OVARIAN CANCER and US: MSI

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Showing posts with label MSI. Show all posts
Showing posts with label MSI. Show all posts

Saturday, May 26, 2012

[Biomarker for colorectal cancer] - Lynch Syndrome/MSI/KRAS/BRAF



[Biomarker for colorectal cancer]

Abstract
Discovery of usable molecular biomarkers is the step closer to a realization of personalized therapy for patients with colorectal cancer(CRC). Herein we present an update of the most recent data on promising biological prognostic and/or predictive markers, including microsatellite instability(MSI) and KRAS/BRAF mutations. Additionally, we propose a new genetic classification for CRC based on MSI and KRAS/BRAF mutation status (a 2 x 3 matrix). The 2 x 3 matrix is constructed of 6 cells that are made by [MSI/non-MSI] x [BRAF mutant/KRAS mutant/wild type of the both genes].

All of CRC including Lynch syndrome could be classified without overlapping into the 6 cells. More interestingly, each cell has each promising biological prognostic and/or predictive feature, which will help clinicians to make personalized treatment strategy for each CRC patient.


Sunday, April 22, 2012

abstract: Postmenopausal hormone therapy is associated with a reduced risk of colorectal cancer lacking CDKN1A expression




 http://cancerres.aacrjournals.org/content/early/2012/04/17/0008-5472.CAN-11-2619.abstract
  
Abstract
Experimental studies have shown that estrogen- or progesterone-activated signaling leads to growth inhibition effects on colon cancer cells through the upregulation of several cell cycle regulators. However, epidemiologic studies evaluating hormone therapy (HT) use and colorectal cancer risk by the status of cell cycle regulators are lacking. In this study, we used data from the prospective Nurses' Health Study to evaluate whether the association between HT use and colorectal cancer risk differs by the molecular pathological status of microsatellite instability (MSI) and expression of cell cycle-related tumor biomarkers, including CDKN1A (p21, CIP1), CDKN1B (p27, KIP1), and TP53 (p53) by immunohistochemistry. Duplication Cox regression analysis was used to determine an association between HT use, cancer risk, and specific tumor biomarkers in 581 incident colon and rectal cancer cases that occurred during 26 years of follow-up among 105520 postmenopausal women. We found a difference between HT use and colorectal cancer risk according to CDKN1A expression (p-value for heterogeneity=0.01). Current HT use was associated with a reduced risk for CDKN1A-nonexpressed (multivariate relative risk (RR)=0.61, 95% confidence interval (CI), 0.46-0.82), but not for CDKN1A-expressed (RR=1.32, 95% CI, 0.76-2.31) tumors. The lower risk for CDKN1A-nonexpressed, but not for CDKN1A-expressed cancers was also present among current users of estrogen-alone therapy. We found no significant difference in the relations between HT use and cancer risk according to MSI, CDKN1B, or TP53 status. Together, our molecular epidemiology findings suggest a preventive effect of HT against colorectal carcinogenesis which depends, in part, on loss of cyclin-dependent kinase inhibitor CDKN1A.

Saturday, April 21, 2012

abstract: Unusual DNA mismatch repair-deficient tumors in Lynch syndrome: a report of new cases and review of the literature.



Unusual DNA mismatch repair-deficient tumors in Lynch syndrome: a report of new cases and review of the literature.

Hum Pathol. 2012 Apr 17;


Abstract

Immunohistochemical detection of DNA mismatch repair proteins and polymerase chain reaction detection of microsatellite instability have enhanced the recognition of mismatch repair-deficient neoplasms in patients with Lynch syndrome and, consequently, led to the identification of tumors that have not been included in the currently known Lynch syndrome tumor spectrum.

