Clinicopathological and genetic characteristics of mucinous carcinomas in the colorectum.

We investigated the clinicopathological and genetic characteristics including patients' gender, age, tumour location, growth pattern, Dukes' stage, DNA ploidy, S-phase fraction, PCNA, apoptosis, c-erbB-2, bcl-2, K-ras, p53, DCC and heat shock protein in 32 mucinous carcinomas versus 261 non-mucinous carcinomas in the colorectum. Sixty percent of mucinous carcinomas were located in the right colon, 13% in the left colon and 27% in the rectum (p=0.01). More mucinous carcinomas grew in expanding pattern than non-mucinous carcinomas (66% vs 39%, p=0.005). Compared with non-mucinous carcinoma, mucinous carcinoma had more K-ras mutations (50% vs 25%, p=0.02), but less p53 expression (72% vs 49%, p=0.02) and less apoptotic activity (19% vs 51%, p=0.01). We further confirm that the mucinous carcinoma in the colorectum represents a distinct clinicopathologic and genetic features as compared to non-mucinous tumour, and may have a different biological behaviour.     

Mucinous carcinomas of the ovary and colorectum: different organ, same dilemma

Mucinous carcinomas are uncommon histological types that affect several organ sites. Primary mucinous carcinomas of the ovary are distinct from other ovarian carcinoma types, but they can pose a particular challenge for correct diagnosis from metastases, which most usually originate from the colorectum. Correct diagnosis is the mainstay of treatment, because standard practice states that protocols are tailored to the primary organ site. Little is known of mutational alterations in primary and metastatic mucinous carcinomas of the ovary, and few markers exist that can discriminate between them. We reviewed commonalities between ovarian and colorectal mucinous carcinomas with respect to aetiology, molecular alterations, differential diagnosis, and implications for treatment. Although primary mucinous carcinomas of the ovary and colorectum share similar mutational patterns and unfavourable outcomes at advanced stage, compared with their non-mucinous counterparts, important differences exist with respect to mucin localisation and specific molecular alterations. Technologies--eg, next-generation sequencing--could aid identification of additional driver molecular changes that will help clarify the relation between mucinous carcinomas from different organ sites. Perhaps, then, we can consider moving towards testing and adoption of therapeutic approaches tailored to molecular characteristics of mucinous carcinomas, irrespective of organ site, so patients' survival can be optimised.     

Is mucinous carcinoma of the colorectum a distinct genetic entity?

Mucinous carcinomas are defined on the basis of the amount of the mucus component in the tumour mass. Apart from this quantitative criterion, a number of clinicopathological parameters (such as localisation, prevalence in different countries and age groups, association with HNPCC and inflammatory processes) and genetic alterations (e.g. frequency of mutation in Ki-ras and p53 genes, level of MUC2 expression) differentiate these tumours from the non-mucinous ones. Since a different set of genetic lesions implies different inducing agents, these observations suggest that there may be a ''mucinous pathway of carcinogenesis''. Further identification of genetic changes characteristic of the mucinous phenotype will help to understand the aetiology of these tumours and possibly establish markers for detection of the high-risk group.     

Lobular and ductal carcinomas of the breast have distinct genomic and expression profiles

Invasive ductal carcinomas (IDCs) and invasive lobular carcinomas (ILCs) are the two major pathological types of breast cancer. Epidemiological and histoclinical data suggest biological differences, but little is known about the molecular alterations involved in ILCs. We undertook a comparative large-scale study by both array-compared genomic hybridization and cDNA microarray of a set of 50 breast tumors (21 classic ILCs and 29 IDCs) selected on homogeneous histoclinical criteria. Results were validated on independent tumor sets, as well as by quantitative RT-PCR. ILCs and IDCs presented differences at both the genomic and expression levels with ILCs being less rearranged and heterogeneous than IDCs. Supervised analysis defined a 75-BACs signature discriminating accurately ILCs from IDCs. Expression profiles identified two subgroups of ILCs: typical ILCs ( approximately 50%), which were homogeneous and displayed a normal-like molecular pattern, and atypical ILCs, more heterogeneous with features intermediate between ILCs and IDCs. Supervised analysis identified a 75-gene expression signature that discriminated ILCs from IDCs, with many genes involved in cell adhesion, motility, apoptosis, protein folding, extracellular matrix and protein phosphorylation. Although ILCs and IDCs share common alterations, our data show that ILCs and IDCs could be distinguished on the basis of their genomic and expression profiles suggesting that they evolve along distinct genetic pathways.     

