A multicentre comparative prospective blinded analysis of EUS and MRI for screening of pancreatic cancer in high-risk individuals.

OBJECTIVE: Endoscopic ultrasonography (EUS) and MRI are promising tests to detect precursors and early-stage pancreatic ductal adenocarcinoma (PDAC) in high-risk individuals (HRIs). It is unclear which screening technique is to be preferred. We aimed to compare the efficacy of EUS and MRI in their ability to detect clinically relevant lesions in HRI. DESIGN: Multicentre prospective study. The results of 139 asymptomatic HRI (>10-fold increased risk) undergoing first-time screening by EUS and MRI are described. Clinically relevant lesions were defined as solid lesions, main duct intraductal papillary mucinous neoplasms and cysts ≥10 mm. Results were compared in a blinded, independent fashion. RESULTS: Two solid lesions (mean size 9 mm) and nine cysts ≥10 mm (mean size 17 mm) were detected in nine HRI (6%). Both solid lesions were detected by EUS only and proved to be a stage I PDAC and a multifocal pancreatic intraepithelial neoplasia 2. Of the nine cysts ≥10 mm, six were detected by both imaging techniques and three were detected by MRI only. The agreement between EUS and MRI for the detection of clinically relevant lesions was 55%. Of these clinically relevant lesions detected by both techniques, there was a good agreement for location and size. CONCLUSIONS: EUS and/or MRI detected clinically relevant pancreatic lesions in 6% of HRI. Both imaging techniques were complementary rather than interchangeable: contrary to EUS, MRI was found to be very sensitive for the detection of cystic lesions of any size; MRI, however, might have some important limitations with regard to the timely detection of solid lesions.

Psychosocial aspects of hereditary cancer (PAHC) questionnaire: development and testing of a screening questionnaire for use in clinical cancer genetics.

BACKGROUND: Up to three-quarters of individuals who undergo cancer genetic counseling and testing report psychosocial problems specifically related to that setting. The objectives of this study were to develop and evaluate the screening properties of a questionnaire designed to assess specific psychosocial problems related to cancer genetic counseling. METHODS: We adopted the European Organisation for Research and Treatment of Cancer Quality of Life Group guidelines to develop the Psychosocial Aspects of Hereditary Cancer (PAHC) questionnaire, a 26-item questionnaire organized into six problem domains: genetics, practical issues, family, living with cancer, emotions, and children. The Distress Thermometer and a question per domain on the perceived need for extra psychosocial services were included as well. We administered the questionnaire and the Hospital Anxiety and Depression Scale to 127 counselees at the time of genetic counseling and 3 weeks after DNA test disclosure. As a gold standard to evaluate the screening properties of the questionnaire, participants underwent a semi-structured interview with an experienced social worker who assessed the presence and severity of problems per domain. RESULTS: A cutoff score representing responses of 'quite a bit' or 'very much' to one or more items within a given problem domain yielded moderate to high sensitivity across domains. A cutoff of 4 on the Distress Thermometer yielded high sensitivity. The questions regarding the perceived need for extra psychosocial services yielded high specificity and negative predictive values. CONCLUSION: The Psychosocial Aspects of Hereditary Cancer questionnaire in combination with the Distress Thermometer can be used as a first-line screener for psychosocial problems within the cancer genetic counseling setting.

Association of PHB 1630 C>T and MTHFR 677 C>T polymorphisms with breast and ovarian cancer risk in BRCA1/2 mutation carriers: results from a multicenter study.

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.

Gastric adenocarcinoma in a 13-year-old boy: a diagnosis not often seen in this age group.

Gastric adenocarcinoma is not uncommon in the adult population, but in the pediatric population it is an extremely rare entity. A 13-year-old boy was referred to a pediatric oncology unit for evaluation of a tumor in the upper abdomen. Further investigation revealed an advanced stage gastric carcinoma with metastases suggestive for a hereditary cause. Awareness for uncommon diagnoses is a key issue in regard of accurate treatment and overall prognosis.

Is early diagnosis of pancreatic cancer fiction? Surveillance of individuals at high risk for pancreatic cancer.

