Molecular architecture of the Spire-actin nucleus and its implication for actin filament assembly

The Spire protein is a multifunctional regulator of actin assembly. We studied the structures and properties of Spire-actin complexes by X-ray scattering, X-ray crystallography, total internal reflection fluorescence microscopy, and actin polymerization assays. We show that Spire-actin complexes in solution assume a unique, longitudinal-like shape, in which Wiskott-Aldrich syndrome protein homology 2 domains (WH2), in an extended configuration, line up actins along the long axis of the core of the Spire-actin particle. In the complex, the kinase noncatalytic C-lobe domain is positioned at the side of the first N-terminal Spire-actin module. In addition, we find that preformed, isolated Spire-actin complexes are very efficient nucleators of polymerization and afterward dissociate from the growing filament. However, under certain conditions, all Spire constructs--even a single WH2 repeat--sequester actin and disrupt existing filaments. This molecular and structural mechanism of actin polymerization by Spire should apply to other actin-binding proteins that contain WH2 domains in tandem.     

Serous Cystadenomas of the Pancreas: Long-term Follow-up Measurement of Growth Rate

Purpose

To measure the growth rate of microcystic subtype serous adenomas of the pancreas diagnosed by imaging.

Methods

For this retrospective study, 241 imaging studies were reviewed from 1998 to 2005. Thirty-one patients met our strict diagnostic imaging inclusion criteria and had at least 18 months of imaging follow-up. Patient demographics and lesion imaging characteristics were tested as predictors of growth.

Results

Growth was measured over a mean period of 42 months. There was a significant (P = .0004) linear growth of tumour for the population. There was significant clustering (P = .001) of the population into 2 growth rates: 0.50 mm/y (n = 23) and 5.5 mm/y (n = 8). The diameter of the lesion at presentation was significantly correlated with growth (r = 0.45; P = .01).

Conclusion

The microcystic subtype of serous cystadenomas of the pancreas diagnosed with imaging criteria demonstrates 2 distinct and slow growth rates. The size of the lesion at presentation is correlated with growth rate.     

Characterization of two Ashkenazi Jewish founder mutations in MSH6 gene causing Lynch syndrome

Founder mutations are an important cause of Lynch syndrome and facilitate genetic testing in specific ethnic populations. Two putative founder mutations in MSH6 were analyzed in 2685 colorectal cancer (CRC) cases, 337 endometrial cancer (EnCa) cases and 3310 healthy controls of Ashkenazi Jewish (AJ) descent from population-based and hospital-based case–control studies in Israel, Canada and the United States. The carriers were haplotyped and the age of the mutations was estimated. MSH6*c.3984_3987dupGTCA was found in 8/2685 CRC cases, 2/337 EnCa cases, and 1/3310 controls, consistent with a high risk of CRC (odds ratio (OR) = 9.9, 95% confidence interval (CI) = 1.2–78.9, p = 0.0079) and a very high risk of EnCa (OR = 19.6, 95% CI = 1.8–217.2, p = 0.0006). MSH6*c.3959_3962delCAAG was identified in 3/2685 CRC cases, 2/337 EnCa cases and no controls. Each mutation was observed on separate conserved haplotypes. MSH6*c.3984_3987dupGTCA and MSH6*c.3959_3962delCAAG probably arose around 585 CE and 685 CE, respectively. No carriers were identified in Sephardi Jews (450 cases and 490 controls). Truncating mutations MSH6*c.3984_3987dupGTCA and MSH6*c.3959_3962delCAAG cause Lynch syndrome and are founder mutations in Ashkenazi Jews. Together with other AJ founder mutations, they contribute substantially to the incidence of CRC and EnCa and are important tools for the early diagnosis and appropriate management of AJ Lynch syndrome patients.     

Pathology features in Bethesda guidelines predict colorectal cancer microsatellite instability: a population-based study

BACKGROUND & AIMS: The revised Bethesda guidelines for Lynch syndrome recommend microsatellite instability (MSI) testing all colorectal cancers in patients diagnosed before age 50 years and colorectal cancers diagnosed in patients between ages 50 and 59 years with particular pathology features. Our aim was to identify pathology and other features that independently predict high MSI (MSI-H). METHODS: Archival tissue from 1098 population-based colorectal cancers diagnosed before age 60 years was tested for MSI. Pathology features, site, and age at diagnosis were obtained. Multiple logistic regression was performed to determine the predictive value of each feature, as measured by an odds ratio (OR), from which a scoring system (MsPath) was developed to estimate the probability a colorectal cancer is MSI-H. RESULTS: Fifteen percent of tumors (162) were MSI-H. Independent predictors were tumor-infiltrating lymphocytes (OR, 9.1; 95% confidence interval [CI], 5.9-14.1), proximal subsite (OR, 4.7; 95% CI, 3.1-7.3), mucinous histology (OR, 2.8; 95% CI, 1.7-4.8), poor differentiation (OR, 1.9; 95% CI, 1.2-3.1), Crohn's-like reaction (OR, 1.9; 95% CI, 1.2-2.9), and diagnosis before age 50 years (OR, 1.9; 95% CI, 1.3-2.9). MsPath score >or=1.0 had a sensitivity of 93% and a specificity of 55% for MSI-H. CONCLUSIONS: The probability an individual colorectal cancer is MSI-H is predicted well by the MsPath score. There is little value in testing for DNA mismatch repair loss in tumors, or for germline mismatch repair mutations, for colorectal cancers diagnosed in patients before age 60 years with an MSPath score <1 (approximately 50%). Pathology can identify almost all MSI-H colorectal cancers diagnosed before age 60 years.     

Exogenous hormones and colorectal cancer risk in Canada: associations stratified by clinically defined familial risk of cancer

Objective This work assessed associations between colorectal cancer risk and postmenopausal/contraceptive hormones; subgroup analyses included women with a clinically defined family history of cancer. Methods A population based case–control study of incident colorectal cancer was conducted among women aged 20–74 years in Ontario and Newfoundland & Labrador, Canada. Incident cases (n = 1,404) were selected from provincial cancer registries and controls (n = 1,203) were identified through property records, and other means, between January 1997 and April 2006. Family history of cancer, exogenous hormone-use, and other risk factors were collected via self-administered questionnaires. Multivariate unconditional logistic regression analyses were used to estimate odds ratios (ORs) and corresponding 95% confidence intervals (CIs). Results Decreased risks of colorectal cancer were observed with ever-users of: hormonal contraceptives (OR: 0.77; CI: 0.65–0.91), estrogen-only postmenopausal hormones (OR: 0.60; CI: 0.47–0.75), and estrogen–progestin postmenopausal hormones (OR: 0.70; CI: 0.52–0.95). Risk estimates were similar between women with and without a strong familial history of cancer. Age at initiation of hormonal contraceptives was associated with colorectal cancer risk; women who initiated use at younger ages (age <22 years: OR: 0.60; CI: 0.47–0.77) experienced a greater reduced risk of disease than women who initiated use at later ages (age 30+: OR: 0.92; CI: 0.68–1.24; p _trend: 0.0026). Conclusions These results indicate that exogenous hormone-use is linked with reduced risk of colorectal cancer among women with a strong familial risk of cancer, consistent with observations on population samples of sporadic colorectal cancer cases. A potential age-effect for use of hormonal contraceptives warrants further attention.