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PubMed1985

Hereditary nonpolyposis colorectal cancer (Lynch syndromes I and II). II. Biomarker studies.

Nine families with the cancer family syndrome (CFS), or Lynch syndrome II, and two with hereditary site-specific colonic cancer (HSSCC), or Lynch syndrome I, were investigated for the following potential biomarkers of genotype status: in vitro tetraploidy of dermal fibroblast monolayer cultures; tritiated thymidine uptake (3HdThd) labeling of colonic mucosa; cytogenetics of peripheral blood mononuclear leukocytes; quantitative serum immunoglobulin determinations; methionine dependence in dermal fibroblasts in tissue culture; segregation analysis; and the study of gene linkage with respect to 25 landmark serum and blood group markers. Positive lod scores of 3.19 for linkage of the Jk (Kidd blood group) with CFS were obtained. Both in vitro tetraploidy and 3HdThd uptake in the distal colonic mucosal crypt compartments were positively associated with cancer risk status in CFS and HSSCC kindreds. There was a high incidence of polymorphisms of centromeric heterochromatin, including complete inversion. These findings are of particular clinical and genetic significance because HNPCC lacks premonitory signs of cancer risk. If confirmed, they could conceivably enable definition of genotype as early as birth in members of HNPCC kindreds, thereby enabling psychologic preparation and intensive cancer education for improved compliance in surveillance/management programs. These studies also provide new clues about the chromosome(s) bearing the presumed cancer gene(s). For example, CFS gene(s) may possibly be located on chromosome 2, where Jk is located. These biomarkers merit intensive study in additional HNPCC kindreds for a more complete assessment of their sensitivity and specificity. Additionally, essential aspects of previous reports involving biologic samples from these and/or similar subject kindreds are included to permit a comprehensive presentation of the combined findings of this consortium to date.

Colon↗
PubMed1990

The Lynch syndrome II and urological malignancies.

The role of host factors in the etiology of carcinoma of the ureter has received only limited attention. We describe 4 Lynch syndrome II kindreds in which carcinoma of the ureter, as well as other forms of urological cancer, have occurred either in obligate gene carriers and/or in association with multiple primary cancers that are integral to this autosomal dominantly inherited disorder. These new findings are in accord with increasing recognition of tumor heterogeneity in the Lynch syndrome II, which currently, in addition to an excess of proximal colonic cancer as well as carcinoma of the endometrium, ovary and small bowel, also may include carcinoma of the ureter as well as other urological forms of cancer as integral lesions in subsets of these families. These observations have important ramifications for better understanding of the etiology, pathogenesis and control of urological cancer in this disorder.

Adult↗
PubMedDate not supplied

Molecular genetics and clinical-pathology features of hereditary nonpolyposis colorectal carcinoma (Lynch syndrome): historical journey from pedigree anecdote to molecular genetic confirmation.

Hereditary nonpolyposis colorectal cancer (HNPCC), also termed Lynch syndrome, was originally called cancer family syndrome. Historically, in 1913 Aldred Warthin, a pathologist, published a family, now known as Family G, which had features of HNPCC. It was first delineated as a hereditary cancer syndrome in the mid-1960s by Lynch. There was an apparent autosomal dominant mode of inheritance of colorectal cancer and certain integral cancers, the most prominent of which was endometrial carcinoma. Prior to the discovery in 1993 and 1994 of genes (hMSH2, hMLH1, hPMS1, hPMS2) known as mis-match repair genes or mutator genes, the diagnosis of HNPCC rested exclusively upon evaluation of clinical findings in concert with a well-documented and extended pedigree. Thus, this disorder has evolved from a medical curiosity into a clinical syndrome wherein molecular biologists provided proof of its hereditary status. These discoveries should aid in elucidating its pathogenesis and carcinogenesis and in the next decade we likely will learn more about chemoprevention and surgical prophylaxis of HNPCC.

Australia↗
PubMed1988

Tumor variation in three extended Lynch syndrome II kindreds.

