Background
Pathogenic germline variants in the mismatch repair (MMR) genes are associated with an increased risk of prostate cancer (PCa). Since 2010 we have recommended MMR carriers annual PSA ...testing from the age of 40. Prospective studies of the outcome of long‐term PSA screening are lacking. This study aimed to investigate the incidence and characteristics of PCa in Norwegian MMR carriers attending annual PSA screening (PSA threshold >3.0 ng/mL) to evaluate whether our recommendations should be continued.
Methods
This is a prospective observational study of 225 male MMR carriers who were recommended annual PSA screening by the Section of Inherited Cancer, Oslo University Hospital from 2010 and onwards. Incidence and tumor characteristics (age, PSA at diagnosis, Gleason score, TNM score) were described. IHC and MSI‐analyses were done on available tumors. Standardized incidence ratio (SIR) was calculated based on data from the Cancer Registry of Norway.
Results
Twenty‐two of 225 (9.8%) had been diagnosed with PCa, including 10/69 (14.5%) MSH2 carriers and 8/61 (13.1%) MSH6 carriers. Ten of 20 (50%) tumors had Gleason score ≥4 + 3 on biopsy and 6/11 (54.5%) had a pathological T3a/b stage. Eight of 17 (47.1%) tumors showed abnormal staining on IHC and 3/13 (23.1%) were MSI‐high. SIR was 9.54 (95% CI 5.98–14.45) for all MMR genes, 13.0 (95% CI 6.23–23.9) for MSH2 and 13.74 for MSH6 (95% CI 5.93–27.08).
Conclusions
Our results indicate that the MMR genes, and especially MSH2 and MSH6, are associated with a significant risk of PCa, and a high number of tumors show aggressive characteristics. While the impact of screening on patient outcomes remains to be more firmly established, the high SIR values we observe provide support for continued PSA screening of MSH2 and MSH6 carriers. Studies are needed to provide optimal recommendations for PSA‐threshold and to evaluate whether MLH1 and PMS2 carriers should not be recommended screening.
Lynch syndrome (LS) is an autosomal dominant inherited disorder caused by germline mutations in DNA mismatch repair (MMR) genes. Mutation carriers are at substantially increased risk of developing ...cancers of the colorectum and endometrium, among others. Given recent recommendations for universal, cost-effective screening of all patients with newly diagnosed colorectal cancer using MMR protein immunohistochemistry, we evaluated MMR protein expression in a series of endometrial cancers in the general population. A total of 605 consecutive cases of primary endometrial cancer at a single institution (1997 to 2013) were evaluated regardless of age, family history, or histologic features. Evaluation methods consisted of immunohistochemistry for the MMR proteins MLH1, MSH2, MSH6, and PMS2, followed by DNA methylation analysis for cases with MLH1/PMS2 deficiency. Germline mutation testing was performed on a subset of cases. Forty MMR-deficient, nonmethylated endometrial cancers were identified: 3 MLH1/PMS2 and 37 MSH6/MSH2 protein deficiencies. Only 25% occurred in women below 50 years of age (range, 39 to 88 y), 1 of which was in a risk-reducing hysterectomy specimen. Only 15% of patients had a prior history of carcinoma, including only 2 patients with prior colorectal carcinoma. Most (80%) of the endometrial cancers were purely endometrioid; there were 2 mixed endometrioid/mucinous, 1 mucinous, 1 serous, 2 clear cell, and 2 carcinosarcoma cases. When grading was applicable, 40% of the endometrial malignancies were FIGO grade 1, 34% grade 2, and 26% grade 3. Thirteen percent arose in the lower uterine segment, and 23% had tumor-infiltrating lymphocytes. Of the tumors with known germline testing, 41% with a LS-associated germline mutation were not associated with any of the traditional indicators that have been recommended for LS screening (ie, age 50 y or younger, personal/family cancer pedigree that meets Bethesda guideline criteria, presence of MMR-associated tumor morphology, or location in the lower uterine segment). These data suggest that a significant number of LS-associated endometrial carcinomas are missed using clinical, histologic, and locational screening parameters and provide support for universal screening of all newly diagnosed endometrial cancers.
Lynch syndrome is associated with pathogenic variants in 4 mismatch repair (MMR) genes that increase lifetime risk of colorectal cancer. Guidelines recommend intensive colorectal cancer surveillance ...with colonoscopy every 1–2 years starting at age 25 years for all carriers of Lynch syndrome–associated variants, regardless of gene product. We constructed a simulation model to analyze the effects of different ages of colonoscopy initiation and surveillance intervals for each MMR gene (MLH1, MSH2, MSH6, and PMS2) on colorectal cancer incidence and mortality, quality-adjusted life-years, and cost.
