[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.

Editorial: Serrated Polyposis: The Last (or Only the Latest - Frontier of Familial Polyposis (Lynch Syndrome/familial/pre-malignant adenomas)

 Wiki:  Sessile serrated adenoma

 In gastroenterology, a sessile serrated adenoma (abbreviated SSA), also known as sessile serrated polyp (abbreviated SSP), is a premalignant flat (or sessile) lesions of the colon, predominantly seen in the cecum and ascending colon.

Editorial: Serrated Polyposis: The Last (or Only the Latest|[quest]|) Frontier of Familial Polyposis|[quest]| : The American Journal of Gastroenterology

The American Journal of Gastroenterology 107, 779-781 (May 2012) | doi:10.1038/ajg.2012.62

Editorial: Serrated Polyposis: The Last (or Only the Latest?) Frontier of Familial Polyposis?

Stephen J Lanspa, Dennis J Ahnen and Henry T Lynch

Abstract

Serrated polyps are thought to be precursors of ~15% of colorectal cancers and clinical criteria for a serrated polyposis (SP) syndrome have been proposed. In this issue of American Journal of Gastroenterology, Win et al. report that family members of individuals who meet the clinical criteria for SP are at increased risk for colorectal and possibly pancreatic cancer. The important data presented by Win et al. strongly support the concept that familial SP exists and help define the patterns of risk in this syndrome. The paper also illustrates the difficulties of trying to define a genetic syndrome on the basis of largely retrospective clinical data and highlights the importance of efforts to define the genetic basis of familial SP and to study these families in a systematic, prospective manner.

abstract: Incidence, prevalence and risk factors for peritoneal carcinomatosis from colorectal cancer - Segelman - 2012 - British Journal of Surgery - Wiley Online Library

Peritoneal Carcinomatosis (Creighton University) includes a variety of tumors that present with extensive metastasis throughout the peritoneal cavity (inside surface of the abdomen) and can be found with gall bladder, liver, colon, appendix, ovarian, pancreas, mesothelioma, pseudomyxoma peritonei, rectal, small bowel and stomach cancers. It is a broad description in which multiple tumors develop in and line the peritoneal abdominal cavity and linings.

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 Incidence, prevalence and risk factors for peritoneal carcinomatosis from colorectal cancer - Segelman - 2012 - British Journal of Surgery

Abstract

Background:

This was a population-based cohort study to determine the incidence, prevalence and risk factors for peritoneal carcinomatosis (PC) from colorectal cancer.

Methods:

Prospectively collected data were obtained from the Regional Quality Registry. The Cox proportional hazards regression model was used for multivariable analysis of clinicopathological factors to determine independent predictors of PC.

Results:

All 11 124 patients with colorectal cancer in Stockholm County during 1995–2007 were included and followed until 2010. In total, 924 patients (8·3 per cent) had synchronous or metachronous PC. PC was the first and only localization of metastases in 535 patients (4·8 per cent). The prevalence of synchronous PC was 4·3 per cent (477 of 11 124). The cumulative incidence of metachronous PC was 4·2 per cent (447 of 10 646). Independent predictors for metachronous PC were colonic cancer (hazard ratio (HR) 1·77, 95 per cent confidence interval 1·31 to 2·39; P = 0·002 for right-sided colonic cancer), advanced tumour (T) status (HR 9·98, 3·10 to 32·11; P < 0·001 for T4), advanced node (N) status (HR 7·41, 4·78 to 11·51; P < 0·001 for N2 with fewer than 12 lymph nodes examined), emergency surgery (HR 2·11, 1·66 to 2·69; P < 0·001) and non-radical resection of the primary tumour (HR 2·75, 2·10 to 3·61; P < 0·001 for R2 resection). Patients aged > 70 years had a decreased risk of metachronous PC (HR 0·69, 0·55 to 0·87; P = 0·003).

Conclusion:

PC is common in patients with colorectal cancer and is associated with identifiable risk factors.

Epigenomics Initiates PMA Submission for Colorectal Cancer Test | GenomeWeb Daily News | MDx | GenomeWeb

For its clinical module, Epigenomics will need to demonstrate that Epi proColon performs at least as well as fecal immunochemical testing, it said, adding that it has been in discussions with FDA about the design for its clinical study, which it expects to initiate in the coming months after the study's protocol has been finalized.

