Advancements in Lynch Syndrome Management: Applying Immunotherapy for Therapeutic Success

Lynch syndrome is the fourth most common cancer in the United States, with an early age of onset and poor prognosis. Here, we present a unique case of a patient with progressive colon cancer due to a late diagnosis of Lynch syndrome showing excellent response to immunotherapy. A 59-year-old male with a history of rectal cancer 30 years ago came to the hospital due to a fever and further found a large necrotic colon mass. Biopsy was positive for colorectal cancer;however, due to the size of the tumor, the patient was deemed not a surgical candidate and offered hospice with palliative chemotherapy. Based on further workup, the patient was diagnosed with Lynch syndrome, with colon cancer determined to be responsive to Immunotherapy. He was started on JEMPERLI (Dosterlimab-gxly), and after three cycles of therapy, imaging and PET scan were repeated, showing decreased activity and extent of the tumor—a tremendous success.

Breast cancer and rectal cancer associated with Lynch syndrome:A case report

BACKGROUND The development mechanisms of Lynch syndrome(LS)-related breast cancer(BC)and rectal cancer are complex and variable,leading to personalized variations in diagnosis and treatment plans.CASE SUMMARY This paper presents a comprehensive review of clinical diagnosis and treatment data from a patient with LS-associated BC and rectal cancer.Moreover,screening data and management guidelines,as well as relevant literature on LS,are included in this report.This study summarizes the molecular pathogenesis,clinicopathological features,and screening and management protocols for LS-associated BC and rectal cancer.CONCLUSION Implementing early screening,prevention,and timely diagnosis and treatment measures is expected to reduce mitigate the incidence and mortality of LS-related BC and rectal cancer.

Neuroendocrine carcinoma of the endometrium concomitant with Lynch syndrome:A case report

BACKGROUND Large-cell neuroendocrine carcinoma(NEC)is an uncommon type of tumor that can occur in the endometrium.This aggressive cancer requires definitive management.Here,we describe the clinical characteristics and treatment of a postmenopausal woman with large cell NEC of the endometrium.CASE SUMMARY A 55-year-old Asian female presented with a 1-year history of postmenopausal vaginal bleeding.Transvaginal ultrasound revealed a thickened endometrium(30.2 mm)and a hypervascular tumor.Computed tomography revealed that the tumor had invaded more than half of the myometrium and spread to the pelvic lymph nodes.The tumor marker,carcinoembryonic antigen,was elevated(3.65 ng/mL).Endocervical biopsy revealed high-grade endometrial carcinoma.She underwent radical hysterectomy,bilateral salpingo-oophorectomy,omentectomy,and bilateral pelvic and para-aortic lymph node dissection.Pathological examination revealed mixed neuroendocrine and endometrioid adenocarcinoma,pT2N0M0,grade 3,and International Federation of Gynecology and Obstetrics stage 2.Immunohistochemistry showed moderate estrogen and progesterone receptor expressions(20%and 1%,respectively),focal CD56 expression(NEC marker),positive staining for vimentin,p53(wild type),and ki67(90%),and loss of expression of PMS2(Lynch syndrome marker).The patient received five cycles of cisplatin and etoposide after surgery.No recurrence was noted after 5 mo.CONCLUSION We report the characteristics and successful management of a rare case of large cell endometrial NEC concomitant with Lynch syndrome.

Surveillance colonoscopy practice in Lynch syndrome in the Netherlands:A nationwide survey

Lynch syndrome, or hereditary nonpolyposis colorectal cancer (HNPCC), is the most common genetic disorder predisposing to colorectal cancer. As regular colonoscopic surveillance has been shown to reduce the incidence of colorectal cancer, this strategy is recommended worldwide. Recently, several advances in colonoscopic techniques have improved detection rates of neoplasia in Lynch syndrome. In this nationwide survey, we evaluated current surveillance colonoscopy practices for Lynch syndrome in the Netherlands and the extent to which advanced techniques have been adopted in routine clinical practice.

