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PubMed1991

Variable gastrointestinal and urologic cancers in a Lynch syndrome II kindred.

There are no premonitory physical signs or biomarkers which can identify the genotypic status in Lynch syndrome II. Diagnosis is therefore dependent on the pedigree, with attention to cancer of all anatomic sites, inclusive of those cardinal features of its natural history. The tumor spectrum in Lynch syndrome II has continued to expand commensurately with increasing interest in this disorder. We report a family showing the constant cancer features of this syndrome but, in addition, occurrences of carcinoma of the bile duct, urologic system, and extremely early-onset carcinoma of the pancreas, in patients in the direct genetic lineage who were considered to be candidates for having inherited the deleterious genotype. Diagnosis of Lynch syndrome II is crucial in targeting its surveillance and management.

Colonic Neoplasms↗
PubMed1992

Gynecologic cancer clues to Lynch syndrome II diagnosis: a family report.

Lynch syndrome II was diagnosed when two sisters manifested early-onset synchronous carcinomas of the ovary and endometrium and a third sister was found to have Duke's A carcinoma of the cecum. A detailed cancer family history indicated paternal transmission of the deleterious genotype. The pattern of carcinoma of the colorectum and extracolonic sites throughout the extended family was then found to be consonant with this hereditary cancer-prone disorder. Lynch syndrome II may be exceedingly difficult to diagnose due to an absence of premonitory clinical signs or biomarkers of genotypic susceptibility. Its recognition is therefore dependent on a detailed cancer family history (all anatomic sites), coupled with knowledge of the pattern of the cancer spectrum, distribution, and natural history, as manifested in this hereditary disorder. We describe the decision logic that was involved in the diagnosis of Lynch syndrome II in this family and indicate the important role of the gynecologists in this process.

Adult↗
PubMed1991

Hereditary nonpolyposis colorectal cancer (Lynch syndromes I & II). Genetics, pathology, natural history, and cancer control, Part I.

Hereditary nonpolyposis colorectal cancer (HNPCC) is common, accounting for about 4-6% of the total colorectal cancer burden. It is heterogeneous and appears to be delineated into two clinical subsets, Lynch syndromes I and II. Lynch syndrome I is characterized by an autosomal dominantly inherited proclivity to early onset colonic cancer with proximal predominance and an excess of multiple primary colonic cancer. Lynch syndrome II has all of these features plus extracolonic cancer sites, the most common of which is endometrial carcinoma. The lack of premonitory physical signs or biomarkers of HNPCC makes diagnosis difficult. A careful family history, tempered by an understanding of the clinical and pathologic features of HNPCC, is the key to its assessment. This paper reviews HNPCC's natural history, its integral extracolonic cancer associations, its differential diagnosis, surveillance, and management strategies. Attention is focused upon the need for biomarker research in the interest of improving control of HNPCC.

Adenomatous Polyposis Coli↗
PubMed1992

Natural history of at-risk Lynch syndrome family members with respect to adenomas.

UNLABELLED: Our goal is to determine colon cancer surveillance strategy in patients at risk for Lynch's syndrome. Asymptomatic persons at 50% risk of having Lynch syndrome (age 25-70 years) were enrolled in colonoscopic screening. Those without adenomas were asked to return in one year. Those with adenomas were asked to return in six months because of concern for rapid malignant degeneration. RESULTS: Twenty-five males and thirty females participated. On initial exam, eight of fifty-five patients (14.5%) had adenomas. Logistic regression showed a significant effect of age on the probability of finding adenomas at initial examination (p < 0.02). Followup was available in 27 patients (mean 35.5 months). Kaplan-Meier estimation of time to finding new or previously missed 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. CONCLUSION: The short-term risk of colorectal cancer in Lynch syndrome relatives without adenomas is low, as is the risk in those who have had all visualized adenomas removed.

Adenoma↗
PubMed2026

Lynch syndrome-associated urothelial carcinoma: clinical and molecular findings from a single-institution cohort.