Using published literature, we developed a Markov simulation model of Lynch syndrome progression for patients with each MMR variant. The model simulated clinical trials of Lynch syndrome carriers, varying age of colonoscopy initiation (5-year increments from 25–40 years), and surveillance intervals (1–5 years). We assessed the optimal strategy for each gene, defined as the strategy with the highest quality-adjusted life-years and incremental cost-effectiveness ratio below a $100,000 willingness-to-pay threshold.
Optimal surveillance for patients with pathogenic variants in the MLH1 and MSH2 genes was colonoscopy starting at age 25 years, with 1- to 2-year surveillance intervals. Initiating colonoscopy at age 35 and 40 years, with 3-year intervals, was cost-effective for patients with pathogenic variants in MSH6 or PMS2, respectively.
We developed a simulation model to select optimal surveillance starting ages and intervals for patients with Lynch syndrome based on MMR variant. The model supports recommendations for intensive surveillance of patients with Lynch syndrome–associated variants in MLH1 or MSH2. However, for patients with Lynch syndrome–associated variants of MSH6 or PMS2, later initiation of surveillance at 35 and 40 years, respectively, and at 3-year intervals, can be considered.
This study analyzed data on risk of colorectal cancer in patients with Lynch syndrome and found that risk varies with genetic alteration associated with the disease, which should be used to determine starting age for colonoscopy surveillance and interval.
Identification of individuals with inherited predispositions to cancer, including Lynch syndrome, can help prevent cancer and cancer-related death by allowing for the uptake of specific cancer ...prevention and screening as well as the use of therapies directed toward the underlying neoplastic process for individuals with advanced cancer. In the 25 years since the discovery of microsatellite instability (MSI) and the first recognition of germline mismatch repair (MMR) gene variants as the etiologic basis of Lynch syndrome, there has been tremendous progress in the understanding of the spectrum of cancer risk associated with Lynch syndrome as well as in cancer prevention and risk-reduction strategies. The past few years, in particular, have brought transformative changes in the treatment of Lynch syndrome-associated cancers with immune checkpoint inhibitors. In parallel, advances in next-generation sequencing (NGS) technologies now allow rapid and scalable somatic and germline sequencing that promises to help identify Lynch syndrome in individuals who otherwise lack classic phenotypes. Last, real progress is being made to understand more sophisticated methods of precision cancer prevention, including chemotherapeutic prevention agents (e.g., aspirin) and strategies that leverage the immune system to facilitate primary cancer prevention in otherwise-healthy Lynch syndrome carriers.
Lynch syndrome (LS) predisposes affected individuals to a high lifetime risk of malignancies, including colorectal, endometrial, gastric, and duodenal cancers. The role of upper GI (UGI) cancer ...screening in LS has been uncertain, but recent studies have evaluated its utility.
Databases were queried through December 2021 to identify studies that examined upper endoscopy screening in LS using EGD. Mantel-Haenszel pooled odds ratios and 95% confidence intervals (CIs) for outcomes were constructed using a random-effects model to identify pooled odds of endoscopic findings in persons with LS. Event rates for detection of gastric and duodenal cancers, high-risk lesions, and clinically actionable findings were calculated. Statistical heterogeneity was assessed using the I2 statistic.
Nine studies were identified with 2356 LS patients undergoing approximately 7838 EGDs. In total, 47 LS-associated UGI cancers (18 gastric and 29 duodenal cancers), 237 high-risk lesions, and 335 clinically actionable findings were identified. The pooled event rate for detection of any UGI cancer, high-risk lesions, and clinically actionable findings during screening were .9% (95% CI, .3-2.1; I2 = 89%), 4.2% (95% CI, 1.6-10.9; I2 = 98%), and 6.2% (95% CI, 2.2-16.5; I2 = 99%), respectively. There was no difference between LS-associated gene and gastric or duodenal cancer detection.
In LS, there is evidence that endoscopic screening detects UGI cancers, precancerous lesions, and other clinically actionable findings that favor its use as a part of cancer risk management in LS.
Approximately 5% to 10% of patients with Lynch syndrome develop urothelial carcinoma. Current screening recommendations vary and are based on expert opinion. Practices need to be evaluated for ...clinical effectiveness. Our program utilizes urinalysis as a screening test, followed by additional evaluation of microscopic hematuria.
This study aimed to determine the clinical utility of a urinalysis-based screening approach for urothelial cancers in patients with Lynch syndrome.
This is a retrospective review of a prospectively maintained cohort.
Patients with Lynch syndrome were managed at a tertiary referral center.
All patients with a Lynch syndrome diagnosis who had a screening urinalysis done as part of our institutional screening protocol (N = 204) were included.
