paywalled: Phenotype and Polyp Landscape in Serrated Polyposis Syndrome: A Series of 100 Patients From Genetics Clinics (Lynch Syndrome...)

 define: hyperplastic

hyperplastic colon polyps

What is a hyperplastic colon polyp?

                    ~~~~~~~~~~~~~~~~~~~~~~~~~~

Phenotype and Polyp Landscape in Serrated Polyposis Syndrome: A Series of 100 Patients From Genetics Clinics

Abstract

Serrated polyposis syndrome (SPS), also known as hyperplastic polyposis, is a syndrome of unknown genetic basis defined by the occurrence of multiple serrated polyps in the large intestine and associated with an increased risk of colorectal cancer (CRC). There are a variety of SPS presentations, which may encompass a continuum of phenotypes modified by environmental and genetic factors. To explore the phenotype of SPS, we recorded the histologic and molecular characteristics of multiple colorectal polyps in patients with SPS recruited between 2000 and 2010 from genetics clinics in Australia, New Zealand, Canada, and the United States. Three specialist gastrointestinal pathologists reviewed the polyps, which they classified into conventional adenomas or serrated polyps, with various subtypes, according to the current World Health Organization criteria. Mutations in BRAF and KRAS and mismatch repair protein expression were determined in a subset of polyps. A total of 100 patients were selected for the study, of whom 58 were female and 42 were male. The total polyp count per patient ranged from 6 to 150 (median 30). The vast majority of patients (89%) had polyposis affecting the entire large intestine. From this cohort, 406 polyps were reviewed. Most of the polyps (83%) were serrated polyps: microvesicular hyperplastic polyps (HP) (n=156), goblet cell HP (n=25), sessile serrated adenoma/polyps (SSA/P) (n=110), SSA/P with cytologic dysplasia (n=28), and traditional serrated adenomas (n=18). A further 69 polyps were conventional adenomas. BRAF mutation was mainly detected in SSA/P with dysplasia (95%), SSA/P (85%), microvesicular HP (76%), and traditional serrated adenoma (54%), whereas KRAS mutation was present mainly in goblet cell HP (50%) and in tubulovillous adenoma (45%). Four of 6 SSA/Ps with high-grade dysplasia showed loss of MLH1/PMS2 expression. CRC was diagnosed in 39 patients who were more often found to have a conventional adenoma compared with patients without CRC (P=0.003). Patients with SPS referred to genetics clinics had a pancolonic disease with a high polyp burden and a high rate of BRAF mutation. The occurrence of CRC was associated with the presence of conventional adenoma.

abstract: Use of Mismatch Repair Immunohistochemistry and Microsatellite Instability Testing: Exploring Canadian Practices

METHODS:

Two web-based questionnaires were administered, a general and a specialist laboratory questionnaire, to establish the availability of such tests, requisite clinical/pathology integration, current mode of test initiation, reporting and recommendation practices, and education and attitudes among pathologists. Technical aspects were reviewed on the basis of specialist laboratory practice.

RESULTS:

Of 76 respondents, 21.5% were unaware or were uncertain whether they had access to MMR immunohistochemistry. Although 78.9% of respondents had access to such testing, an integrated approach to the identification of patients with LS is lacking, being limited to just 9 centers. The majority (70%) of testing is clinician initiated, with variable implementation of reflex testing and divergent practices in recommendation to test. Standardized reporting is lacking in many centers. Education on MMR in endometrial cancer is poor compared with that in colorectal cancer (P<0.0001).

(Blogger's Note: and so it would be safe to assume, based on this abstract, that the full spectrum of Lynch Syndrome related cancers requires obviously increased attention. As a further note, this and similar abstracts should take the opportunity to detail, in the background section, the full cancer spectrum - a one-line sentence is all that is required.)

INTERPRETATION:

This multicenter questionnaire highlights heterogenous practices in dMMR testing and LS identification, both in clinical terms and with regard to technical aspects of testing. An integrated multidisciplinary approach is lacking, and there is a need to educate physicians and resolve ethical issues. A Canadian consensus statement and national guidelines on dMMR testing are urgently needed, requiring input from pathologists, clinicians, and genetic counselors.

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.

The Gastrointestinal Phenotype of Germline Biallelic Mismatch Repair Gene Mutations (Lynch Syndrome)

Abstract
OBJECTIVES:A novel cancer syndrome associated with biallelic mismatch repair (MMR) mutations has been described recently. Patients presenting with childhood-onset gastrointestinal (GI) cancers may carry biallelic MMR mutations and have a distinct phenotype from classic Lynch syndrome. The aim of this study was to characterize patients with GI small bowel and/or colorectal cancers (CRCs) who have germline biallelic MMR mutations.
METHODS:A search of a Canadian GI cancer registry and literature review to identify patients with biallelic MMR was conducted.
RESULTS:The database identified 237 patients with intestinal cancer diagnosed before the age of 35 years. Five (2.1%) patients had biallelic MMR mutations. Overall, 32 individuals, from 29 families, with biallelic MMR gene mutations and GI cancers were identified by the registry and literature review. Among the 29 patients with CRCs, the mean age of first cancer diagnosis was 16.4 years (range: 5-28).

MicroRNA (miR-155) Linked To Shut-Down Of DNA-Repair Genes

In research:

"The study, led by researchers at the Ohio State University Comprehensive Cancer Center-Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, shows that microRNA-155 (miR-155) can inhibit the activity of genes that normally correct the damage when the wrong bases are paired in DNA.

The loss or silencing of these genes, which are called mismatch repair genes, causes inherited cancer-susceptibility syndromes and contributes to the progression of colorectal, uterine, ovarian and other cancers."

"Overall, Croce says, "Our findings suggest that miR-155 expression might be an important stratification factor in the prognosis and treatment of cancer patients and provide an additional analytical test for exploring the etiology of microsatellite-instability tumors when the standard tests do not provide a conclusive diagnosis."