PMS2 cause Lynch syndrome and result in different but imprecisely known cancer risks. This study aimed to provide age and organspecific cancer risks according to gene and gender and to determine survival after cancer. Methods: We conducted an international, multicenter prospective observational study using independent test and validation cohorts of carriers of class 4 or class 5 variants. After validation the cohorts were merged providing 6350 participants and 51,646 followup years. Results: There were 1808 prospectively observed cancers. Pathogenic MLH1 and MSH2 variants caused high penetrance dominant cancer syndromes sharing similar colorectal, endometrial, and ovarian cancer risks, but older MSH2 carriers had higher risk of cancers of the upper urinary tract, upper gastrointestinal tract, brain, and particularly prostate. Pathogenic MSH6 variants caused a sex-limited trait with high endometrial cancer risk but only modestly increased colorectal cancer risk in both genders. We did not demonstrate a significantly increased cancer risk in carriers of pathogenic PMS2 variants. Ten-year crude survival was over 80% following colon, endometrial, or ovarian cancer. Conclusion: Management guidelines for Lynch syndrome may require revision in light of these different gene and gender-specific risks and the good prognosis for the most commonly associated cancers.

A 453 bp fragment of infB, the gene encoding translation initiation factor 2, was sequenced and compared from 66 clinical isolates and type strains of Haemophilus species and related bacteria. Analysis of the partial infB sequences obtained suggested that the human isolates dependent on X and V factor, H. influenzae, H. haemolyticus, H. aegyptius and some cryptic genospecies of H. influenzae, were closely related to each other. H. parainfluenzae constituted a heterogeneous group within the boundaries of the genus, whereas H. aphrophilus/paraphrophilus and Actinobacillus actinomycetemcomitans were only remotely related to the type species of the genus Haemophilus. H. parahaemolyticus and H. paraphrohaemolyticus took up an intermediary position and may not belong in the genus Haemophilus sensu stricto. Ambiguous results were obtained with seven isolates tentatively identified as H. segnis, which fell into two discrete clusters. The delineation of ' Haemophilus sensu stricto ' as suggested by infB analysis supports previous results obtained by DNA hybridization, in contrast to the delineation inferred from 16S rRNA sequence comparison.

The lymphocyte bulky PAH-DNA adduct levels have been studied in persons occupationally exposed to ambient air pollution. The exposure group consisted of 90 healthy, nonsmoking bus drivers from the Copenhagen area, divided into three exposure groups according to driving area, and 60 rural controls (smokers and non-smokers). PAH-DNA adducts were determined by 32P-postlabelling with the butanol enrichment procedure. The bus drivers answered a comprehensive questionnaire on passive smoking, residential area, diet and other potential confounding variables. A significantly higher adduct level was observed in bus drivers working in central Copenhagen (1.214 fmol/microg DNA, n = 49) compared with both those driving in the dormitory (median: 0.507 fmol/microg DNA, P = 0.046, n = 16) and suburban (median: 0.585 fmol/microg DNA, P = 0.041, n = 25) areas. All three groups had higher adduct levels than rural controls (0.074 fmol/microg DNA, n = 60, P< 0.001). No significant influence on adduct levels was demonstrated from potential confounders, including smoking and diet. The effect of the metabolizing enzymes, GSTM1 and NAT2, on adduct levels was investigated. No statistically significant effects were observed on adduct levels from GSTM1 or NAT2, either individually or combined, but a non-significant trend was seen for individuals with GSTM1*0/0 (null), since they had higher adduct levels in all exposure groups. This study demonstrated that lymphocyte PAH-DNA adduct levels were related to levels of exposure to urban air pollution and indicated that these adducts might be helpful as a means of classifying better different exposure groups for epidemiological studies. Furthermore, it demonstrated the ability of 32P-postlabelling to discern small differences in low exposure to ambient air pollution and suggested a possible effect of GSTM1*0/0 on DNA adduct levels.

We report on a nonconsanguineous family in which two siblings with cutaneous manifestations leading to a diagnosis of neurofibromatosis type 1 (NF1) developed CNS tumors at an early age. In addition, one of them developed a T-cell lymphoma. Neither parent had NF1. The mother was known to be heterozygous for a MSH6 mutation, and the father was found to be heterozygous for a different MSH6 mutation. Screening of MSH2, MLH1, MSH6, PMS1, PMS2, and MLH3 in the affected children disclosed that they both were compound heterozygote for the MSH6 mutations of their parents. Most recently, about a dozen other cases of inherited bi-allelic deficiency of mismatch repair (MMR) genes associated with early onset CNS tumors, hematologic malignancy, gastrointestinal neoplasia, café-au-lait spots, and other NF1 features have been reported. In the present study, we summarize the clinical findings of 27 individuals homozygous or compound heterozygous for an MMR gene mutation reported in the medical literature. We suggest that biparentally inherited mutations of one of the MMR genes should be considered in children with multiple café-au-lait spots who have early-onset CNS tumors, hematologic malignancies, or early onset gastrointestinal neoplasia.

No abstract

The aetiology of Mayer–Rokitansky–Küster–Hauser (MRKH) syndrome, characterized by uterovaginal agenesis in 46,XX women, remains poorly understood. Since familial occurrences are rare, genetic findings reported so far only apply to a minority of mainly sporadic cases and most studies have not included other family members enabling segregation analysis. Herein, we report on the investigation of a unique three-generation family of two female cousins with MRKH syndrome and unilateral renal agenesis (RA) and two deceased male relatives with RA. We performed whole-exome sequencing (WES) in eight family members leading to the identification of a novel pathogenic (CADD = 33) c.705G>T missense variant in GREB1L, a gene recently identified as a novel cause of RA. Previous reports include several cases of female fetuses with bilateral RA and uterus agenesis, which support GREB1L as an important gene in both kidney and female genital tract development. The pedigree is compatible with autosomal dominant inheritance with incomplete penetrance following a parent-origin-specific manner, which could be due to imprinting. To our knowledge, this is the first investigation of a larger MRKH syndrome pedigree using WES, and we suggest GREB1L as a novel and promising candidate gene in the aetiology of MRKH syndrome.

Human exposure to genotoxic compounds present in ambient air has been sdied using selected biomarkers in nonsmoking Danish bus drivers and pol workers. A li n variadion in biomarker levels was observed. Significantly higher levels of bulky carcinogen-DNA adducts (75.42 adducts/108 nucleotides) and of 2-amino-apidic semialdehyde (AAS) in plasma proteins (56.7 pmollmg protein) were observed in bus drivers working in the central part of Copenhagen, Denmark In contrast, significantly higher levels of AAS in hemoglobin (55,8 pmollmg protn), malondialdeh in plasma (0.96 nol/m plasma) nd polycic aromatic hydrocarbon (PAH)-albumin adduct (3.38 finol/pg lbumin) were observed in the suburban group. The biomarker levels in postal workers were similar to the levels in suburban bus drivers. In the combined group of bus drivers and postal workers, negative corlations were observed between bulky carcinogen-DNA adduct and PAH-albumin levels (p -0.005), and between DNA adduct and .y-glutamyl semialdhyde (GGS)

If genetic screening of HNPCC families depended on immunohistochemical results, a substantial number of families harboring a pathogenic mutation in MSH6 and the vast majority of families harboring an MSH6 unclassified variant would not be detected.