Here, we report 4 such unusual tumors. Three of the 4, a peritoneal mesothelioma, a pancreatic acinar cell carcinoma, and a pancreatic well-differentiated neuroendocrine tumor, represented tumor types that, to the best of our knowledge, have not been previously reported in Lynch syndrome. The fourth tumor was an adrenocortical carcinoma, which has rarely been reported previously in Lynch syndrome. Three of our 4 patients carried a pathogenic germ-line mutation in a mismatch repair gene. The unusual tumor in each of the 3 patients showed loss of the mismatch repair protein corresponding to the mutation. The fourth patient did not have mutation information but had a history of colonic and endometrial carcinomas; both lacked MSH2 and MSH6 proteins. Interestingly, none of the 4 unusual tumors revealed microsatellite instability on polymerase chain reaction testing, whereas an appendiceal carcinoma from 1 of the study patients who was tested simultaneously did. The recognition of such tumors expands the repertoire of usable test samples for the workup of high-risk families.

As yet, however, there are no data to support the inclusion of these tumors into general screening guidelines for detecting Lynch syndrome, nor are there data to warrant surveillance for these tumors in patients with Lynch syndrome.

Wednesday, February 01, 2012

abstract: Clinical Effects of Adjuvant Active Specific Immunotherapy Differ between Patients with Microsatellite-Stable and Microsatellite-Instable Colon Cancer



Blogger's Note:  the abstract does not detail MSI-L/MSI-H (colon cancer in Lynch Syndrome)


Experimental Design:
Microsatellite status was assessed on archival tumor material from patients with stage II and III colon cancer. Microsatellite status was next associated with clinical outcome in control and ASI treatment groups using Kaplan–Meier analysis.



Conclusion:

This retrospective study indicated that patients with MSI tumors did well, irrespective of treatment arm and tumor stage. The data also indicate that the clinical benefit, measured as recurrence-free survival, from adjuvant ASI treatment of patients with colon cancer was restricted to patients with MSS Dukes B tumors

Tuesday, January 18, 2011

full free access: Absence of microsatellite instability in mucinous carcinomas of the breast (Lynch Syndrome)



Note: some key excerpt; see also Supplemental Tables 1-4

"Microsatellite instability (MSI) is a form of genetic instability that results from defects in DNA mismatch repair. MSI is reported to be rare in unselected breast cancers, however it is a common feature in subsets of colorectal, ovarian and endometrial cancers. In these anatomical sites, MSI-high carcinomas often display a mucinous histology. The aim of this study was to determine whether mucinous carcinomas of the breast would more frequently display MSI-high than invasive ductal carcinomas of no special type (IDC-NSTs). The expression of four MSI markers (i.e. MSH2, MSH6, MLH1 and PMS2) was immunohistochemically assessed in 35 mucinous breast carcinomas and 35 histological grade- and oestrogen receptor (ER) status-matched IDC-NSTs, and in a series of 245 invasive breast cancers...........
........
Subsets of colorectal [24], gastric [31], pancreatic [31], ovarian [32] and endometrial tumours [22,31,33], and particularly those occurring in the hereditary nonpolyposis colorectal cancer (HNPCC) or Lynch syndrome [31], are characterised by microsatellite instability. Interestingly, however, MSI-H appears to be vanishingly rare in breast cancer [21,34]. Likewise, breast cancers displaying an MSI-L status are remarkably rare, whereas in tumours from other anatomical sites, such as colorectal, endometrial or ovarian cancers [27], this phenomenon is not as uncommon. Of note, in some anatomical sites (e.g. colorectal and ovarian), tumours displaying microsatellite instability often display a mucinous histology [32,35,36]. However, the prevalence of MSI in mucinous carcinomas of the breast has not yet been systematically addressed........
...........All 35 pure mucinous carcinomas of the breast analysed were positive for MLH1 and MSH6 as determined by IHC, and 33 out of 35 (94.2%) and 32 out of 34 cases (94.1%) showed expression of MSH2 and PMS2, respectively (Table 2 and Figure 1)............cont'd

Monday, September 27, 2010

Prognostic value of microsatellite instability (MSI) and PTEN expression in women with endometrial cancer: results from studies of the NCIC Clinical Trials Group (NCIC CTG)