Simplified microsatellite instability detection protocol provides equivalent sensitivity to robust detection strategies in Lynch syndrome patients

Objective:Germline mutations in mismatch repair(MMR)genes cause Lynch syndrome(LS).LS is an inherited disease,and an important consequence of MMR deficiency is microsatellite instability(MSI)phenotype.MSI phenotype influences the efficacy of5 fluorouracil(5-FU)chemotherapy.Reproducible,cost effective,and easy to perform laboratory tests are required to include MSI detection in routine laboratory practice.Evaluation of CAT25 as monomorphic short tandem repeat sequence enables CAT25 to be an efficient screening tool among hereditary nonpolyposis colorectal cancer(HNPCC)patients compared with other methods used currently.Methods:Based on Amsterdam II criteria,31 patients in 31 families were shortlisted from a total number of 1,659 colorectal cancer patients.MSI status was examined in these patients using CAT25 and a commercially available Promega MSI five-markerbased detection system as well as immunohistochemical(IHC)staining of four important MMR proteins.Patients were scored as high microsatellite instable(MSI-H),low(MSI-L),or stable(MSS).MSI status determined by CAT25 single mononucleotide marker was compared with that of five mononucleotide markers,Promega commercial kit,and IHC method.Results:MMR protein deficiency was observed on 7/31 probands using IHC methodology and 6/31 categorized as MSI-H using commercial kit or CAT25 single marker.The sensitivity and specificity of the CAT25 single marker were the same as those detected by five-marker Promega commercial kit in our patients.Conclusions:Based on our results,the performance of the CAT25 single mononucleotide marker for MSI status determination in our HNPCC patients is the same as that of the five-marker-based commercial kit.

Identification of novel Lynch syndrome mutations in Chinese patients with endometriod endometrial cancer

Objective:Lynch syndrome(LS)predisposes patients to early onset endometrioid endometrial cancer(EEC).However,little is known about LS-related EEC in the Chinese population.The aim of this study was to investigate the prevalence of LS and to identify the specific variants of LS in Chinese patients with EEC.Methods:We applied universal immunohistochemistry screening to detect the expression of mismatch repair(MMR)proteins,which was followed by MLH1 methylation analysis to identify suspected LS cases,next-generation sequencing(NGS)to confirm LS,and microsatellite instability(MSI)analysis to verify LS.Results:We collected 211 samples with EEC.Twenty-seven(27/211,12.8%)EEC cases had a loss of MMR protein expression.After MLH1 methylation analysis,16 EEC cases were suggested to be associated with LS.Finally,through NGS and MSI analysis,we determined that 10 EEC(10/209,4.78%)cases were associated with LS.Among those cases,3 unreported mutations(1 frameshift and 2 nonsense)were identified.M SH6 c.597_597delC,found in 4 patients,is likely to be a founder mutation in China.Conclusions:We demonstrated the feasibility of a process for LS screening in Chinese patients with EEC,by using universal immunohistochemistry screening followed by MLH1 methylation analysis and confirmation through NGS and MSI analysis.The novel mutations identified in this study expand knowledge of LS.

Epithelial-mesenchymal transition in colorectal cancer tissue of patients with Lynch syndrome

AIM: To explore the epithelial-mesenchymal transition (EMT) in tissue from patients with Lynch syndrome, and to interpret biological behaviour of Lynch syndrome.

Identification of patients at-risk for Lynch syndrome in a hospital-based colorectal surgery clinic

AIM:To determine the prevalence of a family history suggestive of Lynch syndrome (LS) among patients with colorectal cancer (CRC) followed in a coloproctology outpatient clinic in Southern Brazil.METHODS:A consecutive sample of patients with CRC were interviewed regarding personal and family histories of cancer.Clinical data and pathology features of the tumor were obtained from chart review.RESULTS:Of the 212 CRC patients recruited,61 (29%) reported a family history of CRC,45 (21.2%) were diagnosed under age 50 years and 11 (5.2%) had more than one primary CRC.Family histories consistent with Amsterdam and revised Bethesda criteria for LS were identified in 22 (10.4%) and 100 (47.2%) patients,respectively.Twenty percent of the colorectal tumors had features of the high microsatellite instability phenotype,which was associated with younger age at CRC diagnosis and with Bethesda criteria (P < 0.001).Only 5.3% of the patients above age 50 years had been previously submitted for CRC screening and only 4% of patients with suspected LS were referred for genetic risk assessment.CONCLUSION:A significant proportion of patients with CRC were at high risk for LS.Education and training of health care professionals are essential to ensure proper management.