Lynch syndrome II is characterized by an autosomal dominantly inherited susceptibility to early onset colon cancer with proximal predominance, an excess of synchronous and metachronous colonic cancer, carcinoma of the endometrium, ovary, and multiple primary cancer excess. Knowledge of the full tumor spectrum in this disorder(s) remains elusive. Cancers that are uncommon in this disease, but present in three extended Lynch syndrome II families, included brain tumors, carcinoma of the bile duct, duodenum, the urological system, and breasts. Long-term followup of these families (as long as two decades) provided the opportunity to trace in depth this tumor spectrum. Full scrutiny of cancer of all anatomic sites in the absence of biomarkers of high sensitivity and specificity to the cancer-prone genotype will be necessary to comprehend more clearly whether these (or other) cancer sites are integral to this disorder, whether common environmental exposures are involved and, finally, whether chance can explain these cancer associations.

Adolescent↗
PubMedDate not supplied

Adenoma follow-up in at-risk Lynch syndrome family members.

Persons at 50% risk of Lynch Syndrome were screened with colonoscopy at six or twelve month intervals. On initial exam, eight of fifty-five patients had adenomas. Follow-up was available in 27 patients (mean 35.5 months). Estimated time to finding new adenomas was 58 months for patients clear on first colonoscopy and 16 months for patients who had adenomas on first exam (p < 0.01). One adenocarcinoma has been found, arising in a tubulovillous adenoma. The short-term risk of colorectal cancer in Lynch syndrome relatives without adenomas is low, as is the risk in those who had all adenomas removed.

Adenoma↗
PubMed2026

Uptake of germline testing for Lynch Syndrome in patients with deficient mismatch repair/ microsatellite-high colorectal cancer in the public hospital system in South Australia.

Lynch syndrome (LS) accounts for approximately 4% of colorectal cancer (CRC) cases and arises from pathogenic variants in mismatch repair (MMR) genes. Australian guidelines recommend universal MMR or microsatellite instability (MSI) screening in all CRC patients; however, real-world uptake remains variable. This study evaluated rates of MMR/MSI screening, germline testing, and genetics referrals across two major public hospitals in South Australia. A retrospective review of 1775 patients discussed at colorectal multidisciplinary team meetings in the Royal Adelaide and Queen Elizabeth hospitals between January 2021 and December 2023 was conducted to identify rates of MMR/MSI screening and subsequent referral of eligible patients to genetics. Of the 1129 colorectal cancer cases identified, MMR/MSI testing was performed in 93.2% (1052/1129), with deficiency detected in 12.5% (131/1052). Of these, 37% (49/131) were eligible for genetics referral after exclusion of somatic causes. Among eligible patients, 73.5% (36/49) were referred, and 43% (21/49) underwent germline testing. LS was confirmed in 12 patients (9% of deficient MMR CRC), while 9 patients (6.9%) were classified as having Lynch-like syndrome. Despite high screening rates, gaps remain in genetics referral and testing. Barriers included lack of reflex testing, loss to follow-up, and patient refusal. Targeted system-level interventions and improved genomic education are needed to enhance adherence to guidelines and optimise patient outcomes.

Humans↗
PubMed2005

The B-Lynch and other uterine compression suture techniques.

BACKGROUND: Postpartum hemorrhage (PPH) remains among the 5 main causes of maternal death in developing and developed countries, and uterine atony is the most common cause (75-90%) of primary PPH. Uterine compression sutures running through the full thickness of both uterine walls (posterior as well as anterior) have recently been described for surgical management of atonic PPH. Christopher B-Lynch was the first to highlight this revolutionary principle, and other uterine compression suture techniques have since been described by Hayman and Cho. OBJECTIVES: Step-by-step description of the B-Lynch brace suture and discussion of the current compression suture techniques. CONCLUSIONS: The different uterine suture techniques have proved to be valuable and safe alternatives to hysterectomy in the control of massive PPH, and the present review can make the surgeon better aware of their effective use and the risks they may entail.

