TP53 germline mutation testing in early-onset breast cancer: findings from a nationwide cohort.

Early-onset breast cancer may be due to Li-Fraumeni Syndrome (LFS). Current national and international guidelines recommend that TP53 genetic testing should be considered for women with breast cancer diagnosed before the age of 31 years. However, large studies investigating TP53 mutation prevalence in this population are scarce. We collected nationwide laboratory records for all young breast cancer patients tested for TP53 mutations in the Netherlands. Between 2005 and 2016, 370 women diagnosed with breast cancer younger than 30 years of age were tested for TP53 germline mutations, and eight (2.2%) were found to carry a (likely) pathogenic TP53 sequence variant. Among BRCA1/BRCA2 mutation negative women without a family history suggestive of LFS or a personal history of multiple LFS-related tumours, the TP53 mutation frequency was < 1% (2/233). Taking into consideration that TP53 mutation prevalence was comparable or even higher in some studies selecting patients with breast cancer onset at older ages or HER2-positive breast cancers, raises the question of whether a very early age of onset is an appropriate single TP53 genetic testing criterion.

Consequences of testing for mismatch repair deficiency of colorectal cancer in clinical practice.

INTRODUCTION: Mismatch repair deficiency (dMMR) can be found in Lynch syndrome (LS)-associated colorectal carcinoma and in 15% of sporadic colorectal cancer (CRC). Outcome of MMR-deficiency testing is important for surgical decisions as extended colectomy is recommended in young LS-patients with CRC. Moreover, the finding of a dMMR tumour has consequences for the choices of adjuvant chemotherapy as MMR-deficient CRC is resistant to 5-fluorouracil (5-FU) monotherapy. Aims of our study are to evaluate whether MMR-deficiency testing leads to (1) identification of LS, (2) change in surgical treatment and (3) adjustment of systemic therapy in patients with dMMR CRC. METHODS: We performed a multicentre, retrospective study, in a community hospital and a University Medical Centre. We included all CRC-patients between 2012 and 2016 who were tested for microsatellite instability. We collected clinical data such as gender, age, referral to clinical geneticist, surgical procedure and choice of chemotherapy. RESULTS: We analysed 225 CRCs. Twenty-four (10.7%) of 225 CRC were MMR-deficient. Of the 24 patients with dMMR CRC, 18 (75%) were referred to the clinical geneticist and in nine (37%) patients a MMR mutation was identified. In one (4%) of the 24 patients, a subtotal colectomy was performed. In seven (35%) out of 20 MMR deficient patients, the chemotherapy regimen was adjusted. CONCLUSIONS: The finding of a dMMR CRC had consequences for decisions on chemotherapy in a relative high proportion of patients. We recommend testing in all patients with CRC independent of age at diagnosis, as proper treatment decisions and genetic counselling are very important.

Prognostic value of insulin-like growth factor 1 and insulin-like growth factor binding protein 3 blood levels in breast cancer.

High circulating insulin-like growth factor 1 (IGF-1) levels are firmly established as a risk factor for developing breast cancer, especially estrogen positive tumors. The effect of circulating IGF-1 on prognosis once a tumor is established is unknown. The authors explored the effect of IGF-1 blood levels and of it's main binding protein, IGFBP-3, on overall survival and occurrence of second primary breast tumors in breast cancer patients, as well as reproductive and lifestyle factors that could modify this risk. Patients were accrued from six hospitals in the Netherlands between 1998 and 2003. Total IGF-1 and IGFBP-3 were measured in 582 plasma samples. No significant association between IGF-1 and IGFBP-3 plasma levels and overall survival was found. However, in a multivariate Cox regression model including standard prognostic variables high IGF-1 levels were related to worse overall survival in patients receiving endocrine therapy (HR = 1.37, 95% CI: 1.11, 1.69, P 0.004). These data at least indicate that higher IGF-1 levels, and as a consequence most likely IGF-1-induced signaling, are related to a less favorable overall survival in breast cancer patients treated with endocrine therapy. Interventions aimed at reducing circulating levels of IGF-1 in hormone receptor positive breast cancer may improve survival.

Renal cancer and pneumothorax risk in Birt-Hogg-Dubé syndrome; an analysis of 115 FLCN mutation carriers from 35 BHD families.

BACKGROUND: Birt-Hogg-Dubé (BHD) syndrome is an autosomal dominant condition caused by germline FLCN mutations, and characterised by fibrofolliculomas, pneumothorax and renal cancer. The renal cancer risk, cancer phenotype and pneumothorax risk of BHD have not yet been fully clarified. The main focus of this study was to assess the risk of renal cancer, the histological subtypes of renal tumours and the pneumothorax risk in BHD. METHODS: In this study we present the clinical data of 115 FLCN mutation carriers from 35 BHD families. RESULTS: Among 14 FLCN mutation carriers who developed renal cancer 7 were <50 years at onset and/or had multifocal/bilateral tumours. Five symptomatic patients developed metastatic disease. Two early-stage cases were diagnosed by surveillance. The majority of tumours showed characteristics of both eosinophilic variants of clear cell and chromophobe carcinoma. The estimated penetrance for renal cancer and pneumothorax was 16% (95% minimal confidence interval: 6-26%) and 29% (95% minimal confidence interval: 9-49%) at 70 years of age, respectively. The most frequent diagnosis in families without identified FLCN mutations was familial multiple discoid fibromas. CONCLUSION: We confirmed a high yield of FLCN mutations in clinically defined BHD families, we found a substantially increased lifetime risk of renal cancer of 16% for FLCN mutation carriers. The tumours were metastatic in 5 out of 14 patients and tumour histology was not specific for BHD. We found a pneumothorax risk of 29%. We discuss the implications of our findings for diagnosis and management of BHD.