MutL homolog 1 germline mutation c.(453+1_454-1)_(545+1_546-1)del identified in lynch syndrome:A case report and review of literature

BACKGROUND Lynch syndrome(LS)is an autosomal dominant hereditary disorder because of germline mutations in DNA mismatch repair genes,such as MutL homolog 1(MLH1),PMS1 homolog 2,MutS homolog 2,and MutS homolog 6.Gene mutations could make individuals and their families more susceptible to experiencing various malignant tumors.In Chinese,MLH1 germline mutation c.(453+1_454-1)_(545+1_546-1)del-related LS has been infrequently reported.Therefore,we report a rare LS patient with colorectal and endometrioid adenocarcinoma and describe her pedigree characteristics.CASE SUMMARY A 57-year-old female patient complained of irregular postmenopausal vaginal bleeding for 6 mo.She was diagnosed with LS,colonic malignancy,endometrioid adenocarcinoma,secondary fallopian tube malignancy,and intermyometrial leiomyomas.Then,she was treated by abdominal hysterectomy,bilateral oviduct oophorectomy,and sentinel lymph node resection.Genetic testing was performed using next-generation sequencing technology to detect the causative genetic mutations.Moreover,all her family members were offered a free genetic test,but no one accepted it.CONCLUSION No tumor relapse or metastasis was found in the patient during the 30-mo followup period.The genetic panel sequencing showed a novel pathogenic germline mutation in MLH1,c.(453+1_454-1)_(545+1_546-1)del,for LS.Moreover,cancer genetic counseling and testing are still in the initial development state in China,and maybe face numerous challenges in the further.

Isolated colonic neurofibroma in the setting of Lynch syndrome:A case report and review of literature

BACKGROUND Gastrointestinal neurofibromas are commonly found in patients diagnosed with neurofibromatosis type 1.However,isolated gastrointestinal neurofibromas are a rare entity and only fourteen cases of isolated colorectal neurofibromas have been documented in literature.Isolated gastrointestinal neurofibromas have not been associated with Lynch syndrome(LS).Patients with LS are at an increased risk of colorectal cancer,and are recommended to undergo screening colonoscopy.CASE SUMMARY A 33-year-old healthy female with a family history of LS was found to have unresectable polyp in the ascending colon on screening colonoscopy suspicious for malignancy.The patient was asymptomatic and had no stigmata of neurofibromatosis.A staging workup for colorectal cancer revealed no evidence of metastatic disease.A discussion with the patient resulted in the decision to undergo a segmental resection with ongoing surveillance.The patient underwent a laparoscopic right hemicolectomy.Histopathology was consistent with a gastrointestinal neurofibroma.Post-operatively,the patient recovered well.She will not require further treatment with regards to her colonic neurofibroma,but will continue to follow-up for ongoing surveillance of her LS.CONCLUSION We present the first case of an isolated colonic neurofibroma in a patient with LS.This case explores considerations for the management of isolated gastrointestinal neurofibromas given the lack of guidelines in literature.

Lynch syndrome pre-screening and comprehensive characterization in a multi-center large cohort of Chinese patients with colorectal cancer

Objective:Lynch syndrome(LS)pre-screening methods remain under-investigated in colorectal cancers(CRCs)in Asia.Here,we aimed to systematically investigate LS pre-screening and comprehensively characterize LS CRCs.Methods:Microsatellite instability(MSI)and germline variants of DNA mismatch repair(MMR)genes were examined in 406 deficient MMR(dMMR)and 250 proficient MMR CRCs.The genetic differences between LS and sporadic CRCs were studied with whole exome sequencing analysis.Results:The incidence of dMMR in Chinese patients with CRCs was 13.8%.Consistency analysis between MMR immunohistochemistry(IHC)and MSI testing showed the kappa value was 0.758.With next-generation sequencing(NGS),germline variants were detected in 154 CRCs.Finally,88 patients with CRC were identified as having LS by Sanger sequencing.Among them,we discovered 21 previously unreported pathogenic germline variants of MMR genes.Chinese patients with LS,compared with sporadic CRCs,tended to be early-onset,right-sided,early-stage and mucinous.Overall,the performance of MMR IHC and MSI testing for LS pre-screening was comparable:the area under the ROC curve for dMMR,MSI-H,and MSI-H/L was 0.725,0.750,and 0.745,respectively.dMMR_MSI-H LS and sporadic CRCs showed substantial differences in somatic genetic characteristics,including different variant frequencies of APC,CREBBP,and KRAS,as well as different enriched pathways of VEGF,Notch,TGFβR,mTOR,ErbB,and Rac protein signal transduction.Conclusions:MMR IHC and MSI testing were effective methods for LS pre-screening.The revealed clinical and somatic genetic characteristics in LS CRCs may have the potential to improve the performance of LS pre-screening in combination with dMMR/MSI.