Female↗
PubMedDate not supplied

Technical description of the B-Lynch brace suture for treatment of massive postpartum hemorrhage and review of published cases.

Massive uncontrolled hemorrhage after childbirth is a leading cause of the pregnancy-related death and resulting morbidity. Uterine atony is the most common cause (75-90%) of primary postpartum hemorrhage. When simple massage of the uterus and uterotonics such as oxytocins, syntometrine and prostaglandins failed to manage this condition, various surgical solutions have been sought, including uterine artery ligation, more complicated stepwise devascularization of the uterus, internal iliac artery ligation and, ultimately, hysterectomy. All these procedures require above average surgical skill. In contrast, the B-Lynch suturing technique (brace suture) is particularly useful because of its simplicity of application, life saving potential, relative safety and capacity for preserving the uterus and subsequent fertility. The adequacy of haemostasis can be assessed both before and immediately after application of the suture. Only if it fails need other more radical surgical methods be considered. The special advantage of this innovative technique is that it presents an alternative to major surgical procedures for controlling pelvic arterial pulse pressure or hysterectomy. To date, this suturing technique, when applied correctly, has been successful with no problems and no apparent complications. This review provides an update on the B-Lynch brace suturing technique, including choice of suture material, use of the technique in early and late gestation, and comparison with other uterine compression surgical techniques. It also includes a comprehensive review and analysis of all published cases and their postoperative follow-up.

Female↗
PubMed2006

Prediction of MLH1 and MSH2 mutations in Lynch syndrome.

CONTEXT: Lynch syndrome is caused primarily by mutations in the mismatch repair genes MLH1 and MSH2. OBJECTIVES: To analyze MLH1/MSH2 mutation prevalence in a large cohort of patients undergoing genetic testing and to develop a clinical model to predict the likelihood of finding a mutation in at-risk patients. DESIGN, SETTING, AND PARTICIPANTS: Personal and family history were obtained for 1914 unrelated probands who submitted blood samples starting in the year 2000 for full gene sequencing of MLH1/MSH2. Genetic analysis was performed using a combination of sequence analysis and Southern blotting. A multivariable model was developed using logistic regression in an initial cohort of 898 individuals and subsequently prospectively validated in 1016 patients. The complex model that we have named PREMM(1,2) (Prediction of Mutations in MLH1 and MSH2) was developed into a Web-based tool that incorporates personal and family history of cancer and adenomas. MAIN OUTCOME MEASURE: Deleterious mutations in MLH1/MSH2 genes. RESULTS: Overall, 14.5% of the probands (130/898) carried a pathogenic mutation (MLH1, 6.5%; MSH2, 8.0%) in the development cohort and 15.3% (155/1016) in the validation cohort, with 42 (27%) of the latter being large rearrangements. Strong predictors of mutations included proband characteristics (presence of colorectal cancer, especially > or =2 separate diagnoses, or endometrial cancer) and family history (especially the number of first-degree relatives with colorectal or endometrial cancer). Age at diagnosis was particularly important for colorectal cancer. The multivariable model discriminated well at external validation, with an area under the receiver operating characteristic curve of 0.80 (95% confidence interval, 0.76-0.84). CONCLUSIONS: Personal and family history characteristics can accurately predict the outcome of genetic testing in a large population at risk of Lynch syndrome. The PREMM(1,2) model provides clinicians with an objective, easy-to-use tool to estimate the likelihood of finding mutations in the MLH1/MSH2 genes and may guide the strategy for molecular evaluation.

Adaptor Proteins, Signal Transducing↗
PubMed2025

Uveal Melanoma and the Lynch Syndrome Tumor Spectrum.