Lynch syndrome-associated urothelial carcinoma (LS-UC) is a rare and undercharacterized clinical entity. While FGFR3 alterations are well described in sporadic urothelial carcinoma, their prevalence and clinical implications in LS-UC remain unclear. We aimed to provide a comprehensive clinical and molecular characterization of LS-UC. We conducted a retrospective single-center study including patients with Lynch syndrome (LS) and histologically confirmed urothelial carcinoma (UC). Clinical, pathological, treatment, and follow-up data were collected. Targeted next-generation sequencing was performed on available tumor samples to assess genomic alterations, with particular attention to FGFR3 mutations. A total of 27 patients with LS-UC were identified, with a predominance of upper urinary tract involvement (70%). Most tumors were diagnosed at an early stage and initially managed with local treatment. During a median follow-up of 92 months, 48% of patients experienced recurrence, with a median time to recurrence of 37 months. Recurrences were predominantly local and were mainly managed with additional surgical or intravesical treatments. No deaths were attributable to UC at last follow-up. Molecular analysis was feasible in 9 cases. FGFR3 mutations were detected in 67% of evaluable samples, with the recurrent p.Arg248Cys hotspot identified in 55% of cases. Additional alterations involved TP53, SWI/SNF complex genes, and PIK3CA, which co-occurred with FGFR3 p.Arg248Cys. No gene fusions were identified. This study expands the limited molecular and clinical evidence on Lynch syndrome-associated urothelial carcinoma. Beyond confirming the recurrent role of FGFR3 (notably p.Arg248Cys), our comprehensive multigene profiling enriches the current genomic knowledge for this rare population. Multi-center collaborative efforts remain essential to aggregate larger datasets and ultimately guide personalized patient management.

Humans↗
PubMed2026

Clinical and genetic characterization of constitutional MLH1 promoter hypermethylation: Implications for Lynch syndrome diagnosis.

PURPOSE: Constitutional MLH1 promoter hypermethylation (CMPH) is a relatively rare cause of Lynch syndrome. While most cases appear to be sporadic, some result from secondary epimutations, mainly caused by germline variants in the MLH1 promoter region. This study describes the clinical phenotype and genetic etiology of CMPH in the largest clinical cohort to date. METHODS: A retrospective analysis was conducted for 422 individuals who underwent clinical CMPH testing. Promoter sequencing was used to identify the underlying variants. Long-read sequencing further characterized MLH1 promoter methylation. RESULTS: CMPH was identified in 15.6% of the study cohort participants. Of these, 63 exhibited clinical features consistent with Lynch syndrome. The most common associated cancers were colorectal cancer, followed by endometrial cancer, breast cancer, and sebaceous neoplasms. Mendelian inheritance of CMPH was observed in 5 families in the study cohort, indicating secondary epimutations. Promoter sequencing identified 8 unique germline variants, including 3 novel variants. Methylation analysis by long-read sequencing revealed mutant allele-specific promoter methylation for these variants. CONCLUSION: Our findings provide the most comprehensive review of the clinical phenotype associated with CMPH and highlight the significant contribution of promoter variants to its etiology. These results underscore the need to include the assessment of constitutional MLH1 promoter methylation for Lynch syndrome diagnosis.

Humans↗
PubMedDate not supplied

HNPCC-Lynch syndrome and idiopathic inflammatory bowel disease. A hypothesis on sharing of genes.

Colon cancer occurring in patients with Lynch Syndrome and in Inflammatory Bowel Disease (IBD) share many features. There is some evidence to support the assumption that multiple genetic factors play an important role in the pathogenesis of idiopathic IBD and Lynch Syndrome. In our previous study, providing detailed medical, genetic and pathologic findings on 202 hereditary non polyposis colorectal cancer (HNPCC) relatives we found in the colonic mucosa features indicating an IBD though all the screened subjects of the family denied symptoms of IBD. Some studies have reported that the rate of undetected IBD ranges from 27 to 38%. Finally, a member of this family, considered not at risk for cancer by genetic analysis results, developed a clinically manifested IBD. The morphological aspects of the disease were not discussed in our previous study. It is possible that many members of this family inherit a major gene giving liability to the disease and are carriers of a subclinical form of IBD with a minimal morphological marker which becomes manifest in some members when other factors intervene. A possible genetic model linking the two diseases can be suggested: IBD needs two major genes for susceptibility (s) and clinical development (D). Both can be present in IBD and Lynch Syndrome, but in the latter a third gene plays a suppressor role on the development gene (D). In conclusion, we hypothesize that the IBD developing gene may be considered as protective against HNPCC, and this condition may result in a selective genetic advantage.

