[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.

PLoS ONE: The KRAS-Variant Is Associated with Risk of Developing Double Primary Breast and Ovarian Cancer (study of pts with both ovarian and breast cancers)

Blogger's Note: the other cancers (KRAS mutations) referred to beyond ovarian and breast cancers include references to lung and melanoma cancers; KRAS mutations have been established in colorectal cancers, however, there are no references on this particular subject within this research article regarding Lynch Syndrome -
an ongoing area of specific research (re: KRAS/Lynch Syndrome/blog posting of May 16, 2012 Jnl ASCP)
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PLoS ONE: The KRAS-Variant Is Associated with Risk of Developing Double Primary Breast and Ovarian Cancer


Table 1. The KRAS-variant is significantly associated with uninformative breast and ovarian cancer patients.
doi:10.1371/journal.pone.0037891.t001

Purpose

A germline microRNA binding site-disrupting variant, the KRAS-variant (rs61764370), is associated with an increased risk of developing several cancers. Because this variant is most strongly associated with ovarian cancer risk in patients from hereditary breast and ovarian families (HBOC), and with the risk of premenopausal triple negative breast cancer, we evaluated the association of the KRAS-variant with women with personal histories of both breast and ovarian cancer, referred to as double primary patients.

Conclusions

These findings further validate the importance of the KRAS-variant in breast and ovarian cancer risk, and support the association of this variant as a genetic marker for HBOC families previously considered uninformative.

Introduction 

Hereditary breast and ovarian cancer (HBOC) syndrome is an inherited cancer-susceptibility syndrome marked by an increased risk of developing both ovarian cancer and breast cancer [1]. Families generally considered as having HBOC syndrome are those with multiple family members that have one of these cancers, especially at young ages, or an individual with a cancer in both organs, a “double primary” patient. While this is a relatively rare presentation, a substantial number of women develop both breast and ovarian primaries over their lifetime. While BRCA1 and BRCA2 are strongly associated with HBOC syndrome [2], a large number of HBOC families and women with double primary cancer do not have detectable genetic mutations (herein referred to as “uninformative” patients).
The chances of identifying a mutation causative for HBOC increase when testing individuals diagnosed with double breast/ovarian primaries [3]–[5]. However, a recent report suggests that the rates of BRCA mutations are not higher in a patient with a double primary without a family history than that for isolated first degree relative pairs with single primaries (14% versus 17% with mutations, respectively) [4]. This supports the importance of family history even in patients with double primary cancers. Although BRCA mutations were found in 49% of double primary patients in this recent analysis, it should be noted that this indicates that over half of double primary patients do not have a known genetic cause for their disease. This is consistent with other reports of these patients [3], [5].............The goal of this study was to determine the association of the KRAS-variant with women with double primary breast and ovarian cancer, to further validate the association of this variant with HBOC families. Findings here support the importance of the KRAS-variant in uninformative HBOC families as well as in predicting the risk of multiple primary cancers in women.......

Association of the KRAS-variant with Multiple Cancers in All Patients

Because the KRAS-variant has been found to be associated with an increased risk for other cancers besides breast and ovarian cancer [11], [15] we tested the hypothesis that the KRAS-variant would predict for an increased risk of developing additional cancers in this double primary cohort, regardless of BRCA mutation status. For 183 of the patients in our study where this information was available, 79.2% (n = 145) had reported just the two cancers (breast and ovarian), 12.0% (n = 22) had two separate primary breast cancers and also ovarian cancer, and 8.7% (n = 16) had cancer in an additional organ outside of the breast and ovary (triple primary).

(Apr 2012) Commentary: Link between endometriosis and ovarian-cancer subtypes : The Lancet Oncology

Link between endometriosis and ovarian-cancer subtypes : The Lancet Oncology

"Previous large epidemiological studies have attempted to identify benign gynaecological disorders that predispose to the development of epithelial ovarian cancer. The only disorder that has been repeatedly1—4 (although not universally5) associated with this cancer is endometriosis. Results of some of these studies have suggested a specific link with endometrioid and clear-cell ovarian cancers, but until now none had the power to allow definitive subgroup analysis based on a contemporary definition of histological subtype.

 

In a study reported in the Lancet Oncology, Celeste Leigh Pearce and colleagues6 assessed self-reported endometriosis data from 13 pooled case—control studies in the Ovarian Cancer Association Consortium (OCAC). They confirm that a history of endometriosis is significantly associated with an increased risk of clear-cell (odds ratio 3·05, 95% CI 2·43—3·84) and endometrioid (2·04, CI 1·67—2·48) ovarian cancers, and for the first time show an association with low-grade serous ovarian cancer (2·11, 1·39—3·20). No association was noted between endometriosis and high-grade serous, mucinous, serous borderline, or mucinous borderline ovarian cancers.