No association between the Arg201Gly polymorphism of the DCC gene and colorectal cancer.

BACKGROUND AND AIMS: In one small study, the DCC Arg201Gly polymorphism has been observed more frequently in colorectal cancer cases compared with controls. We wondered whether these results could be replicated in a much larger study. METHODOLOGY: The DCC Arg201 Gly polymorphism was genotyped in 625 unselected Caucasian colorectal cancer patients and 220 controls. Association analysis was used to search for a difference between patients and controls. Subgroup analyses were performed for site of tumour, gender, age at diagnosis, family history of colorectal cancer and modified Dukes classification. RESULTS: The association analyses revealed no difference in Arg201Gly genotype frequency between patients and controls, neither overall nor for different subgroups according to site of tumour, gender, age at diagnosis, family history of colorectal cancer and modified Dukes classification. CONCLUSION: No association was observed between the Arg201Gly polymorphism of DCC and colorectal cancer risk.

Genes other than BRCA1 and BRCA2 involved in breast cancer susceptibility.

This review focuses on genes other than the high penetrance genes BRCA1 and BRCA2 that are involved in breast cancer susceptibility. The goal of this review is the discovery of polymorphisms that are either associated with breast cancer or that are in strong linkage disequilibrium with breast cancer causing variants. An association with breast cancer at a 5% significance level was found for 13 polymorphisms in 10 genes described in more than one breast cancer study. Our data will help focus on the further analysis of genetic polymorphisms in populations of appropriate size, and especially on the combinations of such polymorphisms. This will facilitate determination of population attributable risks, understanding of gene-gene interactions, and improving estimates of genetic cancer risks.

Outcome after laparoscopic cholecystotomy and cholecystectomy in children with symptomatic cholecystolithiasis: a preliminary report.

Laparoscopic cholecystectomy (LCE) has become the procedure of choice for symptomatic gallstones in children. However, there is concern about the disadvantages of cholecystectomy. Numerous postoperative symptoms and a possible correlation of the procedure with a higher incidence of right-sided colon carcinoma have been described. Therefore, it has been suggested to remove the gallstones via a cholecystotomy, leaving the gallbladder in place. This is the first report on the functional and symptomatic outcome of laparoscopic cholecystotomy (LCO) versus LCE in a consecutive series of children. A follow-up study of all children who underwent surgery for symptomatic gallstone disease from 1993 to 1999 was performed. Nine underwent LCO and 8 standard LCE. The procedure was chosen according to the preference of the surgeon. Patients and parents underwent a standardized follow-up interview. The intensitiy of six gastrointestinal symptoms was graded from 0 to 3. The patients and parents scored the symptomatic outcome using a 100-point visual analogue scale. There were no intraoperative complications. Bleeding of a port site required suturing in 1 patient after LCO, and fever with a further uneventful course occurred in another after LCE. The mean duration of hospital stay was 3.0 days after LCO and 2.4 days after LCE. In 1 patient a missed gallstone was identified 4 weeks after LCO. The patient underwent LCE with a further uneventful course. At follow-up (mean 20.7 months after LCO, 28.3 months after LCE, P = n.s.) there was a tendency toward a lower incidence of symptoms after LCO. Symptoms were reported by 3 of 8 patients after LCO and 5 of 8 after LCE. The mean score of the symptomatic outcome was not statistically different. All patients with LCO were free of stones on ultrasound examination with normal contraction of the gallbladder. LCO thus represents an alternative approach. We consider LCO for children with symptomatic cholecystolithiasis before the onset of puberty. However, data on the long-term outcome from larger series are mandatory before a general recommendation can be given.

Comparison of several indium-111 ligands in labeling blood cells: effect of diethylpyrocarbonate and CO2.

The effect of oxine sulfate, oxine sulfonate, tropolone, and Merc (2 mercaptopyridine-1-oxide) were compared with oxine, with respect to their capability of labeling blood cells when complexed to indium-111 (111In). Indium-111 oxine sulfate performed similarly to [111In]oxine with regard to cell labeling capability. Indium-111 oxine sulfonate had no labeling ability. Indium-111 tropolone and Merc were not superior to [111In]oxine as cell labeling agents. Carbon dioxide (CO2) and a CO2 generating compound, diethyl pyrocarbonate, dramatically improved the cell labeling ability in plasma of [111In]tropolone and Merc. In the case of oxine, this improvement was less distinct. Theoretical aspects of the CO2 cell labeling stimulating effect are discussed in terms of intra- and extracellular transferrin and lactoferrin iron (indium) binding capacity. Indium-111 tropolone behaved favorably with respect to inhibition of leukocyte migration, compared with oxine and Merc. Combined with the property of easy cell labeling and good solubility in water, also in the complexed state, tropolone must be regarded as the most suitable cell labeling ligand.

A motility test of leukocytes under agar.

A migration test under agar for leukocytes was developed. Leukocytes moved quite a distance under anaerobic Blood Agar Base (blood agar), a Gibco product. Migration on stained and coloured plates was visualized by projection with a profile projector, making the use of a light microscope superfluous. A migration index was defined. Reproducibility was good enough to allow paired comparisons of leukocyte populations subjected to different treatments. Migration was the result of spontaneous and chemotactically directed migration. Cell-labelling complexes as 111In-oxinate and 111In-tropolonate--ligand concentration 3.5 micrograms/mL in the ultimate cell preparation--did not affect leukocyte migration. 111In-pyrithionate (mercapto pyridine-N-oxide) significantly impaired cell motility. The motility test described could be used as retrospective analysis in abscess localization studies using 111In labelled leukocytes.