Evidence for breast cancer as an integral part of Lynch syndrome.

Lynch syndrome, an autosomal dominant cancer predisposition caused by mutations in DNA mismatch repair (MMR) genes, mainly mainly mutL homolog 1, OMIM 120436 (MLH1) and mutS homolog 2, OMIM 609309 (MSH2), encompasses a tumor spectrum including primarily gastrointestinal, endometrial, and ovarian cancer. This study aimed at clarifying the heavily debated issue of breast cancer being part of Lynch syndrome. Detailed clinical data on cancer occurrence in Swiss female MLH1/MSH2 mutation carriers were gathered, all available breast cancer specimens assessed for molecular evidence for MMR deficiency (i.e., microsatellite instability (MSI), MMR protein expression, and somatic (epi)genetic MMR gene alterations) and compiled with the scarce molecular data available from the literature. Seventy unrelated Swiss Lynch syndrome families were investigated comprising 632 female family members at risk of which 92 were genetically verified mutation carriers (52 MLH1 and 40 MSH2). On contrast to endometrial and ovarian cancer, which occurred significantly more often and at younger age in MLH1/MSH2 mutation carriers (median 50.5 and 49.0 years; P < 0.00001), overall cumulative breast cancer incidence closely mirrored the one in the Swiss population (56.5 years). Six (85.7%) of seven breast cancer specimens available for molecular investigations displayed the hallmarks of MMR deficiency. Combined with data from the literature, MSI was present in 26 (70.3%) of 37 and altered MMR protein expression in 16 (72.7%) of 22 breast cancer specimens from MLH1/MSH2 mutation carriers. These findings, thus, provide strong molecular evidence for a pivotal role of MMR deficiency in breast cancer development in Lynch syndrome.

Infertility in cryptorchidism is linked to the stage of germ cell development at orchidopexy.

BACKGROUND: Cryptorchidism represents the most common endocrine disease in boys, with infertility frequently observed in unilateral as well as bilateral forms. In this study, we examined the role of Ad (dark) spermatogonia for fertility in cryptorchid boys. The hypothesis to be proven was that boys lacking Ad spermatogonia will develop infertility despite a successful orchidopexy at an early age. METHODS: To estimate total sperm count, one of the most predictive parameters of male fertility, we analyzed the ejaculatein 218 cryptorchid men and correlated it with the developmental stage of their germ cells at the time of successful surgery. RESULTS: Abnormal sperm concentration (<40 x 10(6)/ejaculate) was found in half of the patients under the study. 47.5% of unilateral and 78% of bilateral cryptorchid males had their sperm concentration in the infertility range according to the WHO standards. If transformation into Ad spermatogonia had occurred, age-related differences in the fertility outcome was observed. The younger the unilateral cryptorchid boys were at surgery, the higher their sperm count. Age-related difference was not found in the group of cryptorchid men having had no A dark spermatogonia at time of surgery, indicating that in this group a successful orchidopexy is insufficient to prevent infertility development and, in particular, the development of azoospermia. CONCLUSION: The presence of Ad spermatogonia at surgery is an excellent prognostic parameter for future fertility. Cryptorchid boys lacking these cells will develop infertility despite successful orchidopexy at an early age.

A diminished postnatal surge of Ad spermatogonia in cryptorchid infants is additional evidence for hypogonadotropic hypogonadism.

BACKGROUND: The aim of this study was to describe the development of Ad spermatogonia in both unilateral and bilateral cryptorchid infants compared to a control population of comparable age and to note particularly the fate of Ad spermatogonia during the normal surge of testosterone and gonadotropin. METHODS: The incidence and development of Ad (dark) adult type of spermatogonia were assessed in 270 testicular biopsies from 159 cryptorchid infants at 1-12 months of age. These results were compared to the control population of the same age. RESULTS: The number of Ad spermatogonia increased markedly after five months of life in the control population. The scrotal testes of unilateral cryptorchid infants also had an increase in the number of Ad spermatogonia but it was distinctly lower than that of the control population. In contrast, this surge was completely absent in the cryptorchid testes. The number of Ad spermatogonia in unilateral cryptorchid testes correlated in a nonlinear fashion with those in the contralateral scrotal testes. The total number of germ cells in the cryptorchid testes in the first six months of life is normal, after which time it declines rapidly. CONCLUSION: The impaired transformation of germ cells into Ad spermatogonia in both unilateral and bilateral cryptorchid infant testes during mini-puberty underscores the importance of hypogonadotropic-hypogonadism in the pathogenesis of this disease.

Testing Significant Homogeneities Within Binary Information Strings.

In a previous paper (Buser, 1982) a nonparametric test has been presented for deciding whether or not a binary coded taxonomic node is significantly homogeneous. In the following tables the corresponding critical values, both for the one and two tailed test, are given.

Celiac disease, pregnancy, small for gestational age: role of extravillous trophoblast.

It is questionable whether development of the intrauterine growth retardation or small for gestational age (SGA) children is related directly to inflammation associated with celiac disease. Localization and the amount of gliadin, Fas-L, as well as the incidence of apoptosis in 32-term placentas, was analyzed immunohistochemically and with in situ hybridization in a blinded fashion; these were correlated with the weight of their newborns. Extravillous trophoblasts (EVTs) from the noncompliant women were overloaded with gliadin; there was a moderate amount or no gliadin present in the controls. The weight of newborns was lower if extravillous trophoblasts were loaded with gliadin (-2.24SD) (p = 0.004). Increased apoptosis of EVT in placentas of noncompliant women was consistent with abundant expression of Fas-L in those cells and was linked to the low birth weight of newborns. Exposure to gliadin alters extravillous trophoblast dynamics by causing an increase in apoptotic shedding. In genetically predisposed individuals, gliadin affects fetal part of the placenta causing children to be small for their age. A gluten-free diet during pregnancy prevents SGA children and, thus, the fetal origin of serious adult diseases.

Evidence for genetic anticipation in hereditary non-polyposis colorectal cancer.

Hereditary non-polyposis colorectal cancer (HNPCC) is an autosomal, dominantly inherited, colorectal cancer (CRC) predisposition syndrome caused by germline mutations in DNA mismatch repair (MMR) genes, predominantly MLH1 and MSH2. Thus far, only limited data exist on the occurrence of genetic anticipation in HNPCC, i.e. the earlier age at diagnosis of CRC in successive generations. Performing nonparametric distribution-free statistical analyses, we investigated 55 parent-child pairs who had been diagnosed with CRC and who came from 21 Swiss HNPCC families with characterised MMR germline mutation (15 in MLH1 and 6 in MSH2). The overall median age at diagnosis was 43 years, with an interquartile range (IQR) of 14 and incidence ages ranging from 18 to 62 years. Descendants of HNPCC patients (median age at diagnosis 39 years, IQR=12) were found to be diagnosed with CRC significantly earlier than their parents (47 years, IQR=10), with the median of the paired age difference amounting to 8 years (IQR=15; P<0.0001). Birth cohort effects could be excluded, since the same, statistically significant, age difference was also observed in the oldest offspring birth cohort (birth year <1916; P=0.01). Genetic anticipation appeared to be more pronounced when the disease allele was transmitted through the father than through the mother (median age difference 11 vs. 4 years, respectively; both P<0.01). If confirmed in larger, ideally prospective studies, these results may have important implications for genetic counselling and clinical management of HNPCC families.