Colorectal Neoplasms, Hereditary Nonpolyposis↗
PubMedDate not supplied

Surgical treatment of uterine atony employing the B-Lynch technique.

Postpartum hemorrhage remains a major cause of maternal morbidity and mortality. Four cases utilizing the B-Lynch technique for control of hemorrhage secondary to uterine atony are presented. The B-Lynch technique appears to be effective in controlling postpartum hemorrhage. More experience is needed before the B-Lynch technique can be accepted as routine practice.

Adolescent↗
PubMed2006

DNA mismatch repair and Lynch syndrome.

The evolutionary conserved mismatch repair proteins correct a wide range of DNA replication errors. Their importance as guardians of genetic integrity is reflected by the tremendous decrease of replication fidelity (two to three orders of magnitude) conferred by their loss. Germline mutations in mismatch repair genes, predominantly MSH2 and MLH1, have been found to underlie the Lynch syndrome (also called hereditary non-polyposis colorectal cancer, HNPCC), a hereditary predisposition for cancer. Lynch syndrome affects predominantly the colon and accounts for 2-5% of all colon cancer cases. During more than 30 years of biochemical, crystallographic and clinical research, deep insight has been achieved in the function of mismatch repair and the diseases that are associated with its loss. We review the biochemistry of mismatch repair and also introduce the clinical, diagnostic and genetic aspects of Lynch syndrome.

Adenosine Triphosphatases↗
PubMed2007

The additive effect of p53 Arg72Pro and RNASEL Arg462Gln genotypes on age of disease onset in Lynch syndrome patients with pathogenic germline mutations in MSH2 or MLH1.

p53 and the prostate-cancer-susceptibility gene RNASEL are tumour suppressor genes involved in apoptosis. We have previously reported that the common, functionally different variants Arg72Pro in p53 and Arg462Gln in RNASEL are associated with the age of disease onset of colorectal cancer in Lynch syndrome patients. To assess the combined effect of both variants, we screened 246 unrelated Lynch syndrome patients with a pathogenic germline mutation either in MSH2 (n=138) or in MLH1 (n=108) and colorectal cancer as first tumour, and 245 healthy controls. The global log rank test revealed significant differences in the age of disease onset for the genotypes of each variant (p=0.0176 for p53 and p=0.0358 for RNASEL) and for the combined genotypes of both variants (p=0.0174). The highest difference in median age of disease onset was seen between homozygotes for the wild-types in both genes (42years [range 22-75]) and homozygotes for the variant alleles in both genes (30years [range 26-47]). A multivariate Cox regression model indicated that only the p53 and RNASEL genotypes had a significant influence on age of disease onset (p=0.016 for p53 and p=0.014 for RNASEL) in an additive mode of inheritance, and that the effects of both variants are purely additive, which supports the notion that the p53 and RNaseL pathways do not interact. These findings may be relevant for preventive strategies in Lynch syndrome.

Adaptor Proteins, Signal Transducing↗
PubMed2004

The B-Lynch technique for postpartum haemorrhage: an option for every gynaecologist.

Postpartum haemorrhage may be a life threatening complication. Seven cases are described in which the B-Lynch surgical technique (a brace like suture over the uterus) was successful in obtaining haemostasis. In four cases, the B-Lynch technique was the first line of treatment. In three cases, the B-Lynch was used after, or in combination with artery or other vessel ligation.

Adult↗
PubMed2005

Two Swedish founder MSH6 mutations, one nonsense and one missense, conferring high cumulative risk of Lynch syndrome.