 

With more than 23 000 participants (7911 with a diagnosis of ovarian cancer), the main strengths of this study are its statistical power and its robust methods. Incidences of reported endometriosis differ substantially between the pooled studies. Although clinicopathological and genetic differences between the populations could reasonably be expected, importantly there was no significant heterogeneity of the association with histological subtype in the different studies.

The main truly novel finding is an association between a history of endometriosis and low-grade serous ovarian cancer. Perhaps surprisingly, serous borderline tumours (from which invasive low-grade serous ovarian cancers are believed to arise7) are not also associated with a history of endometriosis.

abstract: KRAS mutations in ovarian low-grade endometrioid adenocarcinoma: association with concurrent endometriosis (study of KRAS/BRAF mutations)

Summary

The association between ovarian endometrioid adenocarcinoma and endometriosis is well established. However, not all endometrioid adenocarcinomas are directly related to endometriosis, and it has been suggested that there may be clinicopathologic differences between endometriosis-positive and endometriosis-negative tumors. Molecular alterations in endometrioid adenocarcinoma include KRAS and BRAF mutations, but the incidence of these abnormalities in previous reports has been highly variable (0%-36% and 0%-24%, respectively).....

Keywords

• Ovary;
• Endometrioid;
• Adenocarcinoma;
• Endometriosis;
• Molecular

Mutational analysis and clinical correlation of 185 consecutive metastatic colorectal patients: Similarities and differences between colon and rectal patients| 2011 ASCO Abstract

Conclusions:

Rectal and colon patients have similar rates of KRAS and PIK3CA mutations. However, BRAF mutations are more common in colon cancer. NRAS mutations are exclusively found in rectosigmoid cancers and may have a different biology than other colorectal cancers. These data suggest that primary tumor location may provide a means to enrich a population for a genotype-directed study.

Markman: KRAS Mutations in Ovarian Cancer -- Maybe Not

Medical News: SGO: Mutation Link to Ovarian Cancer Disputed - in Meeting Coverage, SGO from MedPage (KRAS mutation)

Expert Opinion on Medical Diagnostics - KRAS mutations - Summary

What the reader will gain: KRAS mutations in mCRC and NSCLC primary tumors predict resistance to EGFR-targeted therapy. In pancreatic cancer, KRAS may prove useful as a diagnostic biomarker to screen for early neoplasia. Furthermore, quantitative KRAS mutation analysis could have the potential to distinguish pancreatic cancer from other conditions such as chronic pancreatitis.

With respect to ovarian and endometrial cancer, further studies should focus on determining reliable biomarkers for predicting response to EGFR-targeted therapy. Besides EGFR inhibition, KRAS may also serve as a diagnostic and predictive biomarker for evolving therapies directed against mutant RAS proteins.

Take home message: KRAS has been recognized as an outstanding predictive biomarker to select mCRC and NSCLC patients for EGFR-targeted therapies; however, multi-determinant approaches including other molecular markers should facilitate the identification of patients likely to respond to such therapies.

See also blog post:

Wednesday, July 21, 2010

A KRAS-Variant in Ovarian Cancer Acts as a Genetic Marker of Cancer Risk (full access)

A KRAS-Variant in Ovarian Cancer Acts as a Genetic Marker of Cancer Risk (full access)

A KRAS-variant as a biomarker of ovarian cancer risk

Note: KRAS has been studied in colorectal cancer impacting on treatment program/no indication if ovarian cancer/Lynch Syndrome patients were included

Conclusions: These findings strongly support the hypothesis that the KRAS-variant is a genetic marker of an increased risk of developing ovarian cancer, and suggests that the KRAS- variant may be a new biomarker of risk for HBOC families without other known genetic abnormalities. In addition, the KRAS-variant predicts for the most deadly ovarian cancers, which are likely the most important to prevent or catch early.

Review Unmasking the complexities of mucinous ovarian carcinoma

Note: mucinous/KRAS is also prevalant in colorectal cancers

Conclusions

Primary mucinous ovarian cancer should be considered separate from the other epithelial ovarian cancers. Ongoing clinical trials in this disease will likely offer improvements in chemotherapeutic agents used to treat women with primary and recurrent mucinous ovarian cancer.