A single-institution hereditary colorectal cancer syndrome registry was queried for patients with Lynch syndrome who had been screened for urothelial carcinomas by urinalysis. Demographics, genotype, family history of urothelial carcinoma, urinalysis results, and subsequent screenings and final diagnosis were gathered for patients between 2008 and 2017.
Two hundred four asymptomatic patients underwent screening by urinalysis. Nineteen patients (9.3%) had microscopic hematuria and were further evaluated with urine cytology, imaging, cystoscopy, and/or Urology consultation. None of the 19 patients with microscopic hematuria had urothelial carcinoma. During the same study period, 5 of 204 (2.4%) patients with Lynch syndrome were diagnosed with urothelial cancer, and all presented with symptoms between screening intervals.
This is a retrospective study, and not all patients underwent the same secondary evaluation.
No urothelial carcinomas were detected by screening urinalysis in our cohort of asymptomatic patients with Lynch syndrome. False-positive testing led to extensive, mostly uninformative, workups. If urothelial cancer screening is to continue, more effective screening approaches need to be identified. See Video Abstract at http://links.lww.com/DCR/B702.
ANTECEDENTES:Aproximadamente el 5-10% de los pacientes con síndrome de Lynch desarrollan carcinoma urotelial. Las recomendaciones actuales de detección varían y se basan en la opinión de expertos. Las prácticas deben evaluarse para determinar su eficacia clínica. Nuestro programa utiliza el análisis de orina como prueba de detección, seguido de una evaluación adicional con hematuria microscópica.OBJETIVO:Determinar la utilidad clínica desde un enfoque de cribado basado en análisis de orina, para cánceres uroteliales en pacientes con síndrome de Lynch.DISEÑO:Revisión retrospectiva de una cohorte mantenida prospectivamente.ENTORNO CLINICO:Pacientes con síndrome de Lynch atendidos en un centro de referencia terciario.PACIENTES:Criterios de inclusión fueron todos los pacientes con diagnóstico de síndrome de Lynch realizándoles un análisis de orina de detección como parte de nuestro protocolo de detección institucional (N = 204).PRINCIPALES MEDIDAS DE VALORACION:Solicitando un registro de síndrome de cáncer colorrectal hereditario de una sola institución para pacientes con síndrome de Lynch previamente evaluados para carcinomas uroteliales mediante análisis de orina. Se recopilaron para los pacientes entre 2008 y 2017, datos demográficos, genotipo, antecedentes familiares de carcinoma urotelial, resultados del análisis de orina, posteriores exámenes de detección posteriores y diagnóstico final.RESULTADOS:Doscientos cuatro pacientes asintomáticos fueron sometidos a cribado mediante análisis de orina. Diecinueve pacientes (9,3%) tenían hematuria microscópica y fueron investigados más a fondo con citología de orina, imágenes, cistoscopia y / o consulta de urología. Ninguno de los 19 pacientes con hematuria microscópica tenían carcinoma urotelial. Durante el mismo período de estudio, 5 de 204 (2,4%) pacientes con síndrome de Lynch fueron diagnosticados con cáncer urotelial y todos presentaron presentando síntomas entre los intervalos de detección.LIMITACIONES:Estudio retrospectivo y no todos los pacientes sometidos a la misma evaluación secundaria.CONCLUSIONES:No se detectaron carcinomas uroteliales mediante análisis de orina de detección en nuestra cohorte de pacientes asintomáticos con síndrome de Lynch. Las pruebas de falsos positivos. Condujeron a estudios exhaustivos y en su mayoría poco informativos. Si se desea continuar con la detección del cáncer de urotelio, es necesario identificar enfoques de detección más efectivos. Consulte Video Resumen en http://links.lww.com/DCR/B702.
To evaluate the cost effectiveness of next-generation sequencing (NGS) panels for the diagnosis of colorectal cancer and polyposis (CRCP) syndromes in patients referred to cancer genetics clinics.
We ...developed a decision model to evaluate NGS panel testing compared with current standard of care in patients referred to a cancer genetics clinic. We obtained data on the prevalence of genetic variants from a large academic laboratory and calculated the costs and health benefits of identifying relatives with a pathogenic variant, in life-years and quality-adjusted life-years (QALYs). We classified the CRCP syndromes according to their type of inheritance and penetrance of colorectal cancer. One-way and probabilistic sensitivity analyses were conducted to assess uncertainty.
Evaluation with an NGS panel that included Lynch syndrome genes and other genes associated with highly penetrant CRCP syndromes led to an average increase of 0.151 year of life, 0.128 QALY, and $4,650 per patient, resulting in an incremental cost-effectiveness ratio of $36,500 per QALY compared with standard care and a 99% probability that this panel was cost effective at a threshold of $100,000 per QALY. When compared with this panel, the addition of genes with low colorectal cancer penetrance resulted in an incremental cost-effectiveness ratio of $77,300 per QALY.