A de novo germline MLH1 mutation in a Lynch syndrome patient with discordant immunohistochemical and molecular biology test results

We describe a patient with a Homo sapiens mutL homolog 1 (MLH1)-associated Lynch syndrome with previous diagnoses of two distinct primary cancers:a sigmoid colon cancer at the age of 39 years, and a right colon cancer at the age of 50 years. The mutation identified in his blood and buccal cells, c.1771delG, p.Asp591Ilefs*25, appears to be a de novo event, as it was not transmitted by either of his parents. This type of de novo event is rare in MLH1 as only three cases have been reported in the literature so far. Further-more, the discordant results observed between repli-cation error phenotyping and immunohistochemistry highlight the importance of the systematic use of both pre-screening tests in the molecular diagnosis of Lynch syndrome.

Genitourinary manifestations of Lynch syndrome in the urological practice

Objective:Lynch syndrome(LS)is an autosomal dominant hereditary disorder resulting from germline mutation in at least one of the four mismatch repair genes or in EPCAM gene.From a clinical perspective,LS patients exhibit an increased predisposition to multiple primary malignancies and early age of onset compared to general population.We aimed to provide a comprehensive overview of all the genitourinary manifestations of LS,focusing on incidence,diagnosis,clinical features,therapeutic strategies,and screening protocols.Methods:Previous literature was assessed through Medline,Scopus,and Google Scholar data-bases.A narrative review of the most relevant articles from January 1996 to June 2021 on urological manifestations of LS was provided.Results:In the LS tumor spectrum,upper tract urothelial carcinoma(UTUC)represents the third most frequent malignancy,and the first most common cancer in the urological field,with an approximately 14-fold increased risk of developing UTUC compared to general population.LS diagnosis among patients experiencing UTUC as first malignancy is a step-by-step process,including(i)clinical criteria,(ii)molecular testing,and(iii)genetic testing to confirm the hereditary disorder.The current European Association of Urology(EAU)guidelines recommend to perform molecular testing among UTUC patients under 65 years old,or UTUC patients with personal history of LS-related tumor,or UTUC patients with one first-degree relative under the age of 50 years with LS-related tumor,or UTUC patients with two first-degree relatives with LS-related tumor regardless of age of onset.Newly diagnosed LS patients should be referred to a multidisci-plinary management,including gastroenterologists and gynecologists.Finally,considering the increased risk of metachronous recurrence,treatments other than radical nephroureterectomy may be a valuable therapeutic alternative.Whether urological malignancies other than UTUC should be included in the LS tumor spectrum is still controversial.Conclusion:Considering the strict association between UTUC and LS,we believe that the urologist should recognize patients at increased risk for hereditary disease according to current EAU clinical criteria and address them to a comprehensive diagnostic algorithm,including molecular evaluationandgenetic testing.To date,literature lacks clear evidence regarding the role of LS in developing bladder cancer,prostate cancer,or renal cell carcinoma,and current data are still inconclusive,highlighting the urgent need for further studies.