Serrated carcinomas form a subclass of colorectal cancer with distinct molecular basis

Serrated colorectal carcinomas (CRCs) are morphologically different from conventional CRCs and have been proposed to follow a distinct pathway of CRC formation. Despite studies of single molecular events in this tumor type, the diagnosis of serrated CRC relies on morphology and the putative unique biological character of these tumors has not been established. Here we show that the gene expression profiling of 37 CRCs separated serrated and conventional CRCs into two distinct branches in unsupervised hierarchical clustering (P-value 7.8 x 10(-7)), and revealed 201 differentially expressed genes representing potential biomarkers for serrated CRC. Immunohistochemistry was utilized to verify the key findings in the 37 CRCs examined by expression profiling, and a separate validation set of 37 serrated and 86 conventional CRCs was examined to evaluate the candidate biomarkers in an extended sample material. Ephrin receptor B2, hypoxia-inducible factor 1-alpha and patched appeared as proteins important for genesis of serrated CRC. This study establishes serrated CRCs as a biologically distinct subclass of CRC and represents a step forward in the molecular classification of these cancers. The study also provides a platform to understand the molecular basis of serrated CRC and in long term may contribute to the development of specific treatment options for this tumor type.     

Mucinous carcinomas of the colon and rectum and their relation to polyps

A study of 44 mucinous carcinomas (MC) from a series of 324 colorectal cancers was made (221 surgical resections and 103 endoscopic biopsies). This study showed that MC were associated, in a significantly higher proportion when compared to non MC, with polypoid adenomas of different kinds (hyperplastic polyps not included), in other segments of the surgical specimen (P less than 0.001). MC originated from adenomas, particularly villous, but also mixed and tubular, in a significantly higher proportion than non-MC (P less than 0.001). Carcinomas arising from adenomas were mucinous in 11/14 cases. The type of adenomas from which MC arose were characterized by usually having areas with a particular arborizing mucus hyperplasia. At the time of resection, MC had metastases (Stages C and D) more frequently then non MC (P less than 0.02).     

Mucinous adenocarcinoma of the thymus: a distinct variant of thymic carcinoma

We analyzed the time trends of lung cancer by histological subtype in Hong Kong during 1991–2005, and examined how the time trends were influenced by the effects of birth cohort and calendar period of diagnosis. Cancer incidence data were obtained from Hong Kong Cancer Registry and population data from Census and Statistics Department. Age-standardized incidence rates were computed by the direct method using WHO 1966 standard population as reference. Period and cohort effects were assessed by using two separate Poisson regression models adjusting for age. From 1991 to 2005, the incidence rates in Hong Kong Chinese males decreased steadily. The decline in overall lung cancer incidence rates was limited primarily to the decrease in squamous cell carcinoma, which could be explained by the decreasing trend of cigarette smoking. Adenocarcinoma had been the most predominant histological subtype all along. The relatively horizontal trend of adenocarcinoma and the lack of cohort effect implied the important roles of gene-environment interaction and/or the use of low-tar and filter tip cigarettes. Our study suggests that different histological subtypes may represent different disease entities with perhaps some distinct risk factors. The hypotheses generated from this ecological study will need confirmation by subsequent analytic studies.     

Papillary carcinomas of the thyroid have pore-deficient nuclei

A significant reduction in nuclear pore density observed in papillary carcinomas compared to normal thyroid, adenomas and follicular carcinomas probably disturbs the nucleo-cytoplasmic transfer of ribonucleoproteins. This may contribute to the slow growth and indolent biological behavior of these tumors where even the presence of regional lymph node metastases does not worsen the prognosis. The signs of nuclear hyperactivity may result from an attempt to compensate for the nuclear membrane defect.     