Lynch syndrome, or hereditary non-polyposis colorectal cancer (HNPCC), is a cancer susceptibility syndrome caused by germline mutations in mismatch-repair genes, predominantly MLH1, MSH2 and MSH6. A majority of the mutations reported are truncating, but for MSH6, missense mutations constitute over one third. Few have been proven pathogenic in functional studies or shown to segregate in families. In this study, we show segregation of the putative pathogenic MSH6 missense mutation c.1346T>C p.Leu449Pro with microsatellite instability-high Lynch syndrome-related tumours lacking MSH6 expression in a large 17th century pedigree. Another large family with the MSH6 nonsense c.2931C>G, p.Tyr977X mutation is similar in tumour spectra, age of onset and cumulative risk. These MSH6 families, despite their late age of onset, have a high lifetime risk of all Lynch syndrome-related cancers, significantly higher in women (89% by age 80) than in men (69%). The gender differences are in part explained by high endometrial (70%) and ovarian (33%) cancer risks added upon the high colorectal cancer risk (60%). The several occurrences of breast cancer are not due to the MSH6 mutations. These findings are of great importance for counselling, management and surveillance of families with MSH6 mutations.

Codon, Nonsense↗
PubMed2005

Women with synchronous primary cancers of the endometrium and ovary: do they have Lynch syndrome?

PURPOSE: Lynch syndrome (hereditary nonpolyposis colorectal cancer; HNPCC) is an autosomal-dominant cancer predisposition syndrome that increases risk for multiple cancers, including colon, endometrial, and ovarian cancer. Revised Bethesda Criteria recommend that patients with two HNPCC-associated cancers undergo molecular evaluation to determine whether they have a mismatch repair (MMR) defect associated with HNPCC. The purpose of our study was to determine the likelihood of MMR defects (MSH2, MSH6, MLH1) in women with synchronous endometrial and ovarian cancer. PATIENTS AND METHODS: Between 1989 and 2004, 102 women with synchronous endometrial and ovarian cancers were identified; 59 patients had tumor blocks available for analysis. Patients were divided into risk groups based on family history: high (met Amsterdam criteria), medium (personal history or first-degree relative with an HNPCC-associated cancer), and low (all others). Protein expression for MSH2, MSH6, and MLH1 was evaluated by immunohistochemistry. Microsatellite instability and MLH1 promoter methylation analyses were performed on a subset of cases. RESULTS: Median age was 50 years. Two patients met Amsterdam criteria for HNPCC. Five additional patients, all medium-risk, had molecular findings consistent with a germline mutation of either MSH2 or MLH1. None of the low-risk patients had molecular results consistent with a germline mutation. CONCLUSION: Overall, 7% of women in our cohort met either clinical or molecular criteria for Lynch syndrome. All of these women had a prior history or a first-degree relative with an HNPCC-associated cancer. Limiting genetic evaluation to women with synchronous endometrial and ovarian cancer who have a family history suggestive of HNPCC may appropriately identify women with Lynch syndrome.

Adult↗
PubMedDate not supplied

Diagnostic approach and management of Lynch syndrome (hereditary nonpolyposis colorectal carcinoma): a guide for clinicians.

ABSTRACT diagnostic workup of familial colorectal cancer is an elaborate and time consuming process in which the family and several medical specialists closely collaborate. However, establishing a diagnosis can be very rewarding. If a mutation is detected in the family, a satisfactory explanation can be provided for an accumulation of tumors at young age, and often of untimely death. Appropriate presymptomatic testing can be offered to reduce mortality among at-risk family members, and relatives not at risk can avoid uncertainty and needlessly intensive surveillance. We show the differential diagnostic considerations when an individual with a family history of colorectal carcinoma is encountered, with emphasis on Lynch syndrome (Hereditary Nonpolyposis Colorectal Carcinoma [HNPCC]). Practical recommendations for laboratory workup of suspected Lynch syndrome, including analysis of tumor tissue by microsatellite instability analysis and immunohistochemistry, and germline DNA analysis are given. Furthermore, the clinical management after a molecular diagnosis has been made is described. The diagnostic scheme presented here allows efficient and effective analysis of colorectal carcinoma cases with (suspected) Lynch syndrome, making optimal use of currently available technology.

