paywalled: Patients with Lynch Syndrome Mismatch Repair Gene Mutations Are at Higher Risk for Not Only Upper Tract Urothelial Cancer but Also Bladder Cancer

Patients with Lynch Syndrome Mismatch Repair Gene Mutations Are at Higher Risk for Not Only Upper Tract Urothelial Cancer but Also Bladder Cancer

Abstract

Background

Lynch syndrome (LS), or hereditary nonpolyposis colorectal cancer, is caused by mutations in mismatch repair (MMR) genes. An increased risk for upper tract urothelial carcinoma (UTUC) has been described in this population; however, data regarding the risk for bladder cancer (BCa) are sparse.

Objective

To assess the risk of BCa in MMR mutation carriers and suggest screening and management recommendations.

Design, setting, and participants

Cancer data from 1980 to 2007 were obtained from the Familial Gastrointestinal Cancer Registry in Toronto for 321 persons with known MMR mutations: mutL homolog 1, colon cancer, nonpolyposis type 2 (E. coli) (MLH1); mutS homolog 2, colon cancer, nonpolyposis type 1 (E. coli) (MSH2); mutS homolog 6 (E. coli) (MSH6); and PMS2 postmeiotic segregation increased 2 (S. cerevisiae) (PMS2).

Outcome measurements and statistical analysis

Standardized incidence ratios from the Ontario Cancer Registry, using the Surveillance Epidemiology and End Results public database, were used to compare cancer risk in patients with MMR mutations with the Canadian population. Microsatellite instability analysis and immunohistochemistry (IHC) of the MMR proteins were also performed and the results compared with matched sporadic bladder tumors.

Results and limitations

Eleven of 177 patients with MSH2 mutations (6.21%, p < 0.001 compared with the Canadian population) were found to have BCa, compared with 3 of 129 patients with MLH1 mutations (2.32%, p > 0.05). Of these 11 tumors, 81.8% lacked expression of MSH2 on IHC, compared with the matched sporadic cases, which all displayed normal expression of MSH2 and MLH1. The incidence of UTUC among MSH2 carriers was 3.95% (p < 0.001), and all tumors were found to be deficient in MSH2 expression on IHC. Mutations in the intron 5 splice site and exon 7 of the MSH2 gene increased the risk of urothelial cancer. Limitations include possible inflated risk estimates due to ascertainment bias.

Conclusions

LS patients with MSH2 mutations are at an increased risk for not only UTUC but also BCa and could be offered appropriate screening.

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Figures and tables from this article:

Fig. 1. Tumor sections at ×200 magnification: (A) abnormal MSH2 expression—nuclear expression is lost in the tumor, with normal nuclear staining in the adjacent tissue; (B) normal MLH1 expression—normal strong nuclear expression in the tumor and normal tissue.

View Within Article

Table 1. Distribution of patients with mismatch repair mutations

M:F = male-to-female; MLH1 = mutL homolog 1, colon cancer, nonpolyposis type 2 (E. coli); MSH2 = mutS homolog 2, colon cancer, nonpolyposis type 1 (E. coli); MSH6 = mutS homolog 6 (E. coli); PMS2 = PSM2 postmeiotic segregation increased 2 (S. cerevisiae).

View Within Article

Table 2. Total incidence of urothelial cancers due to MLH1 and MSH2

MLH1 = mutL homolog 1, colon cancer, nonpolyposis type 2 (E. coli); MSH2 = mutS homolog 2, colon cancer, nonpolyposis type 1 (E. coli); NS = not significant.

View Within Article

Table 3. Urothelial cancers in patients with confirmed MSH2 mutations and comparison with matched sporadic bladder cancer patients

− = absent expression; +  = normal expression; CR = colorectal; Dx = diagnosis; EM = endometrial; F = female; GA = gastric; HG = high grade; IHC = immunohistochemistry; LG = low grade; LS = Lynch syndrome; M = male; MSH2 = mutS homolog 2, colon cancer, nonpolyposis type 1 (E. coli); MSI = microsatellite instability; MSI-H = high microsatellite instability; MSS = microsatellite stable; OR = occupational risk; OV = ovarian; RP = renal pelvis; U = ureter.Patients H1 and H2 are related.