The clinical module for the PMA submission will include results of the head-to-head comparison with fecal immunochemical testing, previously announced data from a clinical validation study in a cohort of prospectively collected samples, and other clinical study results.

Last month, the Berlin, Germany-based molecular diagnostics firm announced clinical validation study results for the test. The test demonstrated 68 percent sensitivity and 80 percent specificity.

abstract: Outcomes for Patients who Develop Both Breast and Colorectal Cancer

BACKGROUND: Patients diagnosed with both breast and colorectal cancer are not uncommon and will likely be seen more often as the population ages and treatment modalities improve. Survival outcomes for such patients have not been previously reported.  

METHODS: The 1988-2007 Surveillance, Epidemiology, and End Results data were used to identify women diagnosed with both breast and colorectal cancer. Disease-specific survival rates were compared.  

RESULTS: We identified 4,835 women who were diagnosed with both breast and colorectal cancer. Of these, 2,844 (58.8%) were diagnosed with breast cancer first and 1,807 (37.4%) were diagnosed with colorectal cancer first; 184 (3.8%) had synchronous cancers. At 5 years following the second cancer diagnosis, 163 (3.4%) died of breast cancer and 477 (9.9%) died of colorectal cancer (P < 0.05). Comparing primary site groups between years 1 and 5 after the second cancer diagnosis showed that the relative risk of death from breast cancer declined by 46%, though it did not reach statistical significance (P = 0.24), while it significantly increased by 46% for colorectal cancer death (P = 0.0004). These findings persisted regardless of patient age, stage at diagnosis, or breast tumor histology.  

CONCLUSION: For women diagnosed with both breast and colorectal cancer, the cumulative risk of death at 5 years following the second cancer diagnosis is 3 times more likely to be due to colorectal cancer than to breast cancer. Colorectal cancer specific mortality increases with time, while breast cancer specific mortality decreases with time. Consideration should be given to these findings when discussing prognosis and making treatment decisions.

Low Bowel Cancer (Colo-rectal cancer) Awareness In UK (in women)

"...In the UK, bowel cancer is the one of the top three most common cancers diagnosed in both men and women, yet nearly three quarters of the women included in the survey did not recognize the disease as being one of the three most prevalent cancers in women."

abstract: Indication for oophorectomy during cytoreduction for intraperitoneal metastatic spread of colorectal or appendiceal origin(cytoreductive surgery/HIPEC)

BACKGROUND: The incidence of ovarian metastases at the time of peritoneal carcinomatosis, and the influence of such metastases on survival after cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC), are unknown.
METHODS: This retrospective analysis included 194 women subjected to CRS and HIPEC since 2001. The incidence of ovarian metastases, disease-free survival and disease-specific survival were analysed.
RESULTS: The histological diagnosis was colorectal cancer carcinomatosis in 108 patients, peritoneal mucinous carcinomatosis (PMCA) in 23 and disseminated peritoneal adenomucinosis (DPAM) in 63. Ninety-nine patients underwent oophorectomy during the HIPEC procedure. Ovarian metastases were confirmed in at least 52 per cent of the patients. There was a significant difference in disease-free survival between women with or without ovarian metastases in both PMCA and DPAM groups (P = 0·044 and P = 0·010 respectively). No significant differences in survival were found in the group with colorectal cancer carcinomatosis.
CONCLUSION: When peritoneal carcinomatosis of colorectal or appendiceal origin is confirmed, at least 52 per cent of ovaries will have synchronous metastases. Disease-free survival after a HIPEC procedure for PMCA or DPAM is significantly lower in women with ovarian metastases. Oophorectomy during CRS for peritoneal carcinomatosis should be strongly considered.

abstract: Indication for oophorectomy during cytoreduction for intraperitoneal metastatic spread of colorectal or appendiceal origin

BACKGROUND: The incidence of ovarian metastases at the time of peritoneal carcinomatosis, and the influence of such metastases on survival after cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC), are unknown.
CONCLUSION: When peritoneal carcinomatosis of colorectal or appendiceal origin is confirmed, at least 52 per cent of ovaries will have synchronous metastases. Disease-free survival after a HIPEC procedure for PMCA or DPAM is significantly lower in women with ovarian metastases. Oophorectomy during CRS for peritoneal carcinomatosis should be strongly considered.

