get insight in the safety of annual US in these patients. Surveillance data and medical records of 199 patients with Birt-Hogg-Dubé syndrome were collected retrospectively using medical files and a questionnaire. These patients were diagnosed in two Dutch hospitals and data were collected until June 2014. A first screening for renal cell carcinoma was performed in 172/199 patients (86%). Follow-up data were available from 121 patients. The mean follow-up period per patient was 4.2 years. Of the patients known to be under surveillance, 83% was screened at least annually and 94% at least every two years. Thirty-eight renal cell carcinomas had occurred in 23 patients. The mean age at diagnosis of the first tumour was 51. Eighteen tumours were visualized by ultrasound. Nine small tumours (7-27 mm) were visible on MRI or CT and not detected using ultrasound. Our data indicate that compliance to renal screening is relatively high. Furthermore, ultrasound might be a sensitive, cheap and widely available alternative for MRI or part of the MRIs for detecting clinically relevant renal tumours in BHD patients,but the limitations should be considered carefully. Data from larger cohorts are necessary to confirm these observations.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
BRCA1/2 mutation carriers with primary breast cancer (PBC) are at high risk of contralateral breast cancer (CBC). In a nationwide cohort, we investigated the effects of chemotherapeutic agents given ...for PBC on CBC risk separately in BRCA1 and BRCA2 mutation carriers.
BRCA1 or BRCA2 mutation carriers with an invasive PBC diagnosis from 1990 to 2017 were selected from a Dutch cohort. We estimated cumulative CBC incidence using competing risks analysis. Hazard ratios (HR) for the effect of neo-adjuvant or adjuvant chemotherapy and different chemotherapeutic agents on CBC risk were estimated using Cox regression.
We included 1090 BRCA1 and 568 BRCA2 mutation carriers; median follow-up was 8.9 and 8.4 years, respectively. Ten-year cumulative CBC incidence for treatment with and without chemotherapy was 6.7% 95%CI: 5.1–8.6 and 16.7% 95%CI: 10.8–23.7 in BRCA1 and 4.8% 95%CI: 2.7–7.8 and 16.0% 95%CI: 9.3–24.4 in BRCA2 mutation carriers, respectively. Chemotherapy was associated with reduced CBC risk in BRCA1 (multivariable HR: 0.46, 95%CI: 0.29–0.74); a similar trend was observed in BRCA2 mutation carriers (HR: 0.63, 95%CI: 0.29–1.39). In BRCA1, risk reduction was most pronounced in the first 5 years (HR: 0.32, 95%CI: 0.17–0.61). Anthracyclines and the combination of anthracyclines with taxanes were associated with substantial CBC risk reduction in BRCA1 carriers (HR: 0.34, 95%CI: 0.17–0.68 and HR: 0.22, 95%CI: 0.08–0.62, respectively).
Risk-reducing effects of chemotherapy are substantial for at least 5 years and may be used in personalised CBC risk prediction in any case for BRCA1 mutation carriers.
•Contralateral breast cancer (CBC) risk is high in BRCA1/2 mutation carriers.•Chemotherapy for primary breast cancer results in decreased CBC risk in BRCA1.•Anthracyclines with/without taxanes show the largest CBC risk reduction in BRCA1.•For BRCA2 similar trends are observed as in BRCA1 mutation carriers.•Chemotherapy must be considered in personalised CBC risk models.
The 7th Birt-Hogg-Dubé (BHD) International Symposium convened virtually in October 2021. The meeting attracted more than 200 participants internationally and highlighted recent findings in a variety ...of areas, including genetic insight and molecular understanding of BHD syndrome, structure and function of the tumor suppressor Folliculin (FLCN), therapeutic and clinical advances as well as patients' experiences living with this malady.
PDF
