Performance of BRCA1/2 mutation prediction models in male breast cancer patients.

To establish whether existing mutation prediction models can identify which male breast cancer (MBC) patients should be offered BRCA1 and BRCA2 diagnostic DNA screening, we compared the performance of BOADICEA (Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm), BRCAPRO (BRCA probability) and the Myriad prevalence table ("Myriad"). These models were evaluated using the family data of 307 Dutch MBC probands tested for BRCA1/2, 58 (19%) of whom were carriers. We compared the numbers of observed vs predicted carriers and assessed the Area Under the Receiver Operating Characteristic (ROC) Curve (AUC) for each model. BOADICEA predicted the total number of BRCA1/2 mutation carriers quite accurately (observed/predicted ratio: 0.94). When a cut-off of 10% and 20% prior probability was used, BRCAPRO showed a non-significant better performance (observed/predicted ratio BOADICEA: 0.81, 95% confidence interval [CI]: [0.60-1.09] and 0.79, 95% CI: [0.57-1.09], vs. BRCAPRO: 1.02, 95% CI: [0.75-1.38] and 0.94, 95% CI: [0.68-1.31], respectively). Myriad underestimated the number of carriers in up to 69% of the cases. BRCAPRO showed a non-significant, higher AUC than BOADICEA (0.798 vs 0.776). Myriad showed a significantly lower AUC (0.671). BRCAPRO and BOADICEA can efficiently identify MBC patients as BRCA1/2 mutation carriers. Besides their general applicability, these tools will be of particular value in countries with limited healthcare resources.

Detection of lactate in the striatum without contamination of macromolecules by J-difference editing MRS at 7T.

Lactate levels are measurable by MRS and are related to neural activity. Therefore, it is of interest to accurately measure lactate levels in the basal ganglia networks. If sufficiently stable, lactate measurements may be used to investigate alterations in dopaminergic signalling in the striatum, facilitating the detection and diagnosis of metabolic deficits. The aim of this study is to provide a J-difference editing MRS technique for the selective editing of lactate only, thus allowing the detection of lactate without contamination of overlapping macromolecules. As a validation procedure, macromolecule nulling was combined with J-difference editing, and this was compared with J-difference editing with a new highly selective editing pulse. The use of a high-field (7T) MR scanner enables the application of editing pulses with very narrow bandwidth, which are selective for lactate. We show that, despite the sensitivity to B0 offsets, the use of a highly selective editing pulse is more efficient for the detection of lactate than the combination of a broad-band editing pulse with macromolecule nulling. Although the signal-to-noise ratio of uncontaminated lactate detection in healthy subjects is relatively low, this article describes the test-retest performance of lactate detection in the striatum when using highly selective J-difference editing MRS at 7 T. The coefficient of variation, σw and intraclass correlation coefficients for within- and between-subject differences of lactate were determined. Lactate levels in the left and right striatum were determined twice in 10 healthy volunteers. Despite the fact that the test-retest performance of lactate detection is moderate with a coefficient of variation of about 20% for lactate, these values can be used for the design of new studies comparing, for example, patient populations with healthy controls.

Multi-center reproducibility of neurochemical profiles in the human brain at 7 T.

The purpose of this work was to harmonize data acquisition and post-processing of single voxel proton MRS ((1) H-MRS) at 7 T, and to determine metabolite concentrations and the accuracy and reproducibility of metabolite levels in the adult human brain. This study was performed in compliance with local institutional human ethics committees. The same seven subjects were each examined twice using four different 7 T MR systems from two different vendors using an identical semi-localization by adiabatic selective refocusing spectroscopy sequence. Neurochemical profiles were obtained from the posterior cingulate cortex (gray matter, GM) and the corona radiata (white matter, WM). Spectra were analyzed with LCModel, and sources of variation in concentrations ('subject', 'institute' and 'random') were identified with a variance component analysis. Concentrations of 10-11 metabolites, which were corrected for T1 , T2 , magnetization transfer effects and partial volume effects, were obtained with mean Cramér-Rao lower bounds below 20%. Data variances and mean concentrations in GM and WM were comparable for all institutions. The primary source of variance for glutamate, myo-inositol, scyllo-inositol, total creatine and total choline was between subjects. Variance sources for all other metabolites were associated with within-subject and system noise, except for total N-acetylaspartate, glutamine and glutathione, which were related to differences in signal-to-noise ratio and in shimming performance between vendors. After multi-center harmonization of acquisition and post-processing protocols, metabolite concentrations and the sizes and sources of their variations were established for neurochemical profiles in the healthy brain at 7 T, which can be used as guidance in future studies quantifying metabolite and neurotransmitter concentrations with (1) H-MRS at ultra-high magnetic field.