Colorectal Neoplasms, Hereditary Nonpolyposis↗
PubMed2002

[Use of the B-Lynch suture technique in postpartum hemorrhage].

BACKGROUND: Serious postpartum haemorrhage occurs in approximately 1.4% of all deliveries in Norway and may result in hysterectomy. Stepwise devascularisation and hysterectomy are technically difficult and time consuming. A simple suture technique, B-Lynch suture, has recently been introduced, by which atonic postpartum haemorrhage may be controlled and hysterectomy avoided. MATERIAL, METHODS AND RESULTS: We have used the B-Lynch technique in five patients with serious postpartum uterine atonia and haemorrhage. In all patients serious bleeding and hysterectomy were avoided. Three of the patients are described in detail, one with failed induction of labour resulting in Caesarean section, one with placenta previa, and one with prolonged normal vaginal delivery. INTERPRETATION: If performed early, the B-Lynch suture technique is less mutilating to the woman; it may prevent excessive blood loss and is probably beneficial for the patient's future fertility. It is easy to perform in Caesarean sections and can be adopted in vaginal deliveries.

Adult↗
PubMed2004

Modified B-Lynch technique for the control of massive postpartum hemorrhage. An alternative to hysterectomy.

The B-Lynch, brace suture technique is a life saving procedure. It is a simple and safe procedure, which has the advantage of preserving the uterus and thus fertility. The efficacy of the procedure can be assessed immediately and complete hemostasis is obtained in most cases. The special advantage of the B-Lynch technique is that it is an alternative to major surgical procedures such as hysterectomy and internal iliac artery ligation. A modified technique of the B-Lynch embracing suture has been performed in the case reported without any apparent complications.

Adult↗
PubMed1993

Emotional autonomy redux: revisiting Ryan and Lynch.

Ryan and Lynch have suggested that emotional autonomy in adolescence, at least as indexed by Steinberg and Silverberg's Emotional Autonomy Scale, is associated with poor family functioning and might therefore be better conceptualized as detachment. In the present study, we contrast adjustment scores among adolescents who differ in both emotional autonomy and perceptions of support in their relationship with their parents. Several thousand adolescents aged 14 through 18 completed Steinberg and Silverberg's emotional autonomy measure, a measure designed to assess the provision of support in the parent-adolescent relationship, and a number of standardized measures of adjustment. Adolescents high in emotional autonomy but low in relationship support show problematic adjustment profiles, consistent with Ryan and Lynch's interpretation of the measure as an index of detachment. Although adolescents high in both emotional autonomy and relationship support report more internal distress and behavior problems than some adolescents, they score higher on measures of psychosocial development and academic competence than their peers. Emotional autonomy in the context of a supportive adolescent-parent relationship may carry some developmental advantages as well as some deleterious consequences suggested by Ryan and Lynch.

Adolescent↗
PubMed1985

Hereditary nonpolyposis colorectal cancer (Lynch syndromes I and II). I. Clinical description of resource.

Hereditary nonpolyposis colorectal cancer (HNPCC) is comprised of the following: the cancer family syndrome (CFS), or Lynch syndrome II, which shows early-onset proximal colonic cancer predominance and other associated extracolonic adenocarcinomas, particularly endometrial carcinoma; and hereditary site-specific colon cancer (HSSCC), or Lynch syndrome I, which shows all of the same characteristics, except for extracolonic cancer. Nine families with CFS and two with HSSCC provided the resource that was tested for biomarkers (see companion article). All families were meticulously evaluated for genealogy and cancer verification. Biologic specimens were obtained during field visits to areas of closest geographic proximity to the families. Cancer education and recommendations for surveillance/management were provided to patients and their physicians. Additionally, 40 families (about 3000 individuals) with either CFS or HSSCC have been ascertained. Syndrome cancers were restricted to direct-line relatives as opposed to nonbloodline relatives, arguing against involvement of environmental factors. One documented clinical feature was a predilection for proximal versus distal colonic cancer in both CFS and HSSCC kindreds. This has important clinical significance in that it clarifies the need for instituting effective surveillance earlier to detect the predominantly proximal colonic cancers.

Adolescent↗