The use of an NGS panel that includes genes associated with highly penetrant CRCP syndromes in addition to Lynch syndrome genes as a first-line test is likely to provide meaningful clinical benefits in a cost-effective manner at a $100,000 per QALY threshold.
Lynch syndrome (LS) is the most common hereditary colorectal cancer (CRC) syndrome, with an estimated prevalence of 2% to 3% of CRC. A prevalence study is needed to provide accurate estimates of the ...true prevalence of LS.
MEDLINE (Ovid), Embase, and Web of Science were searched. Prevalence was calculated by random effects meta-analysis models. I2 score was used to assess heterogeneity across studies. Meta-regression was performed for between-study variance.
A total of 51 studies were included in this review. The overall pooled yield of LS screening was 2.2% based on all methods of detection. Studies performing germline tests on all participants with CRC reported higher prevalence (5.1%) as opposed to studies only performing germline tests on participants with tumors with mismatch repair deficiency (1.6%) or microsatellite instability (1.1%). Selected cohorts of CRC had a higher prevalence of germline LS diagnoses.
LS prevalence across multiple ethnic, geographic, and clinical populations is remarkably similar. Universal germline testing of patients presenting with cancer identifies that most CRCs are attributed to LS. Young patients presenting with CRC and those who fulfill criteria for a familial risk provide the highest returns for LS identification. Our study supports the universal germline CRC screening for LS.
Today most patients with Lynch syndrome (LS) survive their first cancer. There is limited information on the incidences and outcome of subsequent cancers. The present study addresses three questions: ...(i) what is the cumulative incidence of a subsequent cancer; (ii) in which organs do subsequent cancers occur; and (iii) what is the survival following these cancers?
Information was collated on prospectively organised surveillance and prospectively observed outcomes in patients with LS who had cancer prior to inclusion and analysed by age, gender and genetic variants.
1273 patients with LS from 10 countries were followed up for 7753 observation years. 318 patients (25.7%) developed 341 first subsequent cancers, including colorectal (n=147, 43%), upper GI, pancreas or bile duct (n=37, 11%) and urinary tract (n=32, 10%). The cumulative incidences for any subsequent cancer from age 40 to age 70 years were 73% for pathogenic
(
), 76% for
carriers and 52% for
carriers, and for colorectal cancer (CRC) the cumulative incidences were 46%, 48% and 23%, respectively. Crude survival after any subsequent cancer was 82% (95% CI 76% to 87%) and 10-year crude survival after CRC was 91% (95% CI 83% to 95%).
Relative incidence of subsequent cancer compared with incidence of first cancer was slightly but insignificantly higher than cancer incidence in patients with LS without previous cancer (range 0.94-1.49). The favourable survival after subsequent cancers validated continued follow-up to prevent death from cancer. The interactive website http://lscarisk.org was expanded to calculate the risks by gender, genetic variant and age for subsequent cancer for any patient with LS with previous cancer.
Mismatch-repair (MMR) immunohistochemistry is used to detect tumor MMR deficiency associated with high-level microsatellite instability (MSI). Rare tumors show heterogenous loss of mutS homolog 6 ...(MSH6) with immunohistochemistry, defined by areas of retained staining and separate areas of complete loss of staining. To investigate the clinical interpretation of this phenomenon, we identified 22 cases of heterogenous MSH6 loss interpreted at Mayo Clinic from January 2001 through December 2012 and reviewed histologic features, MSH6 and other MMR immunohistochemistry, and accompanying MSI testing results (n=20). Heterogenous MSH6 loss was seen in colorectal carcinoma (n=18), endometrial carcinoma (n=3), and sebaceous neoplasm (n=1). In the 18 colorectal carcinoma cases, it accompanied complete loss of mutL homolog 1 (MLH1) or PMS2, or both. Heterogenous MSH6 loss was characterized by MSI and MSH6 C8 tract instability in treatment-naive cases and showed mucinous or signet-ring zones in one quarter of cases. Two cases status post neoadjuvant chemoradiation showed heterogenous MSH6 loss but were microsatellite and C8 tract stable. C8 tracts were unstable in 2 of 4 MSH6-associated Lynch syndrome (LS) tumors, but all 4 showed complete MSH6 loss on immunohistochemistry. Further, 12 such MSH6-associated LS cases showed complete MSH6 loss. In conclusion, heterogenous MSH6 loss is uncommon, usually caused by instability in MSH6 exon 5 polycytosine tract, and not associated with germline MSH6 mutation. Although heterogenous MSH6 loss provides evidence against germline MSH6 mutation, patients whose tumors exhibit this immunolabeling pattern may have LS due to a defect in a different MMR gene.
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