View Within Article

Table 4. Urothelial cancers in patients with confirmed MLH1 mutations

− = absent expression; +  = normal expression; CR = colorectal; HG = high grade; IHC = immunohistochemistry; LG = low grade; LS = Lynch syndrome; M = male; MLH1 = mutL homolog 1, colon cancer, nonpolyposis type 2 (E. coli); MSI = microsatellite instability; MSI-H = high microsatellite instability; OR = occupational risk; RP = renal pelvis.

paywalled: Preferences for outcomes associated with decisions to undergo or forego genetic testing for Lynch syndrome

Preferences for outcomes associated with decisions to undergo or forego genetic testing for Lynch syndrome

Abstract

BACKGROUND:

Current guidelines recommend offering genetic testing for Lynch syndrome to individuals whose tumors suggest this condition and to relatives of affected individuals. Little is known, however, regarding how patients view the prospect of such testing. In addition, data on preferences (utilities) for the potential outcomes of testing decisions for use in cost-effectiveness analyses are lacking.

METHODS:

Time tradeoff utilities were elicited for 10 potential outcomes of Lynch syndrome testing decisions and 3 associated cancers from 70 participants, representing a range of knowledge about and experiences with Lynch syndrome.

RESULTS:

Highest mean utilities were assigned to scenarios in which only the assessor's sibling had Lynch-associated colorectal cancer (ranging from 0.669 ± 0.231 to 0.760 ± 0.220). Utilities assigned to scenarios in which the assessor had Lynch-associated colorectal cancer ranged from 0.605 ± 0.252 to 0.682 ± 0.246, whereas the lowest mean utilities were assigned to 2 of the general cancer states (0.601 ± 0.238 and 0.593 ± 0.272 for colorectal and ovarian cancer respectively). Only 43% of the sample assigned higher values to undergoing Lynch testing and receiving negative results versus foregoing Lynch testing, whereas 50% assigned higher values to undergoing rather than foregoing surgery to prevent a subsequent cancer.

CONCLUSIONS:

Genetic testing for Lynch syndrome, regardless of results, can have profound effects on quality of life; the utilities we collected can be used to incorporate these effects into cost-effectiveness analyses. Importantly, preferences for the potential outcomes of testing vary substantially, calling into question the extent to which patients would avail themselves of such testing if it were offered to them. Cancer 2012. © 2012 American Cancer Society

Podcast/RSS video: Lynch Syndrome Educational Support Workshop | Memorial Sloan-Kettering Cancer Center (68 min.)

Podcast/RSS video: Lynch Syndrome Educational Support Workshop | Memorial Sloan-Kettering Cancer Center

Runtime

68:00

Medical experts from Memorial Sloan-Kettering discuss Lynch syndrome, a genetic disorder that can cause colon and other cancers.

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.

paywalled: Causes of death of mutation carriers in Finnish Lynch syndrome families.

Fam Cancer. 2012 Jun 9. [Epub ahead of print]

Abstract

Lynch syndrome (LS) is an autosomal dominant cancer syndrome including increased life-long risk for colorectal (CRC) and endometrial (EC) cancer, but also for cancers of other types. The risk for CRC is up to 70-80 % and for EC up to 50-60 %. Due to screening and early diagnosing the mortality related to CRC and EC seems to be low. In spite of many studies on surveillance of mutation carriers, there is no comprehensive evaluation on causes of death in LS families. The disease history and cause of death of all the deceased, tested mutation carriers and their mutation negative relatives in the Finnish LS families (N = 179) was examined utilizing hospital records and relevant national registries. Out of 1069 mutation carriers 151 had succumbed; 97 (64 %) from cancer. Out of 1146 mutation-negative family 44 members had died; 11 (25 %) of them from cancer. In 12 (7.7 %) of the deceased mutation carriers no cancer had been diagnosed. The mean age of death from cancer was 63.2 years vs. 68.8 years from non-cancer causes. Only 7.9 % of the patients with CRC had died from CRC and 5 % of those with EC, respectively. 61 % of the cancer deaths were related to extra-colonic, extra-endometrial cancers. The cumulative overall and cancer specific death rates were significantly increased in Mut+ compared to Mut- family members. Even surveillance yields decrease in the life-long risk and mortality of the most common cancers CRC and EC in LS, almost all mutation carriers will contract with cancer, and two thirds of the deceased have died from cancer. This should be taken in account in genetic counseling. Mutation carriers should be encouraged to seek help for abnormal symptoms.