Markedly elevated cell turnover is characteristic of small, deeply invasive carcinomas of the colorectum

BACKGROUND: Small, deeply invasive carcinomas invading the muscularis propria or deeper and measuring < or = 2 cm in greatest dimension (S-ADV) are rare in comparison with their larger counterparts (NS-ADV), and their clinicopathologic features are obscure. METHODS: S-ADV and NS-ADV cases as well as cases of submucosal carcinoma (SM-CA) were comparatively assessed for: 1) clinicopathologic findings; 2) Ki-67, mitotic, and apoptotic indices; 3) cathepsin G, p53, and bcl-2 immunoreactivities; and 4) c-Ki-ras mutations. RESULTS: S-ADV and SM-CA, which both are significantly smaller than NS-ADV, did not differ in size, but the frequency of moderately and poorly differentiated carcinoma elements at the leading edges was observed to be higher than in the central cores only in S-ADV, as was tumor "budding" of small clusters of undifferentiated carcinoma cells. The frequency of severe lymphatic involvement in S-ADV was as high as in NS-ADV, and significantly greater than in SM-CA. The Ki-67, mitotic, and apoptotic indices for S-ADV were significantly increased compared with those for NS-ADV and/or SM-CA. Expression of cathepsin G in S-ADV tumor and stromal cells was significantly decreased compared with NS-ADV and/or SM-CA cases. No significant differences in the expression of either p53 or bcl-2 or the incidence of c-Ki-ras mutations were observed among the three groups. CONCLUSIONS: S-ADV can be considered a distinct type of deeply invasive carcinoma, presenting with poor tumor differentiation at the leading edge, and with increased tumor cell proliferation despite its small size.     

Angiomatous meningiomas have a distinct genetic profile with multiple chromosomal polysomies including polysomy of chromosome 5

Meningiomas are a diverse group of tumors with a broad spectrum of histologic features. There are over 12 variants of meningioma, whose genetic features are just beginning to be described. Angiomatous meningioma is a World Health Organization (WHO) meningioma variant with a predominance of blood vessels. They are uncommon and confirming the histopathologic classification can be challenging. Given a lack of biomarkers that define the angiomatous subtype and limited understanding of the genetic changes underlying its tumorigenesis, we compared the genomic characteristics of angiomatous meningioma to more common meningioma subtypes. While typical grade I meningiomas demonstrate monosomy of chromosome 22 or lack copy number aberrations, 13 of 14 cases of angiomatous meningioma demonstrated a distinct copy number profile – polysomies of at least one chromosome, but often of many, especially in chromosomes 5, 13, and 20. WHO grade II atypical meningiomas with angiomatous features have both polysomies and genetic aberrations characteristic of other atypical meningiomas. Sequencing of over 560 cancer-relevant genes in 16 cases of angiomatous meningioma showed that these tumors lack common mutations found in other variants of meningioma. Our study demonstrates that angiomatous meningiomas have distinct genomic features that may be clinically useful for their diagnosis.     

Pathological features and genetic alterations in colorectal carcinomas with characteristics of nonpolypoid growth

We sought to clarify pathological features and genetic alterations in colorectal carcinomas with characteristics of nonpolypoid growth. Colorectal carcinomas resected at Showa University Hospital in Tokyo included 86 with characteristics of polypoid growth (PG) and 21 with those of nonpolypoid growth (NPG). Mutations of APC, Ki-ras, and p53 genes, as well as microsatellite instability (MSI), were analysed using fluorescence-based polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP). Carcinomas with an NPG pattern were smaller than PG tumours (P<0.0001). Carcinomas with a PG pattern were more likely to harbour Ki-ras mutations (36%) than NPG tumours (0%; P<0.0001). Mutation types in the APC gene differed significantly between PG and NPG carcinomas (P=0.0189), including frameshift mutations in 66% of PG carcinomas but no NPG carcinomas. Presence of a p53 mutation at a 'hot spot' also was more likely in PG carcinomas (37%) than in NPG carcinomas (0%; P=0.0124). No significant difference in presence of MSI was evident between carcinomas with PG and NPG patterns. In conclusion, significant genetic differences were evident between carcinomas with PG and NPG patterns. Genetic changes in NPG carcinomas differed from those of the conventional adenoma-carcinoma sequence. Assuming that some nonpolypoid growth lesions transform rapidly into advanced carcinomas, 20% of all colorectal carcinomas may progress in this manner.     