Abstract

AIM: The impact of PTEN status and microsatellite instability (MSI) on the prognosis of women with endometrial cancer is controversial. The aim of this study was to investigate MSI and PTEN expression in two patient populations using data from NCIC CTG studies.
METHODS: Archival paraffin embedded tumour from women with endometrial cancer enrolled in NCIC CTG studies: EN5 (stage I/II) and IND 126, 148 and 160 (advanced/recurrent disease) were examined for MSI using BAT25/26 and for PTEN expression using immunohistochemistry. PTEN and MSI status were correlated with clinicopathologic variables and survival using data from NCIC CTG trial databases.
RESULTS: PTEN and MSI results were available from 128 and 163 patients, respectively. MSI+ tumours were more common in women enrolled in EN5 compared to the IND studies (p=0.01). PTEN negative tumours were associated with improved survival in both univariate (hazard ratio (HR) 0.55, 95% confidence interval (CI) 0.32-0.94; p=0.03) and multivariate (adjusted HR 0.54, 95% CI 0.30-0.96; p=0.03) analyses in women enrolled in IND studies. Microsatellite stable tumours were associated with an improved prognosis in univariate (HR 0.18, 95% CI 0.06-0.51; p<0.0001)>
CONCLUSIONS: PTEN negative tumours in women with advanced disease are associated with improved survival. MSI+ tumours are more common in early stage disease and in this group of women are associated with a worse prognosis

Thursday, September 16, 2010

Genetic Instability Influences Drug Response in Cancer Cells (abstract)



Abstract

One of the main reasons why most patients with advanced cancer are not curable with the therapies available is the broad heterogeneity of cancer cells, inherently related to their genomic instability that reflects defects of cell cycle checkpoints and DNA mismatch repair (MMR). The present paper reviews Today's knowledge of MMR. Microsatellite (DNA repetitive sequences) instability (MSI) used as a surrogate marker of MMR defects was associated with a predisposition to somatic mutations of several genes including those involved in the neoplastic transformation and tumor progression. Lynch syndrome is an autosomal dominant cancer predisposition syndrome caused by germ line mutation in genes involved in MMR such as hMLH1 or hMLH2, or less frequently hMLH6 or hPMS2; it is associated with a high risk of intestinal cancer (CRC) and other tumors including endometrial, stomach, kidney and brain (AND ovarian cancer). There is ample preclinical evidence that cells deficient in MMR are resistant to methylating agents and to some antimetabolites, including 5FU, which is the drug used most for the CRC, whereas they are equally sensitive to oxaliplatin and possibly more sensitive to irinotecan. More studies are needed on the importance of MMR for sensitivity to different anticancer regimens and drugs, so this knowledge can guide rational therapy according to the tumor MMR status.

Friday, July 09, 2010

abstract: The Clinical Molecular Diagnostics Laboratory and Microsatellite Instability Testing of Colorectal Cancer



Note: this abstract gives an overview of Lynch Syndrome testing eg. immunohistochemistry (testing of tumour); Microsatellite (MSI); improved survival rates, treatment options (relating to test results)

full free access: Genomic aberrations in borderline ovarian tumors



Note: this paper is long and technical but of importance given, in part, the connection to Lynch Syndrome (MSI testing, microsatellite). Microsatellite testing is a test commonly used for suspected Lynch Syndrome patients. Specific research regarding ovarian cancer (epithelial) /MSI is limited.

Background
"According to the scientific literature, less than 30 borderline ovarian tumors have been karyotyped and less than 100 analyzed for genomic imbalances by CGH."

Saturday, May 15, 2010

Expert Reviews full access: On the advent of MSI testing of all colorectal cancers and a substantial part of other Lynch syndrome-related neoplasms



Worldwide, more than 1 million people present with colorectal cancer (CRC) annually. Of these, 2–5% occur in the context of Lynch syndrome (LS), the most common hereditary CRC predisposing syndrome (formerly designated as hereditary nonpolyposis CRC [HNPCC]). LS is characterized by a high lifetime risk for the development of CRC (20–70%), endometrial cancer (15–70%) and other extracolonic cancers (<15%). These extracolonic malignancies include carcinomas of the small intestine, stomach, pancreas and biliary tract, ovarium, brain, upper urinary tract and skin. .......germline mutation in one of the MMR genes MLH1, MSH2, MSH6 or PMS2.