pdf: Family perspectives in lynch syndrome becoming a family at risk, patterns of communication and influence on relations

pdf:  Family perspectives in lynch syndrome becoming afamily at risk, patterns of communication andinfluence on relations 

Family perspectives in lynch syndrome becoming a family at risk, patterns of communication and influence on relations

Family perspectives in lynch syndrome becoming a family at risk, patterns of communication and influence on relations

The complete article is available as a provisional PDF. The fully formatted PDF and HTML versions are in production.

 Abstract:
Background: A growing number of individuals are diagnosed with hereditary cancer. Though increased levels of anxiety and depression have been demonstrated around the time of genetic counselling, most individuals handle life at increased risk well. Data have, however, been collected on individual basis, which led us to focus on family perspectives of hereditary cancer.

Methods: Lynch syndrome represents a major type of hereditary colorectal and gynaecological cancer. We preformed open-ended interviews with 27 informants from 9 Lynch syndrome families. Inductive content analysis revealed three major themes: transition to a risk family, patterns of communication and influence on family relations and individual roles.

Results: Family members described how learning about Lynch syndrome shifted focus from daily issues to concerns about cancer. Changes in communication related to difficulties in talking to children about heredity and informing new family members and distant relatives about an increased risk of cancer. Influence on relations was exemplified by family members taking on different roles, e.g. females often being responsible for coordinating information about heredity and providing support. Families in which members had experienced cancer at young age typically informed children soon after learning about heredity and at young age, whereas families with experience of cancer at higher age postponed information and thereby also genetic counselling.

Conclusions: Three major family perspectives are described in Lynch syndrome families; becoming a risk family, patterns of communication and influence on family relations. Since these issues are central, our findings suggests that such family perspectives should be considered during genetic counselling in order to contribute to information spread, help family members cope with the increased risk, and motivate family members at risk to undergo surveillance.

[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.

Interval colon cancer in a Lynch syndrome patient under annual colonoscopic surveillance: a case for advanced imaging techniques? (including Lynch Syndrome background information/research)

 Blogger's Note: worth reading even for those without colorectal cancer but with a familial interest in Lynch Syndrome cancers, discusses research on surveillance timing, discordance in mutation carriers, risk variances (% risk) etc...

Background
Lynch syndrome confers increased risk for various malignancies, including colorectal cancer.
Colonoscopic surveillance programs have led to reduced incidence of colorectal cancer and reduced mortality from colorectal cancer. Colonoscopy every 1–2 years beginning at age 20– 25, or 10 years earlier than the first diagnosis of colorectal cancer in a family, with annual colonoscopy after age 40, is the recommended management for mutation carriers. Screening programs have reduced colon cancer mortality, but interval cancers may occur.

Lynch syndrome is defined as the presence of a germline mutation in a DNA mismatch repair gene [1]. Mutation carriers have increased risk for various malignancies, including carcinomas of the colorectum (CRC), endometrium, ovary, small bowel, stomach, biliary tract, bladder, ureter and renal pelvis [2].

Interval colon cancer in a Lynch syndrome patient under annual colonoscopic surveillance: a case for advanced imaging techniques?

"This report highlights several features of Lynch syndrome. First, individuals carrying deleterious mutations in a DNA mismatch repair gene (MLH1, MSH2, MSH6, PMS2) deserve annual colonoscopic examinations with a careful search for, and removal of, all mucosal lesions. Second, adenoma is the precursor lesion for CRC in Lynch syndrome.....

paywalled: Quality of Life After Surgery for Colon Cancer in Patients With Lynch Syndrome: Partial Versus Subtotal Colectomy.