Association of cancer with comorbid inflammatory conditions and treatment in patients with Lynch syndrome

BACKGROUND Individuals with Lynch syndrome(LS)and hereditary non-polyposis colorectal cancer(HNPCC)are at increased risk of both colorectal cancer and other cancers.The interplay between immunosuppression,a comorbid inflammatory condition(CID),and HNPCC on cancer risk is unclear.AIM To evaluate the impact of CIDs,and exposure to monoclonal antibodies and immunomodulators,on cancer risk in individuals with HNPCC.METHODS Individuals prospectively followed in a hereditary cancer registry with LS/HNPCC with the diagnosis of inflammatory bowel disease or rheumatic disease were identified.We compared the proportion of patients with cancer in LS/HNPCC group with and without a CID.We also compared the proportion of patients who developed cancer following a CID diagnosis based upon exposure to immunosuppressive medications.RESULTS A total of 21 patients with LS/HNPCC and a CID were compared to 43 patients with LS/HNPCC but no CID.Cancer occurred in 84.2% with a CID compared to 76.7% without a CID(P=0.74)with no difference in age at first cancer diagnosis 45.5±14.6 vs 43.8±7.1 years(P=0.67).LS specific cancers were diagnosed in 52.4% with a CID vs 44.2% without a CID(P=0.54).Nine of 21(42.9%)patients were exposed to biologics or immunomodulators for the treatment of their CID.Cancer after diagnosis of CID was seen in 7(77.8%)of exposed individuals vs 5(41.7%)individuals unexposed to biologics/immunomodulators(P=0.18).All 7 exposed compared to 3/5 unexposed developed a LS specific cancer.The exposed and unexposed groups were followed for a median 10 years and 8.5 years,respectively.The hazard ratio for cancer with medication exposure was 1.59(P=0.43,95%CI:0.5-5.1).CONCLUSION In patients with LS/HNPCC,the presence of a concurrent inflammatory condition,or use of immunosuppressive medication to treat the inflammatory condition,might not increase the rate of cancer occurrence in this limited study.

Uptake and outcomes of small intestinal and urinary tract cancer surveillance in Lynch syndrome

BACKGROUND Lynch syndrome(LS)is a hereditary cancer predisposition syndrome associated with increased risk of multiple cancers.While colorectal cancer surveillance decreases mortality in LS and is recommended by guidelines,there is lack of evidence for the efficacy of surveillance for extra-colonic cancers associated with LS,including small intestinal cancer(SIC)and urinary tract cancer(UTC).Given the limited evidence,guidelines do not consistently recommend surveillance for SIC and UTC,and it remains unclear how often individuals will choose to undergo and follow through with extra-colonic surveillance recommendations.AIM To study factors associated with SIC and UTC surveillance uptake and outcomes in LS.METHODS This is an IRB-approved retrospective analysis of individuals with LS seen at a tertiary care referral center.Included individuals had a pathogenic or likely pathogenic variant in MLH1,MSH2,MSH6,PMS2,or EPCAM,or were a confirmed obligate carrier,and had at least one documented visit to our center.Information regarding SIC and UTC surveillance was captured for each individual,and detailed personal and family history was obtained for individuals who had an initial LS management visit in our center’s dedicated high-risk LS clinic between January 1,2017 and October 29,2020.During these initial management visits,all patients had in-depth discussions of SIC and UTC surveillance with 1 of 3 providers experienced in LS management to promote informed decision-making about whether to pursue SIC and/or UTC surveillance.Statistical analysis using Pearson’s chi-squared test and Wilcoxon rank-sum test was completed to understand the factors associated with pursuit and completion of SIC and UTC surveillance,and a P value below 0.05 was deemed statistically significant.RESULTS Of 317 individuals with LS,86(27%)underwent a total of 105 SIC surveillance examinations,with 5 leading to additional work-up and no SICs diagnosed.Additionally,99(31%)patients underwent a total of 303 UTC surveillance examinations,with 19 requiring further evaluation and 1 UTC identified.Of 155 individuals who had an initial LS management visit between January 1,2017 and October 29,2020,63(41%)chose to undergo SIC surveillance and 58(37%)chose to undergo UTC surveillance.However,only 26(41%)and 32(55%)of those who initially chose to undergo SIC or UTC surveillance,respectively,successfully completed their surveillance examinations.Individuals with a pathogenic variant in MSH2 or EPCAM were more likely to initially choose to undergo SIC surveillance(P=0.034),and older individuals were more likely to complete SIC surveillance(P=0.007).Choosing to pursue UTC surveillance was more frequent among older individuals(P=0.018),and females more frequently completed UTC surveillance(P=0.002).Personal history of cancer and family history of SIC or UTC were not significantly associated with electing nor completing surveillance.Lastly,the provider discussing SIC/UTC surveillance was significantly associated with subsequent surveillance choices.CONCLUSION Pursuing and completing SIC/UTC surveillance in LS is influenced by several factors,however broad incorporation in LS management is likely unhelpful due to low yield and frequent false positive results.