小细胞肺癌分子遗传学研究进展

小细胞肺癌(small cell lung cancer,SCLC)恶性程度高、预后差,现有的靶向药物治疗基本无效,迫切需要深入了解其分子特征从而筛选有效的治疗靶点。二代测序等全基因组研究技术为肿瘤的研究、诊治批量增加遗传标志物,SCLC的遗传位点亦不断被发现和解读。本文对近年SCLC分子遗传特征的研究进展进行综述。     

Loss of protein expression of hMLH1 and hMSH2 with double primary carcinomas of the stomach and colorectum

The frequency of synchronous or metachronous multiple primary carcinomas in patients with gastrointestinal carcinoma or colorectal carcinoma (CRC) has been reported to be approximately 10%. We determined the role of hMSH2 and hMLH1 in double carcinomas with both GC and CRC. Fifty-six patients with synchronous or metachronous colorectal carcinoma with gastric carcinoma (CRC with GC), and 69 patients with CRC alone was included in our study. We investigated their clinicopathological characteristics, family history and immunohistochemical stains of hMSH2 and hMLH1 were compared between the patients with CRC alone and those with both CRC with GC. The defective protein expression of hMSH1 and/or hMLH1 in colorectal carcinomas was significantly higher in patients with both CRC with GC than in those with CRC alone (p < 0.0001). The survival rate in patients with both CRC with GC was significantly lower than that in those with CRC alone (p < 0.01), in addition, the survival rate in patients with defective protein expression of hMSH2 and/or hMLH1 was higher than in those with a positive protein expression of hMSH2 and/or hMLH1 in CRC with GC (p < 0.05). The incidence of defective protein expression of hMSH2 and/or hMLH1 in CRC with GC patients suggests that abnormalities in the function of hMSH2 and hMLH1 may play an important role in carcinogenesis. Our findings indicate that the CRC patients who demonstrate a defective protein expression of hMSH2 and/or hMLH1 have a higher risk of developing secondary carcinoma in the gastrointestinal tract.     

Altered folate availability modifies the molecular environment of the human colorectum: implications for colorectal carcinogenesis

Low folate status increases colorectal cancer risk. Paradoxically, overly abundant folate supplementation, which is not uncommon in the United States, may increase risk. The mechanisms of these effects are unknown. We conducted two translational studies to define molecular pathways in the human colon altered either by folate supplementation or by dietary folate depletion (followed by repletion). In the first study, 10 healthy, at-risk volunteers (with documented stable/normal folate intake) received supplemental folic acid (1 mg/d) for 8 weeks. In the second study, 10 similar subjects were admitted to a hospital as inpatients for 12 weeks to study folate depletion induced by a low folate diet. A repletion regimen of folic acid (1 mg/d) was provided for the last 4 of these weeks. Both studies included an 8-week run-in period to ensure stabilized folate levels prior to intervention. We obtained 12 rectosigmoid biopsies (from 4 quadrants of normal-appearing mucosa 10-15 cm from the anal verge) at baseline and at measured intervals in both studies for assessing the primary endpoints: genome-wide gene expression, genomic DNA methylation, promoter methylation (depletion/repletion study only), and p53 DNA strand breaks. Serum and rectosigmoid folate concentrations accurately tracked all changes in folate delivery (P < 0.05). In the first study, gene array analysis revealed that supplementation upregulated multiple inflammation- and immune-related pathways in addition to altering several 1-carbon-related enzymes (P < 0.001). In the second study, folate depletion downregulated genes involved in immune response, inflammation, the cell cycle, and mitochondrial/energy pathways; repletion reversed most of these changes. However, changes in gene expression after repletion in the second study (involving immune response and inflammation) did not reach the levels seen after supplementation in the first study. Neither genomic nor promoter-specific DNA methylation changed during the course of the depletion/repletion protocol, and genomic methylation did not change with supplementation in the first study. p53 DNA strand breaks increased with depletion after 12 weeks. In sum, depletion downregulates, whereas repletion or supplementation upregulates pathways related to inflammation and immune response. These findings provide novel support to the concept that excessive folate supplementation might promote colorectal carcinogenesis by enhancing proinflammatory and immune response pathways. These results indicate that modest changes in folate delivery create substantial changes in the molecular milieu of the human colon.     