(31)P magnetic resonance spectroscopy of the breast and the influence of the menstrual cycle.

Phosphorus metabolite ratios are potential biomarkers in breast cancer diagnosis and treatment monitoring. Our purpose was to investigate the metabolite ratios phosphomonoester to phosphodiester, phosphoethanolamine (PE) to glycerophosphoethanolamine (GPE), and phosphocholine (PC) to glycerophosphocholine (GPC) in glandular breast tissue, and the potential effect of the menstrual cycle, using (31)P magnetic resonance spectroscopy (MRS) at 7T. Seven women with regular menstrual cycles each underwent four examinations using a 3D (31)P multi-echo magnetic resonance spectroscopic imaging sequence. Peak integrals were assessed using IDL and JMRUI software. First, T2 relaxation times were calculated using multi-echo data pooled across subjects and time points. Subsequent, metabolite ratios were calculated for each phase of the menstrual cycle using the calculated T2 values to account for when combining the free induction decay and all five echoes. The metabolite ratios were calculated both on group level and individually. T2 decay fits resulted in a T2 relaxation time for PE of 154 ms (95 % CI 144-164), for PC of 173 ms (95 % CI 148-205), for Pi of 188 ms (95 % CI 182-193), for GPE of 48 ms (95 % CI 44-53), and for GPC of 23 ms (95 % CI 21-26). The metabolite ratios analyzed on group level showed negligible variation throughout the menstrual cycle. Individual results did show an apparent intra-individual variation; however, not significant due to the measurements' uncertainty. To conclude, phospholipids in glandular tissue as measured with (31)P MRS at 7 T are not significantly affected by the menstrual cycle.

Silencing of the glycerophosphocholine phosphodiesterase GDPD5 alters the phospholipid metabolite profile in a breast cancer model in vivo as monitored by (31) P MRS.

Abnormal choline phospholipid metabolism is an emerging hallmark of cancer, which is implicated in carcinogenesis and tumor progression. The malignant metabolic phenotype is characterized by high levels of phosphocholine (PC) and relatively low levels of glycerophosphocholine (GPC) in aggressive breast cancer cells. Phosphorus ((31) P) MRS is able to non-invasively detect these water-soluble metabolites of choline as well as ethanolamine phospholipid metabolism. Here we have investigated the effects of stably silencing glycerophosphoester diesterase domain containing 5 (GDPD5), which is an enzyme with glycerophosphocholine phosphodiesterase activity, in MDA-MB-231 breast cancer cells and orthotopic tumor xenografts. Tumors in which GDPD5 was stably silenced with GDPD5-specific shRNA contained increased levels of GPC and phosphoethanolamine (PE) compared with control tumors.

Improved efficiency on editing MRS of lactate and γ-aminobutyric acid by inclusion of frequency offset corrected inversion pulses at high fields.

γ-Aminobutyric acid (GABA) and lactate are metabolites which are present in the brain. These metabolites can be indicators of psychiatric disorders or tumor hypoxia, respectively. The measurement of these weakly coupled spin systems can be performed using MRS editing techniques; however, at high field strength, this can be challenging. This is due to the low available B1 (+) field at high fields, which results in narrow-bandwidth refocusing pulses and, consequently, in large chemical shift displacement artifacts. In addition, as a result of the increased chemical shift displacement artifacts and chemical shift dispersion, the efficiency of the MRS method is reduced, even when using adiabatic refocusing pulses. To overcome this limitation, frequency offset corrected inversion (FOCI) pulses have been suggested as a mean to substantially increase the bandwidth of adiabatic pulses. In this study, a Mescher-Garwood semi-localization by adiabatic selection and refocusing (MEGA-sLASER) editing sequence with refocusing FOCI pulses is presented for the measurement of GABA and lactate in the human brain. Metabolite detection efficiencies were improved by 20% and 75% for GABA and lactate, respectively, when compared with editing techniques that employ adiabatic radiofrequency refocusing pulses. The highly efficient MEGA-sLASER sequence with refocusing FOCI pulses is an ideal and robust MRS editing technique for the measurement of weakly coupled metabolites at high field strengths.