Screening and diagnosis of endometrial cancer in Lynch syndrome

Lynch syndrome （LS） is an autosomal dominant inherited cancer predisposition syndrome caused by a mismatch of DNA repair （MMR system）. Lifetime risk of developing endometrial and ovarian cancer in LS is higher than in the general population and gynecologic screening appears interesting. Screening is based on several tests： pelvic ultrasound, endometrial biopsy and hysteroscopy for endometrial cancer, pelvic ultrasound and CA125 for ovarian cancer. Those tests appear efficient for the diagnosis of gynecologic cancers in LS. Nevertheless, screening tests have not proved clinical benefit until now, and potential problems of compliance, risk of false negative cases, and interval cancer associated with screening do justify offering prophylactic surgery to patients. Women with LS should be informed of the potential benefits and risks of screening and the importance of evaluation in case of gynecologic symptoms or abnormal bleeding. Chemoprevention by progestin-containing oral contraceptives and the treatment ofthe potential benefits and risks of screening and the importance of evaluation in case of gynecologic symptoms or abnormal bleeding. Chemoprevention by progestin-containing oral contraceptives and the treatment of premalignant lesion are available options for reducing the risk of endometrial cancer in LS population.

Comparison of screening strategies for Lynch syndrome in patients with newly diagnosed endometrial cancer:a prospective cohort study in China

Background: The prevalence of Lynch syndrome and screening strategies for this disorder in Chinese patients with endometrial cancer have seldom been investigated. Such data would be essential for the screening, prevention, genetic counseling, and treatment of Lynch syndrome. The purpose of this prospective study was to determine the accuracy of the mismatch repair (MMR) protein immunohistochemistry (IHC), microsatellite instability (MSI) test, and clinical diagnostic criteria in screening for Lynch syndrome-associated endometrial cancer (LS-EC) in a prospective Chinese cohort. Methods: All patients with newly diagnosed endometrial cancer (EC) were evaluated using clinical diagnostic criteria (Amsterdam II criteria and the revised Bethesda guidelines), MSI test, and IHC of MMR proteins in tumor tissues. For all patients, the screening results were compared with results of germline sequencing for pathogenic variants of MMR genes. Results: Between December 2017 and August 2018, a total of 111 unselected patients with newly diagnosed EC were enrolled. Six patients (5.4%) harbored a pathogenic germline mutation of MMR genes: 1 had a mutation in MutL homolog 1 (MLH1), 2 in MutS homolog 2 (MSH2), and 3 in MutS homolog 6 (MSH6). The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for identifying LS-EC were 33.3%, 88.6%, 14.3%, and 95.9%, for the clinical criteria, 66.7%, 75.0%, 14.3%, and 97.3% for IHC of MMR proteins, 100%, 89.9%, 33.3%, and 100% for MSI test, and 100%, 72.4%, 20.0% and 100% for combined IHC and MSI test, respectively. The combination of IHC and MSI test had higher sensitivity and PPV than the clinical criteria (p = 0.030). MSI test and IHC were highly concordant for LS-EC screening (73/77, 94.8%). Conclusion: The accuracy of the combination of IHC of MMR proteins and MSI test for screening LS among Chinese patients with EC was superior to that of the clinical criteria.

Classification and genetic counselling for a novel splicing mutation of the MLH1 intron associated with Lynch syndrome in colorectal cancer