Pancreatic cancer represents one of the most deadly human malignancies with an overall 5-year survival of less than 5%. Despite improvements in imaging techniques and surgical techniques, survival statistics have hardly improved over the past decades. To improve the dismal outlook it would be highly desirable to develop a program to detect precursor lesions or small asymptomatic early cancers at the time when the disease is still at a curable stage. Screening the general population for disease presence is not feasible at present because of the relatively low disease incidence and the lack of a noninvasive, reliable and cheap screening tool. Targeted surveillance programs, however, in individuals at high risk for developing pancreatic cancer, like mutation carriers of pancreatic cancer prone hereditary (tumor) syndromes or individuals with a strong family history of pancreatic cancer without a known underlying genetic defect, might be feasible. Careful consideration of the criteria put forward by Wilson and Jungner as published by the World Health Organization on the principles and practice of screening for disease, indicate that surveillance in this high-risk population by means of endosonography (EUS) and/or magnetic resonance imaging (MRI) represents a promising development, though experimental. It nicely points out which open questions need to be addressed. Among others, these include how to acquire a better understanding of the natural behavior and progression of precursor lesions towards invasive cancer, how to firmly establish the performance characteristics of EUS and MRI for the detection of (early) lesions in individuals at high risk for pancreatic cancer, and how to determine which lesions can be safely observed with continued surveillance and which lesions justify resection.

TP53 germline mutation testing in 180 families suspected of Li-Fraumeni syndrome: mutation detection rate and relative frequency of cancers in different familial phenotypes.

BACKGROUND Li-Fraumeni syndrome (LFS) is a rare autosomal dominant cancer predisposition syndrome. Most families fulfilling the classical diagnostic criteria harbour TP53 germline mutations. However, TP53 germline mutations may also occur in less obvious phenotypes. As a result, different criteria are in use to decide which patients qualify for TP53 mutation analysis, including the LFS, Li-Fraumeni-like (LFL) and Chompret criteria. We investigated which criteria for TP53 mutation analysis resulted in the highest mutation detection rate and sensitivity in Dutch families. We describe the tumour spectrum in TP53-positive families and calculated tumour type specific relative risks. METHOD A total of 180 Dutch families referred for TP53 mutation analysis were evaluated. Tumour phenotypes were verified by pathology reports or clinical records. RESULTS A TP53 germline mutation was identified in 24 families. When the Chompret criteria were used 22/24 mutations were detected (sensitivity 92%, mutation detection rate 21%). In LFS and LFL families 18/24 mutations were found (sensitivity 75%). The two mutations detected outside the 'Chompret group' were found in a child with rhabdomyosarcoma and a young woman with breast cancer. In the mutation carriers, in addition to the classical LFS tumour types, colon and pancreatic cancer were also found significantly more often than in the general population. CONCLUSION We suggest TP53 mutation testing for all families fulfilling the Chompret criteria. In addition, TP53 mutation testing can be considered in the event of childhood sarcoma and breast cancer before 30 years. In addition to the risk for established LFS tumour types, TP53-positive individuals may also have an elevated risk for pancreatic and colon cancer.

The yield of first-time endoscopic ultrasonography in screening individuals at a high risk of developing pancreatic cancer.

OBJECTIVES: Approximately 10-15% of all pancreatic cancers (PCs) may be hereditary in origin. We investigated the use of endoscopic ultrasonography (EUS) for the screening of individuals at high risk for developing PC. In this paper the results of first-time screening with EUS are presented. METHODS: Those eligible for screening in this study were first-degree family members of affected individuals from familial pancreatic cancer (FPC) families, mutation carriers of PC-prone hereditary syndromes, individuals with Peutz-Jeghers syndrome, and mutation carriers of other PC-prone hereditary syndromes with clustering (> or =2 cases per family) of PC. All individuals were asymptomatic and had not undergone EUS before. RESULTS: Forty-four individuals (M/F 18/26), aged 32-75 years underwent screening with EUS. Thirteen were from families with familial atypical multiple-mole melanoma (FAMMM), 21 with FPC, 3 individuals were diagnosed with hereditary pancreatitis, 2 were Peutz-Jeghers patients, 3 were BRCA1 and 2 were BRCA2 mutation carriers with familial clustering of PC, and 1 individual had a p53 mutation. Three (6.8%) patients had an asymptomatic mass lesion (12, 27, and 50 mm) in the body (n=2) or tail of the pancreas. All lesions were completely resected. Pathology showed moderately differentiated adenocarcinomas with N1 disease in the two patients with the largest lesions. EUS showed branch-type intraductal papillary mucinous neoplasia (IPMN) in seven individuals. CONCLUSIONS: Screening of individuals at a high risk for PC with EUS is feasible and safe. The incidence of clinically relevant findings at first screening is high with asymptomatic cancer in 7% and premalignant IPMN-like lesions in 16% in our series. Whether screening improves survival remains to be determined, as does the optimal screening interval with EUS.