Introduction of ultra-high-field MR brain imaging in infants: vital parameters, temperature and comfort.

Background: Brain MRI in infants at ultra-high-field scanners might improve diagnostic quality, but safety should be evaluated first. In our previous study, we reported simulated specific absorption rates and acoustic noise data at 7 Tesla. Methods: In this study, we included twenty infants between term-equivalent age and three months of age. The infants were scanned on a 7 Tesla MRI directly after their clinically indicated 3 Tesla brain MRI scan. Vital parameters, temperature, and comfort were monitored throughout the process. Brain temperature was estimated during the MRI scans using proton MR spectroscopy. Results: We found no significant differences in vital parameters, temperature, and comfort during and after 7 Tesla MRI scans, compared to 3 Tesla MRI scans. Conclusions: These data confirm our hypothesis that scanning infants at 7 Tesla MRI appears to be safe and we identified no additional risks from scanning at 3 Tesla MRI.

Increased frequency of 20q gain and copy-neutral loss of heterozygosity in mismatch repair proficient familial colorectal carcinomas.

Many hereditary nonpolyposis colorectal cancers (CRCs) cannot be explained by Lynch syndrome. Other high penetrance genetic risk factors are likely to play a role in these mismatch repair (MMR)-proficient CRC families. Because genomic profiles of CRC tend to vary with CRC susceptibility syndromes, our aim is to analyze the genomic profile of MMR-proficient familial CRC to obtain insight into the biological basis of MMR-proficient familial CRC. We studied 30 MMR-proficient familial colorectal carcinomas, from 15 families, for genomic aberrations, including gains, physical losses, and copy-neutral loss of heterozygosity LOH (cnLOH) using SNP array comparative genomic hybridization. In addition, we performed somatic mutation analysis for KRAS, BRAF, PIK3CA and GNAS. The frequency of 20q gain (77%) is remarkably increased when compared with sporadic CRC, suggesting that 20q gain is involved in tumor progression of familial CRC. There is also a significant increase in the frequency of cnLOH and, as a consequence, a reduced frequency of physical loss compared with sporadic CRC. The most frequent aberrations observed included gains of 7p, 7q, 8q, 13q, 20p and 20q as well as physical losses of 17p, 18p and 18q. Most of these changes are also observed in sporadic CRC. Mutations in KRAS were identified in 37% of the MMR-proficient CRCs, and mutations in BRAF were identified in 16%. No mutations were identified in PIK3CA or chromosome 20 candidate gene GNAS. We show that the patterns of chromosomal instability of MMR-proficient familial CRC are clearly distinct from those from sporadic CRC. Both the increased gain on chromosome 20 and the increased levels of cnLOH suggest the presence of yet undiscovered germline defects that can, in part, underlie the cancer risk in these families.

Evaluation of RAD51C as cancer susceptibility gene in a large breast-ovarian cancer patient population referred for genetic testing.

Despite extensive analysis of the BRCA1 and BRCA2 genes, germline mutations are detected in <20% of families with a presumed genetic predisposition for breast and ovarian cancer. Recent literature reported RAD51C as a new breast cancer susceptibility gene. In this study, we report the analysis of 410 patients from 351 unrelated pedigrees. All were referred for genetic testing and we selected families with at least one reported case of ovarian cancer in which BRCA1&2 mutations were previously ruled out. We analyzed the coding exons, intron-exons boundaries, and UTRs of RAD51C. Our mutation analysis did not reveal any unequivocal deleterious mutation. In total 12 unique sequence variations were identified of which two were novel. Our study and others suggest a low prevalence of RAD51C mutations with an exception for some founder populations. This observation is in favor of the rare allele hypothesis in the debate over the nature of the genetic contribution to individual susceptibility to breast and ovarian cancer and further genome-wide studies in high risk families are warranted.

Increase in SNR for 31P MR spectroscopy by combining polarization transfer with a direct detection sequence.

The sensitivity of (31)P MRS can be increased using higher magnetic fields, but also by using (1)H to (31)P polarization transfer techniques where the sensitivity is determined by the polarization of the proton spins and thus the signal-to-noise per unit time is unaffected by the slow T(1) relaxation properties of the (31)P spins. This implies that (31)P spins can be manipulated during the T(1) relaxation of the (1)H spins without affecting the signal-to-noise of the (1)H to (31)P polarization transferred spins. It is shown here that by combining (1)H to (31)P polarization transfer with a direct (31)P detection sequence in one repetition time, one can gain more signal-to-noise per unit of time as compared to a polarization transfer sequence alone. Proof of principle was demonstrated by phantom measurements and additionally the method was applied to the human calf muscle and to the human breast in vivo at 7 T.