IMPORTANCE: To date, no environmental factors and few therapeutic options are known for uveal melanoma (UM), the most common malignant intraocular primary tumor in adults. Identification of new predisposition factors could lead to better monitoring and possibly improved treatments of patients with UM. OBJECTIVE: To identify new genetic alterations predisposing for UM. DESIGN, SETTING, AND PARTICIPANTS: This was a prospective cohort study conducted at Institut Curie in Paris, France, among 381 consecutive patients diagnosed with UM between July 2021 and February 2023. UM was diagnosed clinically by ophthalmologists, and a senior pathologist confirmed the diagnosis when tumor or biopsy was available. All participants received genetic counseling and consented to extended genetic testing. A panel of 122 genes predisposing to cancer were analyzed by targeted sequencing on germline DNA from these patients. MAIN OUTCOMES AND MEASURES: Frequency of pathogenic variants (PVs) in genes from a targeted panel, with classification of germline PVs done according to the American College of Medical Genetics and Genomics guidelines and the French Unicancer Genetics Group. RESULTS: A total of 79 PVs were identified in 70 participants (41 female and 29 male; mean [SD] age, 60.6 [15.3] years). Among them, 21 were found in clinically relevant genes, with an enrichment in the mismatch repair (MMR) genes, involved in Lynch syndrome, a frequent predisposition to colon and endometrial cancers. This finding suggested MMR germline PVs could also predispose to UM. One tumor was available from a participant carrying a MLH1 germline PV. The tumor exhibited a monosomy 3 with loss of the wild-type allele of MLH1, located on chromosome 3. Loss of expression of MLH1 was observed by immunohistochemistry, and MMR variant signatures SBS6, ID1, and ID2 were identified from the whole-genome sequencing of this tumor, supporting the possibility that MLH1 contributes to the oncogenesis of this UM. CONCLUSIONS AND RELEVANCE: This prospective germline study on patients with UM provided evidence supporting the notion that MMR germline alterations are enriched among patients with UM and may contribute to oncogenesis of UM, and that UM may therefore be a rare tumor manifestation of Lynch syndrome.

Humans↗
PubMed1990

Risk of cancer death in first-degree relatives of patients with hereditary non-polyposis cancer syndrome (Lynch type II): a study of 130 kindreds in the United Kingdom.

To estimate the relative risks of cancer in first-degree relatives of index patients, 130 pedigrees of dominantly inherited Lynch type II cancer family syndrome have been analysed. The risk of death from all causes was significantly increased in women over 45 years of age and the overall liability to cancer in women was greater than for men. A sevenfold increase in risk of colon cancer was found in both sexes. In female relatives the risk of breast cancer was increased fivefold and lifetime risk of breast cancer was 1 in 3.7. A screening programme based on estimated risks could be offered to first-degree relatives of index patients with Lynch type II cancer family syndrome.

Adolescent↗
PubMed1989

Analysis of the Lynch-Granger model for olfactory cortex.

The behavior of the Lynch-Granger model for layer-II piriform cortex is reviewed, and a simple neural model with similar properties is introduced. This model allows us to understand the observed functionality of the Lynch-Granger model intuitively, and suggests which of the many biological facts introduced into the original model are relevant to this particular behavior.

Computer Simulation↗
PubMed2005

Successful of the B-Lynch compression suture in the management of massive postpartum hemorrhage: case reports and review.

The authors describe three patients who developed massive primary postpartum hemorrhage and review the case reports. In two patients, primary postpartum hemorrhage was due to uterine atony, and in one patient it was due to atony and thrombophilia. In all three patients, excellent effect was achieved with hemorrhage reduction by a compression B-Lynch suture alone, with bimanual compression following medicamentous uterotonic therapy. B-Lynch suture is an efficient, safe, and simple method for the treatment of primary postpartum hemorrhage during cesarean section, which successfully reduces the number of urgent postpartum hysterectomies, also preserving subsequent fertility. In our opinion, the method should be included in the algorithm of primary postpartum hemorrhage management at all obstetric departments.

Adult↗
PubMed2005

The tumor spectrum in the Lynch syndrome.