Early onset of renal cancer in a family with Birt-Hogg-Dubé syndrome.

Birt-Hogg-Dubé syndrome is a hereditary syndrome characterized by benign disease of skin and lungs and a risk of malignant renal tumors. We describe a clinical and genetic study of a large Dutch family with a novel mutation in the FLCN gene. Renal cancer at very young age occurred in one branch of this family, while in other branches, cutaneous and pulmonary symptoms predominated. A variety of congenital anomalies and connective tissue abnormalities were observed, possibly associated with the gene mutation.

A family with complement factor D deficiency.

A complement factor D deficiency was found in a young woman who had experienced a serious Neisseria meningitidis infection, in a deceased family member with a history of meningitis, and in three relatives without a history of serious infections. The patient and these three relatives showed a normal activity of the classical complement pathway, but a very low activity of the alternative complement pathway and a very low capacity to opsonize Escherichia coli and N. meningitidis (isolated from the patient) for phagocytosis by normal human neutrophils. The alternative pathway-dependent hemolytic activity and the opsonizing capacity of these sera were restored by addition of purified factor D. The family had a high degree of consanguinity, and several other family members exhibited decreased levels of factor D. The gene encoding factor D was found to contain a point mutation that changed the TCG codon for serine 42 into a TAG stop codon. This mutation was found in both alleles of the five completely factor D-deficient family members and in one allele of 21 other members of the same family who had decreased or low-normal factor D levels in their serum. The gene sequence of the signal peptide of human factor D was also identified. Our report is the first, to our knowledge, to document a Factor D gene mutation. The mode of inheritance of factor D deficiency is autosomal recessive, in accordance with the localization of the Factor D gene on chromosome 19. Increased susceptibility for infections in individuals with a partial factor D deficiency is unlikely.

Kabuki syndrome - report of six cases and review of the literature with emphasis on ocular features.

Six cases of Kabuki syndrome (KS) with ocular anomalies are reported and the variety of ocular features reported in the literature for this syndrome is described. Routine ocular examinations are recommended for every patient with KS because of the high proportion of ocular anomalies found in these patients, the presence of which can hamper development if not adequately addressed.

The gene for hypotrichosis of Marie Unna maps between D8S258 and D8S298: exclusion of the hr gene by cDNA and genomic sequencing.

Hypotrichosis of Marie Unna (MU) is an autosomal dominant hair-loss disorder with onset in childhood. A genomewide search for the gene was performed in a large Dutch family using 400 fluorescent microsatellite markers. Linkage was detected with marker D8S258, and analysis of this family and a further British kindred with additional markers in the region gave a combined maximum two-point LOD score of 13.42, with D8S560. Informative recombinants placed the MU gene in a 2.4-cM interval between markers D8S258 and D8S298. Recently, recessive mutations in the hr gene were reported in families with congenital atrichia, and this gene was previously mapped close to the MU interval. By radiation-hybrid mapping, we placed the hr gene close to D8S298 but were unable to exclude it from the MU interval. This, with the existence of the semidominant murine hr allele, prompted us to perform mutation analysis for this gene. Full-length sequencing of hr cDNA obtained from an affected individual showed no mutations. Similarly, screening of all exons of the hr gene amplified from the genomic DNA of an affected individual revealed no mutations. Analysis of expressed sequences and positional cloning of the MU locus is underway.

Ophthalmologic abnormalities in encephalocraniocutaneous lipomatosis.

Encephalocraniocutaneous lipomatosis (ECCL) is a sporadically occurring disorder that belongs to the group of neurocutaneous syndromes. Important characteristics of the case we present are: intracranial lipomas, a skull hamartoma, bilateral lipodermoids and jaw tumors (ossifying fibromas and compound odontomas). We propose four minimal criteria for the diagnosis of ECCL and review the ocular abnormalities reported to date.