A founder BRCA2 mutation in non-Afrikaner breast cancer patients of the Western Cape of South Africa.

Founder mutations in BRCA1 and BRCA2 have been reported in many different populations. We studied 105 Coloured and 16 Black Xhosa women residing in the Western Cape of South Africa diagnosed with breast cancer. We screened these patients using our standard panel of six previously reported SA Afrikaner and Ashkenazi Jewish BRCA1/2 mutations and identified only two Afrikaner mutations. Further screening by the protein truncation test (BRCA1 exon 11, and BRCA2 exons 10 and 11) revealed an additional four deleterious mutations (BRCA1 c.1504_ 1508del,p.Leu502AlafsX2, BRCA2 c.2826_2829del,p.Ile943LysfsX16, c.6447_6448dup,p.Lys2150IlefsX19 and c.5771_5774del,p.Ile1924Argfs X38). The latter, also known in Breast Cancer Information Core nomenclature as 5999del4, was identified in 4 of 105 (3.8%) Coloureds and 4 of 16 (25%) Xhosa women, which makes it a frequent founder mutation in the Western Cape Province. Although this mutation was previously reported to occur in the Netherlands, haplotype analysis indicated two distinct origins for the Dutch and South African mutations, excluding the possibility of a common Dutch ancestor and suggesting gene flow from the indigenous tribes such as the Xhosa to the Coloured population instead. Further studies to determine the carrier rate of this variant in the Xhosa and other SA populations are warranted.

Quantitative short echo time 1H MRSI of the peripheral edematous region of human brain tumors in the differentiation between glioblastoma, metastasis, and meningioma.

PURPOSE: To assess metabolite levels in peritumoral edematous (PO) and surrounding apparently normal (SAN) brain regions of glioblastoma, metastasis, and meningioma in humans with (1)H-MRSI to find biomarkers that can discriminate between tumors and characterize infiltrative tumor growth. MATERIALS AND METHODS: Magnetic resonance (MR) spectra (semi-LASER MRSI, 30 msec echo time, 3T) were selected from regions of interest (ROIs) under MRI guidance, and after quality control of MR spectra. Statistical testing between patient groups was performed for mean metabolite ratios of an entire ROI and for the highest value within that ROI. RESULTS: The highest ratios of the level of choline compounds and the sum of myo-inositol and glycine over N-acetylaspartate and creatine compounds were significantly increased in PO regions of glioblastoma versus that of metastasis and meningioma. In the SAN region of glioblastoma some of these ratios were increased. Differences were less prominent for metabolite levels averaged over entire ROIs. CONCLUSION: Specific metabolite ratios in PO and SAN regions can be used to discriminate glioblastoma from metastasis and meningioma. An analysis of these ratios averaged over entire ROIs and those with most abnormal values indicates that infiltrative tumor growth in glioblastoma is inhomogeneous and extends into the SAN region.

Childhood brain tumours due to germline bi-allelic mismatch repair gene mutations.

Childhood brain tumours may be due to germline bi-allelic mismatch repair (MMR) gene mutations in MLH1, MSH2, MSH6 or PMS2. These mutations can also lead to colorectal neoplasia and haematological malignancies. Here, we review this syndrome and present siblings with early-onset rectal adenoma and papillary glioneural brain tumour, respectively, due to novel germline bi-allelic PMS2 mutations. Identification of MMR protein defects can lead to early diagnosis of this condition. In addition, assays for these defects may help to classify brain tumours for research protocols aimed at targeted therapies.

7-T (1) H MRS with adiabatic refocusing at short TE using radiofrequency focusing with a dual-channel volume transmit coil.

In vivo MRS of the human brain at ultrahigh field allows for the identification of a large number of metabolites at higher spatial resolutions than currently possible in clinical practice. However, the in vivo localization of single-voxel spectroscopy has been shown to be challenging at ultrahigh field because of the low bandwidth of refocusing radiofrequency (RF) pulses. Thus far, the proposed methods for localized MRS at 7 T suffer from long TE, inherent signal loss and/or a large chemical shift displacement artifact that causes a spatial displacement between resonances, and results in a decreased efficiency in editing sequences. In this work, we show that, by driving a standard volume coil with two RF amplifiers, focusing the B 1+ field in a certain location and using high-bandwidth adiabatic refocusing pulses, a semi-LASER (semi-localized by adiabatic selective refocusing) localization is feasible at short TE in the human brain with full signal acquisition and a low chemical shift displacement artifact at 7 T.