Quality of Life After Surgery for Colon Cancer in Patients With Lynch Syndrome: Partial Versus Subtotal Colectomy

BACKGROUND:: Lynch syndrome is a disorder caused by mismatch repair gene mutations. Mutation carriers have a high risk of developing colorectal cancer. In patients with Lynch syndrome in whom colon cancer has been diagnosed, in general, subtotal colectomy instead of partial colectomy is recommended because of the substantial risk of metachronous colorectal cancer. However, the effect of more extensive surgery on quality of life and functional outcome is unknown. 

 OBJECTIVE:: The aim of this study was to investigate quality of life and functional outcome in patients with Lynch syndrome after partial colectomy and subtotal colectomy.

An alternative approach to identify women at risk for colorectal cancer. | 2012 ASCO Annual Meeting Abstracts

An alternative approach to identify women at risk for colorectal cancer. | 2012 ASCO Annual Meeting Abstracts

Abstract:
Background: 
Hereditary colorectal cancer (CRC) is preventable; however, identification of individuals at sufficiently high risk to warrant heightened surveillance is difficult. Lynch Syndrome (LS) is an inherited cancer syndrome due to germline mutation in a DNA mismatch repair gene. For women with LS, the lifetime risk of endometrial cancer (EC) is 64% and CRC is 54%. Fifty percent of women with LS will present with EC or ovarian cancer prior to CRC. Therefore, women with LS associated EC represent an ideal group for CRC prevention. The optimal method to identify women with LS associated EC is not known. The purpose of this study was to determine the utility of Amsterdam II and Society of Gynecologic Oncology (SGO) Criteria (modified Bethesda criteria that use EC as the sentinel cancer) in identifying women with LS associated EC. Our ultimate goal is to identify women at increased risk of CRC.


Our data suggest that classic clinical screening criteria are inadequate to detect patients with LS who present with EC, potentially missing up to 25% of these patients.

Gene	MLH1	MSH2	MSH6	PMS2	Total
Total number	14	27	11	7	59
Median age at diagnosis (range)	52 (42-79)	44 (33-81)	56 (31-76)	66 (45-87)	50 (31-87)
Diagnosis at greater than 50 years	7	8	9	6	30
FH CRC	3	16	4	3	26
Amsterdam criteria	3	13	0	1	17
SGO criteria	11	22	7	4	44

paywalled: Recurrent and founder mutations in the PMS2 gene - Clinical Genetics

Recurrent and founder mutations in the PMS2 gene - Tomsic - Clinical Genetics

Germline mutations in PMS2 are associated with Lynch syndrome (LS), the most common known cause of hereditary colorectal cancer.

Mutation detection in PMS2 has been difficult due to the presence of several pseudogenes, but a custom-designed long-range PCR strategy now allows adequate mutation detection. Many mutations are unique. However some mutations are observed repeatedly, across individuals not known to be related, due to the mutation being either recurrent, arising multiple times de novo at hot spots for mutations, or of founder origin, having occurred once in an ancestor. Previously, we observed 36 distinct mutations in a sample of 61 independently ascertained Caucasian probands of mixed European background with PMS2 mutations.

Eleven of these mutations were detected in more than one individual not known to be related and of these, six were detected more than twice. These six mutations accounted for 31 (51%) ostensibly unrelated probands. Here we performed genotyping and haplotype analysis in four mutations observed in multiple probands and found two (c.137G>T and exon 10 deletion) to be founder mutations, one (c.903G>T) a probable founder, and one (c.1A>G) where founder mutation status could not be evaluated. We discuss possible explanations for the frequent occurrence of founder mutations in PMS2.

paywalled: Mismatch repair analysis of inherited MSH2 and/or MSH6 variation pairs found in cancer patients - Kantelinen - Human Mutation - Wiley Online Library

Mismatch repair analysis of inherited MSH2 and/or MSH6 variation pairs found in cancer patients - Kantelinen - Human Mutation