Owing to the MMR deficiency in LS tumors, a microsatellite instability (MSI) phenotype is present. MSI, however, is also found in approximately 10–13% of sporadic CRCs (in total, MSI is present in approximately 15% of all CRCs). In addition to MSI, most LS tumors lack expression in the tumor cell nuclei of one of the four MMR proteins, MLH1, MSH2, MSH6 or PMS2.

Early detection of LS is of great importance, particularly in presymptomatic mutation carriers, since colonoscopic surveillance has proven to reduce CRC morbidity and mortality by 65–70% [6] and prophylactic surgery may prevent endometrial and ovarium carcinoma effectively.

Different models and strategies have been developed to identify patients with LS. In 1990, the Amsterdam criteria I were developed to provide a basis for uniformity in collaborative studies to find the disease-causing gene. These criteria were designed to be highly specific at the expense of sensitivity. They were criticized because extra-colonic tumors were not taken into account, thereby excluding classical LS families....Therefore, the Amsterdam criteria II were established in 1999"

Friday, May 07, 2010

Clinical Significance of Microsatellite Instability in Sporadic Epithelial Ovarian Tumors



Abstract: CONCLUSION: MSI was infrequent in ovarian tumors, including both borderline and malignant tumors. MSI was found to be uncommon in sporadic ovarian tumors, even by using additional MSI markers. The clinical significance of MSI is not strong in patients with sporadic ovarian tumors.

Link to full text (pdf file):


DISCUSSION
....MSI is caused by mutations in the mismatchrepair genes (MMR). MSI has been implicated in the pathogenesis of colon, endometrial, and gastric
carcinomas that occur in the setting of HNPCC (Lynch Syndrome), and also in a subset of sporadic cancers such as upper urinary tract, stomach, colon, andendometrial carcinomas.
In ovarian cancers, the reported incidence of MSI ranges from 0 to 37%, depending on the number and type of markers. Sood et al. first
reported the incidence of MSI in ovarian cancer using the NCI criteria.....Therefore, further study of molecular events that are correlated with ovarian tumors is needed."

Microsatellite instability in colorectal cancer. abstract




Thursday, May 06, 2010

Atypical identification of Lynch syndrome by immunohistochemistry and microsatellite instability analysis on jejunal adenocarcinoma



Note: abstract/free full text (pdf)
*this case describes a patient with many different cancers in the family including breast cancer, MSH6 deficiency

"LS (Lynch Syndrome) has been traditionally described in terms of earlyonset colorectal and endometrial cancers. Although this remains a confirmed association, we are learning more about the variability of LS and the prevalence of other cancers associated with this condition. The majority of cases of LS are reported to be caused by MLH1 and MSH2 gene mutations, but as evaluation for this condition becomes more widespread and routine in cases beyond the classically reported presentation, it is likely that we will come to find that the prevalence of other mismatch gene mutations is much higher than previously suspected."

Friday, April 23, 2010

Thursday, January 07, 2010

full free access-focus on Lynch Syndrome Ultradeep Sequencing of a Human Ultraconserved Region Reveals Somatic and Constitutional Genomic Instability



"Genomic instability is a common trait of cancer cells and plays a pivotal role in promoting carcinogenesis in several hereditary tumours. One of the best-known examples is the Lynch syndrome, an autosomal dominant condition associated with heterozygous mutations in mismatch repair (MMR) genes. During their lifespan, individuals affected by the Lynch syndrome...... The tumourigenic process starts when mutations hit oncogenes and/or tumour suppressors, often in actively renovating tissues such as endometrium, ovary, and colon. In the latter case, the genetic condition is known as hereditary non-polyposis colorectal cancer (HNPCC), which represents the most common form of inherited colorectal cancer.... Since more than 90% of HNPCC show MSI this has become a common diagnostic marker..."