Mucinous cancers have fewer genomic alterations than more common classes of breast cancer

Mucinous cancers of the breast are distinguished histologically by their abundant pools of mucin and low degree of nuclear pleomorphism. Relative to the more common breast cancers of no distinctive type (ductal carcinoma), mucinous cancers have a relatively favorable prognosis. In a study of chromosomal changes in mucinous cancers, we evaluated the extent of loss of heterozygosity (LOH) at chromosomal regions commonly deleted in usual infiltrating ductal carcinoma, including markers on chromosomal arms 1p, 1q, 3p, 6q, 8p, 9p, 11p, 11q, 13q, 16q, 17p, and 17q. Remarkably, we found an average frequency of LOH of only 1.9 of these 12 chromosomal arms in 18 cases of mucinous carcinoma, compared to an average frequency of LOH of 6.4 of these same chromosomal arms in cases of infiltrating ductal cancer. In three of the 18 cases of mucinous carcinoma studied, including one case with regional lymph node metastases, no LOH was seen at any of the 12 chromosomal regions studied. We considered the possibility of other chromosomal loci being more commonly affected in mucinous cancers and conducted comparative genomic hybridization on six of the cases. These studies demonstrated a low overall frequency of genomic copy number changes (mean of 3.1 changes per case) and failed to reveal any other chromosomal locus with frequent losses that had not been evaluated by microsatellite analysis. Together, these data indicate that mucinous cancers of the breast do not have the extensive genomic alterations that are typically found in more common variants of breast cancer. Thus, mucinous cancers most likely have less genetic instability than most other forms of breast cancer and the molecular pathogenesis of this form of breast cancer is likely to be substantially different than that of usual ductal breast cancer.     

Obstructing carcinomas of the colon and rectum have a smaller size compared with those of non-obstructing carcinomas

The aim of the current study was to elucidate the histopathological characteristics of obstructing carcinoma of the colon and rectum. We studied 72 patients with colorectal carcinoma, including 13 with obstructing carcinoma. The obstruction carcinomas occurred in sigmoid colon significantly more frequently than did non-obstructing carcinomas (p=0.007). The mean size of the obstructing carcinomas was 3.7+/-0.9 cm, which was significantly smaller than that of non-obstructing carcinomas (5.4+/-1.9 cm, p=0.003). The proportion of lymph node metastasis in obstructing carcinomas was 66.9%, which was significantly higher than that in non-obstructing carcinomas (42.4%, p=0.021). The proportion of carcinomas classified into Dukes' C or D in obstructing carcinomas was 84.6% and was significantly higher than that in non-obstructing carcinomas (52.5%, p=0.026). The pathogenesis of obstruction in colorectal carcinoma can be also derived from the contraction of the intestinal lumen caused by the condensation of cancer cells.     

Occurrence of Aurora A positive multipolar mitoses in distinct molecular classes of colorectal carcinomas and effect of Aurora A inhibition

Aurora A “over‐”expression may induce supernumerary centrosomes, respective multipolar mitoses, and aneuploidy. Here, we examined Aurora A positive multipolar mitoses in aneuploid, microsatellite‐stable (MSS, “CIN‐type”) versus near‐diploid, microsatellite‐instable (MSI, “MIN‐type”) colorectal carcinomas (CRC) and CRC cell lines as well as the effect of Aurora A inhibition in CRC cell lines. In situ, three‐dimensional immunofluorescence (3D‐IF) revealed Aurora A positive multipolar mitoses in both CIN‐ (n = 8) and MIN‐ (n = 10) type primary CRCs with similar frequencies (CIN: 27 ± 14%; MIN: 34 ± 14%, P = 0.224). In vitro, Aurora A positive multipolar mitoses were detected in asynchronized or thymidine synchronized CIN‐type (HT29, CaCo‐2), but not MIN‐type (HCT116, DLD‐1) CRC cells. Nocodazole treatment arrested mitotic cells with multiple centrosomal Aurora A signals in CIN‐ and MIN‐type CRC cells, albeit to a lower extent in CaCo‐2 cells. This was associated with concomitant activation of Aurora A (T288 phosphorylation) and Polo‐like kinase 1 (PLK‐1, T210 phosphorylation). Aurora A inhibition by siRNA resulted in increased apoptosis (>50%) in all cell lines, but did not abolish PLK‐1 expression. Double 3D‐IF revealed that Aurora A siRNA treated, still viable CIN‐type (HT29, CaCo‐2) CRC cells were Aurora A negative and mostly in prophase/(pro)metaphase with maintained phosphorylated PLK‐1 T210 expression. Aurora A positive multipolar mitoses occur in both aneuploid, CIN‐ and near‐diploid MIN‐type CRCs. This appears to be largely independent of Aurora A expression alone. Although Aurora A inhibition causes apoptosis in both CIN‐ and MIN‐type CRC cells, remaining PLK‐1 activation by other factors may affect therapeutic Aurora inhibition. © 2011 Wiley Periodicals, Inc.