Colorectal and endometrial cancer are the characteristic tumors of the Lynch syndrome. We reviewed the available evidence on the occurrence of other types of cancer in the syndrome, aiming to identify those types that can be included in the tumor spectrum, based on this evidence. We chose to define the tumor spectrum as comprising the cancers for which Lynch syndrome patients are at elevated risk. We found sufficiently strong and consistent evidence to include gastric cancer, small bowel cancer, hepatobiliary tract cancer, upper urologic tract cancer, ovarian cancer, and brain tumors in this spectrum, in addition to colorectal and endometrial cancer. We predict that the spectrum will expand as additional studies are reported, especially as prospective studies of mutation carriers are completed.

Colorectal Neoplasms, Hereditary Nonpolyposis↗
PubMed2005

Gynecologic Cancers in Lynch Syndrome/HNPCC.

Recent studies have estimated that the lifetime risk of endometrial cancer in women with Lynch syndrome/hereditary non-polyposis colorectal cancer syndrome (Lynch/HNPCC) is 40-60%. This risk equals or exceeds their risk for colon cancer. While much research has been done to define the natural history and molecular features of Lynch/HNPCC associated colon cancer, there has been considerably less research defining Lynch/HNPCC associated endometrial cancer. This article will review current information regarding the clinico-pathologic features of Lynch/HNPCC associated endometrial cancer. In addition, current consensus guidelines for endometrial cancer screening and prevention for women with Lynch/HNPCC will be discussed. Given the increased risk of multiple cancers, changing the name of this syndrome from hereditary non-polyposis colorectal cancer syndrome to Lynch Syndrome may benefit both patients and clinicians. Clinicians caring for women with Lynch/HNPCC may stress colon cancer screening and prevention without reviewing endometrial cancer risks and symptoms or screening and prevention options. Perhaps more importantly, women with Lynch/HNPCC may focus on colon cancer risks and lack understanding of endometrial cancer risks. With increasing evidence that women with Lynch/HNPCC have significant risks for both colon and endometrial cancers, we believe a multi-disciplinary approach to the management of these individuals is crucial.

Colorectal Neoplasms, Hereditary Nonpolyposis↗
PubMed2000

B-Lynch suture for postpartum hemorrhage.

BACKGROUND: Postpartum hemorrhage is a major contributor to maternal morbidity and mortality. Numerous medical and surgical therapies have been used, but none has been uniformly successful. CASE: Two women with postpartum hemorrhage due to uterine atony after cesarean for twins are presented. Neither responded to medical management. In the first subject, O'Leary uterine artery ligation and utero-ovarian branch ligations were done without benefit. The B-Lynch suture immediately sustained correction of hemorrhage in both subjects. Magnetic resonance imaging and hysterosalpingogram after the first case showed no uterine defects. CONCLUSION: The B-Lynch suture might be a valuable addition to the surgical treatment of postpartum hemorrhage due to uterine atony.

Adolescent↗
PubMed2004

[Lynch syndrome pediatric: about a case].

A duodenal carcinoma centered on the vater ampulla is reported in a child of 15 years with Lynch syndrome. This case illustrates the problem of early diagnosis and treatment of Lynch syndrome associated tumors.

Adenocarcinoma↗
PubMed1999

[Explanation of enigmas of the Lynch syndrome thanks to a new carcinogenesis model characterized by an unorthodox initiation process].

The genotype-phenotype relationship of Lynch syndrome displays many enigmatic features which cannot be explained satisfactorily by the prevailing concepts of carcinogenesis and genetic predisposition to cancer. We propose here a new model of carcinogenesis divided into two and only two evolutive phases: a) a preliminary phase starting with the counter-selective loss of mismatch repair function, in which most clones with the RER mutator phenotype are eliminated through apoptosis or an accelerated ageing process; b) an explosive phase that is initiated only if mutations blocking apoptosis and senescence, rapidly acquired during the short life span of the non-transformed RER+ clones, eventually rescue one mismatch repair-deficient cell that gives rise to the malignant clone. Carcinogenesis is proposed here to progress irreversibly and very rapidly once initiated. We shall show how this model provides a meaningful etiologic and pathogenic interpretation of all the curious features of Lynch syndrome.

Adenoma↗