Background:Lynch-syndrome-associated cancer is caused by germline pathogenic mutations in mismatch repair genes.The major challenge to Lynch-syndrome screening is the interpretation of variants found by diagnostic testing.This study aimed to classify the MLH1 c.1989t5G>A mutation,which was previously reported as a variant of uncertain significance,to describe its clinical phenotypes and characteristics,to enable detailed genetic counselling.Methods:We reviewed the database of patients with Lynch-syndrome gene detection in our hospital.A novel variant of MLH1 c.1989t5G>A identified by next-generation sequencing was further investigated in this study.Immunohistochemical staining was carried out to assess the expression of MLH1 and PMS2 protein in tumour tissue.In silico analysis by Alamut software was used to predict the MLH1 c.1989t5G>A variant function.Reverse transcription-polymerase chain reaction and sequencing of RNA fromwhole bloodwere used to analyse the functional significance of this mutation.Results:Among affected family members in the suspected Lynch-syndrome pedigree,the patient suffered from late-stage colorectal cancer but had a good prognosis.We found the MLH1 c.1989t5G>A variant,which led to aberrant splicing and loss of MLH1 and PMS2 protein in the nuclei of tumour cells.An aberrant transcript was detectable and skipping of MLH1 exon 17 in carriers of MLH1 c.1989t5G>A was confirmed.Conclusions:MLH1 c.1989t5G>A was detected in a cancer family pedigree and identified as a pathological variant in patients with Lynch syndrome.Themutation spectrumof Lynch syndrome was enriched through enhanced genetic testing and close surveillancemight help future patients who are suspected of having Lynch syndrome to obtain a definitive early diagnosis.

Co-occurrence of germline pathogenic variants for different hereditary cancer syndromes in patients with Lynch syndrome

Background:Lynch syndrome(LS)is a hereditary condition characterized by a high risk of colorectal cancer,endometrial cancer,and other neoplasia associated with germline alterations in DNA mismatch repair genes.The classical genetic diagnostic strategy for LS consists of the Sanger sequencing of genes associated with the suspected syndrome.Next-generation sequencing(NGS)enables the simultaneous sequencing of a large number of hereditary cancer genes.Here,we aimed to study whether other germline pathogenic variants of hereditary cancer genes are present in patients with LS.Methods:A cohort of 84 probands with a previous genetic diagnosis of LS by Sanger sequencing was reanalyzed using NGS via a commercial panel of 94 hereditary cancer genes by hybrid capture.The American College of Medical Genetics and Genomics criteria were used to classify the clinical significance of the variants.The findings of NGS were confirmed by Sanger sequencing.When possible,genetic analyses of the new findings in the proband’s relativeswere also performed by Sanger sequencing.Results:We identified five families(6%),out of 84,with at least two germline pathogenic variants conferring to high or moderate risk in different dominant cancer-predisposing genes:[MLH1-BRCA2-NBN],[MLH1-BRCA1],[MSH2-ATM],[MSH6-NF1],and[MLH1-FANCA].Interestingly,only one out of these five families exhibited a clinical phenotype associated with the new pathogenic variants.The family with three pathogenic variants of the[MLH1-BRCA2-NBN]genes showed a high aggregation of tumors associated with LS and breast and ovarian cancer syndrome.Conclusions:Our results showed that the co-occurrence of more than one pathogenic variant in cancer-predisposing genes was remarkable among cases of LS.Inmost cases,no clinicial manifestations were associated with the secondary pathogenic variants.Further studies are needed to confirm these findings and elucidate their clinical impact.Reanalysis of LS families should be considered only in families with mixed clinical phenotypes.

Dual primary gastric and colorectal cancer:The known hereditary causes and underlying mechanisms

In this editorial,I commented on the paper by Lin et al,published in this issue of the World Journal of Gastrointestinal Oncology.The work aimed at analysing the clinicopathologic characteristics and prognosis of synchronous and metachronous cancers in patients with dual primary gastric and colorectal cancer(CRC).The authors concluded the necessity for regular surveillance for metachronous cancer during postoperative follow-up and reported the prognosis is influenced by the gastric cancer(GC)stage rather than the CRC stage.Although surveillance was recommended in the conclusion,the authors did not explore this area in their study and did not include tests used for such surveillance.This editorial focuses on the most characterized gastrointestinal cancer susceptibility syndromes concerning dual gastric and CRCs.These include hereditary diffuse GC,familial adenomatous polyposis,hereditary nonpolyposis colon cancer,Lynch syndrome,and three major hamartomatous polyposis syndromes associated with CRC and GC,namely Peutz-Jeghers syndrome,juvenile polyposis syndrome,and PTEN hamartoma syndrome.Careful assessment of these syndromes/conditions,including inheritance,risk of gastric and colorectal or other cancer development,genetic mutations and recommended genetic investigations,is crucial for optimum management of these patients.