Abstract

Mismatch repair (MMR) malfunction causes the accumulation of mismatches in the genome leading to genomic instability and cancer. The inactivation of an MMR gene (MSH2, MSH6, MLH1 or PMS2) with an inherited mutation causes Lynch syndrome (LS), a dominant susceptibility to cancer. MMR gene variants of uncertain significance (VUS) may be pathogenic mutations which cause LS, may result in moderately increased cancer risks, or may be harmless polymorphisms. Our study suggests that an inherited MMR VUS individually assessed as proficient may, however, in a pair with another MMR VUS found in the same colorectal cancer (CRC) patient have a concomitant contribution to the MMR deficiency. Here, eight pairs of MMR gene variants found in cancer patients were functionally analyzed in an in vitro MMR assay. Although the other pairs do not suggest a compound deficiency, the MSH2 VUS pair c.380A>G/c.982G>C (p.Asn127Ser/p.Ala328Pro), which nearly halves the repair capability of the wild type MSH2 protein, is presumed to increase the cancer risk considerably. Moreover, two MSH6 variants, c.1304T>C (p.Leu435Pro) and c.1754T>C (p.Leu585Pro), were shown to be MMR deficient. The role of one of the most frequently reported MMR gene VUS, MSH2 c.380A>G (p.Asn127Ser), is especially interesting, since its concomitant defect with another variant could finally explain its recurrent occurrence in CRC patients.

American Society for Clinical Pathology: Molecular Testing in Colorectal Cancer (Lynch Syndrome/MLH1, MSH2, MSH6, PMS2/MSI-H/KRAS/BRAF.....)

Blogger's Note: focus (obviously) on colorectal cancer, however, the cancer spectrum of Lynch Syndrome is noted in this paper as well as the shortcomings of the Bethesda Guidelines

 Molecular Testing in Colorectal Cancer

Conclusion

In summary, current standard-of-care molecular testing of CRC is aimed at detecting Lynch syndrome and KRAS mutations. However, with recent rapid development of biological agents targeted against components of the EGFR signaling cascade in the treatment of CRCs, mutational analysis of the genes in the EGFR signaling pathway may become a standard of care for patients with CRC in the near future. Ideally, identifying molecular prognostic and predictive factors may allow us to identify high-risk patients with stage II CRC who will benefit from chemotherapy after surgery. In addition, this may allow us to determine patients’ eligibility for targeted biological therapies.

May 7th: The connection between genes and colon cancer (Lynch Syndrome/FAP) - MD Anderson Cancer Center - audio/ iTunes

The connection between genes and colon cancer - MD Anderson Cancer Center

Cancer Newsline - 05/07/2012

About 20% of colon cancer cases are related to a strong family history of colon cancer. Eduardo Vilar-Sanchez, M.D., Ph.D., Assistant Professor in the Department of Clinical Cancer Prevention at The University of Texas MD Anderson Cancer Center, focuses his discussion on the main types of genetic colon cancers including hereditary nonpolyposis colorectal cancer syndrome or HNPCC (also called Lynch syndrome) and familial adenomatous polyposis (FAP).

• Listen to The connection between genes and colon cancer
• Download The onnection between genes and colon cancer on iTunes

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.

paywalled: Risk of Colonic Neoplasia After Proctectomy for Rectal Cancer in Hereditary Nonpolyposis Colorectal Cancer (Lynch Syndrome)

abstract

Abstract

Objective: To define the neoplastic risk in the remaining colon after proctectomy for rectal cancer in patients with hereditary nonpolyposis colorectal cancer (HNPCC). (Lynch Syndrome)

Conclusions: Surgeons and patients need to be aware of substantial risk for metachronous neoplasia after proctectomy. Selection of operation should be individualized, but total proctocolectomy and ileoanal pouch should be strongly considered. If patients undergo proctectomy alone, close surveillance is mandatory.

paywalled: Prevalence of mismatch repair-deficient crypt foci in Lynch syndrome: a pathological study : The Lancet Oncology

Prevalence of mismatch repair-deficient crypt foci in Lynch syndrome: a pathological study : The Lancet Oncology

Methods
"Resections done for small and large bowel cancer between January, 2002, and January, 2011, were retrieved. We systematically analysed non-tumorous mucosa from carriers of a Lynch syndrome mutation (set 1: ten patients) and control patients without Lynch syndrome (set 1: nine patients) for MMR protein expression (MLH1, MSH2, and EPCAM) with immunohistochemistry.....