Peutz-Jeghers syndrome: a systematic review and recommendations for management.

Peutz-Jeghers syndrome (PJS, MIM175200) is an autosomal dominant condition defined by the development of characteristic polyps throughout the gastrointestinal tract and mucocutaneous pigmentation. The majority of patients that meet the clinical diagnostic criteria have a causative mutation in the STK11 gene, which is located at 19p13.3. The cancer risks in this condition are substantial, particularly for breast and gastrointestinal cancer, although ascertainment and publication bias may have led to overestimates in some publications. Current surveillance protocols are controversial and not evidence-based, due to the relative rarity of the condition. Initially, endoscopies are more likely to be done to detect polyps that may be a risk for future intussusception or obstruction rather than cancers, but surveillance for the various cancers for which these patients are susceptible is an important part of their later management. This review assesses the current literature on the clinical features and management of the condition, genotype-phenotype studies, and suggested guidelines for surveillance and management of individuals with PJS. The proposed guidelines contained in this article have been produced as a consensus statement on behalf of a group of European experts who met in Mallorca in 2007 and who have produced guidelines on the clinical management of Lynch syndrome and familial adenomatous polyposis.

COGENT (COlorectal cancer GENeTics): an international consortium to study the role of polymorphic variation on the risk of colorectal cancer.

It is now recognised that a part of the inherited risk of colorectal cancer (CRC) can be explained by the co-inheritance of low-penetrance genetic variants. The accumulated experience to date in identifying these variants has served to highlight difficulties in conducting statistically and methodologically rigorous studies and follow-up analyses. The COGENT (COlorectal cancer GENeTics) consortium includes 20 research groups in Europe, Australia, the Americas, China and Japan. The overarching goal of COGENT is to identify and characterise low-penetrance susceptibility variants for CRC through association-based analyses. In this study, we review the rationale for identifying low-penetrance variants for CRC and our proposed strategy for establishing COGENT.

31P magnetic resonance spectroscopic imaging with polarisation transfer of phosphomono- and diesters at 3 T in the human brain: relation with age and spatial differences.

Tissue levels of the compounds phosphocholine (PC), phosphoethanolamine (PE), glycerophosphocholine (GPC) and glycerophosphoethanolamine (GPE) can be studied by in vivo 31P MRS. However, the detection of the signals of these compounds suffers from low sensitivity and contamination by underlying broad resonances of other phosphorylated compounds. Improved sensitivity without this contamination can be achieved with a method for optimal polarisation transfer of 1H to 31P spins in these molecules, called selective refocused insensitive nuclei-enhanced polarisation transfer (sRINEPT). The aim of this study was to implement a three-dimensional magnetic resonance spectroscopic imaging (MRSI) version of sRINEPT on a clinical 3 T magnetic resonance system to obtain spatially resolved relative levels of PC, PE, GPC and GPE in the human brain as a function of age, which could be used as a reference dataset for clinical applications. Good signal-to-noise ratios were obtained from voxels of 17 cm(3) of the parietal and occipital lobes of the brain within a clinically acceptable measurement time of 17 min. Eighteen healthy subjects of different ages (16-70 years) were examined with this method. A strong inverse relation of the PE/GPE and PC/GPC ratios with age was found. Spatial resolution was sufficient to detect differences in metabolite ratios between white and grey matter. Moreover, we showed the feasibility of this method for clinical use in a pilot study of patients with brain tumours. The sRINEPT MRSI technique enables the exploration of phospholipid metabolism in brain diseases with a better sensitivity than was possible with earlier 31P MRS methods.

SLV330, a cannabinoid CB1 receptor antagonist, ameliorates deficits in the T-maze, object recognition and Social Recognition Tasks in rodents.