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

message from Colorectal Cancer Assoc of Canada - Roche study requests colorectal cancer participants - Montreal, Toronto, Vancouver

Note: message received Jan 17th, deadline Jan 13th ??

abstract: Risk of colorectal and endometrial cancers in EPCAM deletion-positive Lynch syndrome: a cohort study : The Lancet Oncology (multi-national study)

Note: (abstract) study includes 194 mutation carriers with references to pancreatic and duodenal cancers; more information on EPCAM genetics can be found by searching this blog

Duodenal cancer - Wikipedia Duodenal cancer is a cancer in the beginning section of the small intestine. It is relatively rare compared to gastric cancer and colorectal cancer. en.wikipedia.org/wiki/Duodenal_cancer

Risk of colorectal and endometrial cancers in EPCAM deletion-positive Lynch syndrome: a cohort study : The Lancet Oncology

Interpretation

EPCAM deletion carriers have a high risk of colorectal cancer; only those with deletions extending close to the MSH2 promoter have an increased risk of endometrial cancer. These results underscore the effect of mosaic MSH2 deficiency, leading to variable cancer risks, and could form the basis of an optimised protocol for the recognition and targeted prevention of cancer in EPCAM deletion carriers.

full free access: Sex Hormones and Colorectal Cancer: What Have We Learned So Far? — J. Natl. Cancer Inst.

full free access: World Jnl Gastroenterology-Approach to early-onset colorectal cancer: Clinicopathological, familial, molecular and immunohistochemical characteristics

 World Journal of Gastroenterology - link to article    

Keywords (article) : Early onset colorectal cancer, Microsatellite instability, Lynch syndrome, Microsatellite stable colorectal cancer

Abstract/full free access: Adherence to cancer screening guidelines across Canadian provinces: an observational study

Note:

1) study period - "We calculated age-cancer-specific screening rates for ages 40-60 using the Canadian Community Health Survey (2003 and 2005), a cross-sectional, nationally representative survey of health status, health care utilization and health determinants in the Canadian population."
2) includes: breast, mammography, PSA

Impact of gene patents and licensing practices on access to genetic testing for inherited susceptibility to cancer: Comparing breast and ovarian cancer

Genetics in Medicine:
April 2010 - Volume 12 - Issue 4
Article
Impact of gene patents and licensing practices on access to genetic testing for inherited susceptibility to cancer:
Comparing breast and ovarian cancers with colon cancers

Abstract

Genetic testing for inherited susceptibility to breast and ovarian cancer can be compared with similar testing for colorectal cancer as a “natural experiment.” Inherited susceptibility accounts for a similar fraction of both cancers and genetic testing results guide decisions about options for prophylactic surgery in both sets of conditions.

One major difference is that in the United States, Myriad Genetics is the sole provider of genetic testing, because it has sole control of relevant patents for BRCA1 and BRCA2 genes, whereas genetic testing for familial colorectal cancer is available from multiple laboratories.

Colorectal cancer-associated genes are also patented, but they have been nonexclusively licensed.

Prices for BRCA1 and 2 testing do not reflect an obvious price premium attributable to exclusive patent rights compared with colorectal cancer testing, and indeed, Myriad's per unit costs are somewhat lower for BRCA1/2 testing than testing for colorectal cancer susceptibility. Myriad has not enforced patents against basic research and negotiated a Memorandum of Understanding with the National Cancer Institute in 1999 for institutional BRCA testing in clinical research. The main impact of patenting and licensing in BRCA compared with colorectal cancer is the business model of genetic testing, with a sole provider for BRCA and multiple laboratories for colorectal cancer genetic testing.

Myriad's sole-provider model has not worked in jurisdictions outside the United States, largely because of differences in breadth of patent protection, responses of government health services, and difficulty in patent enforcement.

Note: see abstract for authors which include: Robert Cook-Deegan, MD. Director, IGSP Center for Genome Ethics, Law & Policy.

open access: Cancer risk in MLH1, MSH2 and MSH6 mutation carriers; different risk profiles may influence clinical management

Subjects carrying a mutation in one of the MMR genes have a higher risk for developing colorectal cancer, but also for endometrial carcinoma and malignancies of the stomach, small bowel, ovaries, upper uroepithelial tract, biliary tract, skin and brain.(pancreas)