May 1st (open access) Commentary including link to original paper: Lynch syndrome: new tales from the crypt : The Lancet Oncology

Blogger's Note: commentary focus is primarily on colorectal cancer:

Lynch syndrome: new tales from the crypt : The Lancet Oncology

"...Unfortunately, these lesions are too small and subtle to be relied upon clinically to suggest a diagnosis of Lynch syndrome. Importantly, the investigators acknowledge that, although they noted these lesions occurred frequently, most patients with Lynch syndrome will develop zero to two cancers, and typically only a few adenomatous polyps, through their lifetimes.5 Small bowel cancers occur in no more than 1—4% of patients with Lynch syndrome,6 yet that organ has one MMR-deficient crypt per 2 cm2 of mucosa. Obviously, most of these lesions do not develop into cancer. So, what happens to them?....."

"...The missing link in this work is the contrast between the large number of MMR-deficient crypts and the relatively small number of clinically relevant neoplasms in this disease. That said, this work is highly novel, underscores the differences between Lynch syndrome and sporadic colorectal cancers, and raises a fresh group of important questions to be addressed."

Original paper - link/reference:

Kloor M, Huth C, Viogt AY, et al. Prevalence of mismatch repair-deficient crypt foci in Lynch syndrome: a pathological study. Lancet Oncol 201210.1016/S1470-2045(12)70109-2. published online May 1. 

2012 Clinicopathological Features and Management of Cancers in Lynch Syndrome (easy to read)

Blogger's Note: nice, easy to read paper

Clinicopathological Features and Management of Cancers in Lynch Syndrome

Abstract
Lynch syndrome (LS) is characterized by an autosomal dominant inheritance of the early onset of colorectal cancer (CRC) and endometrial cancer, as well as increased risk for several other cancers including gastric, urinary tract, ovarian, small bowel, biliary tract, and brain tumors. The syndrome is due to a mutation in one of the four DNA mismatch repair (MMR) genes MLH1, MSH2, MSH6, or PMS2. The majority of LS patients and families can now be identified, and the underlying mutation detected using genetic diagnostics. Regular surveillance for CRC and endometrial cancer has proved beneficial for mutation carriers. However, screening for other tumors is also recommended even though experiences in the screening of these tumors is limited. Prophylactic colectomy, prophylactic hysterectomy, and bilateral salpingo-oophorectomy may be reasonable options for selected patients with LS. This paper describes the features and management of LS.

1. Introduction (The syndrome is due to a mutation in one of the four DNA mismatch repair (MMR) genes MLH1, MSH2, MSH6, or PMS2.)

2. Genetic Characteristics of Lynch Syndrome
3. Identification of Lynch Syndrome
4. Tumor Spectrum of Lynch Syndrome
5. Colorectal Cancer (>MLH1 and MSH2; <MSH6;)
6. Endometrial Cancer (MSH6 mutations are at higher risk)
7. Gastric Cancer (seems to be not different between different mutations)
8. Uroepithelial and Kidney Cancers (predominately MSH2)
9. Other Tumors

• 9.1. Ovarian Cancer        Ovarian cancer has been shown to occur in excess in LS. Two Finnish studies [5, 45] have shown a lifetime risk for ovarian cancer in LS ranging between 9% and 12% compared to 1.3% in the general population. Recently, Watson et al. [6] reported a lifetime risk of 7% in a large series from four LS research centers. They also found that MSH2 family members had nearly twice the incidence rate observed in MLH1 family members, and the highest risk period for ovarian cancer was from age 40 to 55 years. Ovarian cancer in LS seems to have a better prognosis than that in the general population or in BRCA1/2 mutation carriers [59]. Information currently available is too limited to assess whether screening for ovarian cancer in LS mutation carriers has any advantages.

• 9.2. Carcinomas of the Biliary Tract and Pancreas (duodenum/jejunum)
• 9.3. Brain Tumors (higher in MSH2 than in MLH1)

10. Conclusions

 (ovarian) reference: 
59.  E. M. Grindedal, L. Renkonen-Sinisalo, H. Vasen et al., “Survival in women with MMR mutations and ovarian cancer: a multicentre study in Lynch syndrome kindreds,” Journal of Medical Genetics, vol. 47, no. 2, pp. 99–102, 2010. View at Publisher · View at Google Scholar · View at Scopus