Cannabinoid CB(1) receptor (CB(1)R) signaling has been suggested to play an important role in the regulation of memory and cognition. In the present study, our aim was to investigate whether the CB(1)R antagonist SLV330 (doses ranging from 0.3 to 10mg/kg, given orally, p.o.) could ameliorate impairments in distinct aspects of cognition using different disruption models in both mice and rats. Effects of SLV330 were tested on working memory deficits in the T-maze Continuous Alternation Task (T-CAT) in mice; episodic memory deficits in the Object Recognition Task (ORT) and Social Recognition Task (SRT) in rats. The acetylcholinesterase inhibitor (AChEI) donepezil (Aricept, approved for symptomatic treatment of Alzheimer's disease) and nicotine were used as reference compounds. SLV330 markedly improved aging and scopolamine-induced memory deficits in the T-CAT in mice with a lowest effective dose (LED) of 1mg/kg p.o., while reversing the cognitive dysfunction induced by the N-methyl-D-aspartate (NMDA) antagonist dizocilpine (MK-801) only at the middle dose of 3mg/kg. In the ORT, we have found that combined administration of subthreshold doses of SLV330 (1mg/kg, p.o.) and the AChEI donepezil (0.1mg/kg, p.o.), that had no discernable effects on performance when given alone, enhanced memory performance in Wistar rats with deficits induced by the muscarinic antagonist scopolamine, suggestive of additive synergistic effects of SLV330 and donepezil on cognitive impairment. Finally, SLV330 was found to have cognition enhancing properties in a time delay paradigm in the SRT at a LED dose of 3mg/kg (p.o.). In conclusion, the CB(1)R antagonist SLV330 was found to clearly improve memory in several preclinical models for cognitive impairment.

Introduction of Ultra-High-Field MR Imaging in Infants: Preparations and Feasibility.

BACKGROUND AND PURPOSE: Cerebral MR imaging in infants is usually performed with a field strength of up to 3T. In adults, a growing number of studies have shown added diagnostic value of 7T MR imaging. 7T MR imaging might be of additional value in infants with unexplained seizures, for example. The aim of this study was to investigate the feasibility of 7T MR imaging in infants. We provide information about the safety preparations and show the first MR images of infants at 7T. MATERIALS AND METHODS: Specific absorption rate levels during 7T were simulated in Sim4life using infant and adult models. A newly developed acoustic hood was used to guarantee hearing protection. Acoustic noise damping of this hood was measured and compared with the 3T Nordell hood and no hood. In this prospective pilot study, clinically stable infants, between term-equivalent age and the corrected age of 3 months, underwent 7T MR imaging immediately after their standard 3T MR imaging. The 7T scan protocols were developed and optimized while scanning this cohort. RESULTS: Global and peak specific absorption rate levels in the infant model in the centered position and 50-mm feet direction did not exceed the levels in the adult model. Hearing protection was guaranteed with the new hood. Twelve infants were scanned. No MR imaging-related adverse events occurred. It was feasible to obtain good-quality imaging at 7T for MRA, MRV, SWI, single-shot T2WI, and MR spectroscopy. T1WI had lower quality at 7T. CONCLUSIONS: 7T MR imaging is feasible in infants, and good-quality scans could be obtained.

Somatic APC mosaicism: an underestimated cause of polyposis coli.

BACKGROUND: The patient with 10 or more adenomas in the colon poses a diagnostic challenge. Beside germline mutations in the APC and MUTYH genes, only four cases of mosaic APC mutations have been reported. AIM: Given the relatively high frequency of de novo APC mutations in familial adenomatous polyposis (FAP), an investigation was carried out into whether the proportion of somatic mosaic APC mutations is currently underestimated. METHODS: Between 1 January 1994 and 31 December 2005 germline mutation analysis was performed in 599 consecutive index patients with polyposis coli referred for diagnostic APC scanning using a combination of denaturing gradient gel electrophoresis (DGGE) and protein truncation test (PTT). Variants were analysed by direct sequencing with primers flanking those used for DGGE and PTT, and quantified using pyrosequencing. RESULTS: Scrutinizing the molecular genetic results and family data of 242 index patients with pathogenic APC mutations led to the identification of 10 mosaic cases (4%). C>T transitions were observed in CGA sites in four of the 10 cases with somatic mosaicism, which is significantly more than 26 of the 232 non-mosaic cases (p = 0.02). Phenotypes of patients with somatic mosaicism ranged from an attenuated form of polyposis coli to florid polyposis with major extracolonic manifestations. CONCLUSIONS: Mosaicism occurs in a significant number of APC mutations and it is estimated that one-fifth of the de novo cases of FAP are mosaic. Clinically, the severity of manifestations in offspring and the recurrence risk for siblings of apparently sporadic polyposis patients may be underestimated due to parental APC mosaicism.