[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.

abstract - Identification of Cancer Patients with Lynch Syndrome: Clinically Significant Discordances and Problems in Tissue-Based Mismatch Repair Testing

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. 

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

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)

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."

Endometrial and ovarian carcinomas with undifferentiated components: clinically aggressive and frequently underrecognized neoplasms

"Endometrial and ovarian carcinomas with undifferentiated components have a broad histologic differential diagnosis, but they show specific histologic features that should enable accurate diagnosis. These tumors can occur in young women, may be associated with microsatellite instability and behave in a clinically aggressive manner." Modern Pathology

Defective mismatch repair, microsatellite mutation bias, and variability in clinical cancer phenotype

Cancer Res. 2010 Jan 15

Shah SN, Hile SE, Eckert KA.
Department of Pathology, Gittlen Cancer Research Foundation, Pennsylvania State University College of Medicine, Hershey, Pennsylvania

Microsatellite instability is associated with 10% to 15% of colorectal, endometrial, ovarian, and gastric cancers, and has long been used as a diagnostic tool for (Lynch Syndrome) hereditary nonpolyposis colorectal carcinoma-related cancers.
Tumor-specific length alterations within microsatellites are generally accepted to be a consequence of strand slippage events during DNA replication, which are uncorrected due to a defective postreplication mismatch repair (MMR) system.
Mutations arising within microsatellites associated with critical target genes are believed to play a causative role in the evolution of MMR-defective tumors.
In this review, we summarize current evidence of mutational biases within microsatellites arising as a consequence of intrinsic DNA sequence effects as well as variation in MMR efficiency.
Microsatellite mutational biases are generally not considered during clinical testing; however, we suggest that such biases may be clinically significant as a factor contributing to phenotypic variation among microsatellite instability-positive tumors.

High weight associated with risk of colorectal tumors without microsatellite instability

Note: the microsatellite test (MSS = stable; MSI-L = low; MSI-H = high) is a blood test and has also been studied in ovarian cancers

"Recent body mass index (people over 30 kg/m2 or more, the cut off for obesity) was positively associated with overall risk of colorectal cancer for men and women combined. It was also associated with risk of MS-stable and MSI-low colorectal tumors, but not with the risk of MSI-high tumors."

Efficacy of Annual Colonoscopic Surveillance in Individuals With Hereditary Nonpolyposis Colorectal Cancer (Lynch Syndrome) - MS status

Note: MS - microsatellite status
  
Methods:In a prospective, multicenter cohort study, 1126 individuals underwent 3474 colonoscopies. We considered individuals from 3 groups of HNPCC families: those with a pathogenic germline mutation in a mismatch repair gene (MUT group), those without a mutation but with microsatellite instability (MSI group), and those who fufilled the Amsterdam criteria without microsatellite instability (MSS group).

Conclusions:
Annual colonoscopic surveillance is recommended for individuals with HNPCC. Less intense surveillance might be appropriate for MSS families.

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..."