Hereditary cancer syndromes

Hereditary cancer syndromes(HCSs)are arguably the most frequent category of Mendelian genetic diseases,as at least 2%of presumably healthy subjects carry highly-penetrant tumor-predisposing pathogenic variants(PVs).Hereditary breast-ovarian cancer and Lynch syndrome make the highest contribution to cancer morbidity;in addition,there are several dozen less frequent types of familial tumors.The development of the majority albeit not all hereditary malignancies involves two-hit mechanism,i.e.the somatic inactivation of the remaining copy of the affected gene.Earlier studies on cancer families suggested nearly fatal penetrance for the majority of HCS genes;however,population-based investigations and especially large-scale next-generation sequencing data sets demonstrate that the presence of some highly-penetrant PVs is often compatible with healthy status.Hereditary cancer research initially focused mainly on cancer detection and prevention.Recent studies identified multiple HCS-specific drug vulnerabilities,which translated into the development of highly efficient therapeutic options.

Preimplantation genetic testing for embryos predisposed to hereditary cancer:Possibilities and challenges

Preimplantation genetic testing(PGT),which was developed as an alternative to prenatal genetic testing,allows couples to avoid pregnancies with abnormal chromosomes and the subsequent termination of the affected fetus.Originally used for early onset monogenic conditions,PGT is now used to prevent various types of inherited cancer conditions based on the development of PGT technology,assisted reproductive techniques(ARTs),and in vitro fertilization(IVF).This review provides insights into the potential benefits and challenges associated with the application of PGT for hereditary cancer and provides an overview of the existing literature on this test,with a particular focus on the current challenges related to laws,ethics,counseling,and technology.Additionally,this review predicts the future potential applications of this method.Although PGT may be utilized to predict and prevent hereditary cancer,each case should be comprehensively evaluated.The motives of couples must be assessed to prevent the misuse of this technique for eugenic purposes,and non-pathogenic phenotypes must be carefully evaluated.Pathological cases that require this technology should also be carefully considered based on legal and ethical reasoning.PGT may be the preferred treatment for hereditary cancer cases;however,such cases require careful case-by-case evaluations.Therefore,this study concludes that multidisciplinary counseling and support for patients and their families are essential to ensure that PGT is a viable option that meets all legal and ethical concerns.

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.

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.

Hereditary non-polyposis colorectal cancer: The rise and fall of a confusing term

The term Hereditary Non-Polyposis Colorectal Cancer （HNPCC） is a poor descriptor of the syndrome described by Lynch. Over the last decade, the term has been applied to heterogeneous groups of families meeting limited clinical criteria, for example the Amsterdam criteria. It is now apparent that not all Amsterdam criteria-positive families have the Lynch syndrome. The term HNPCC has also been applied to clinical scenarios in which CRCs with DNA microsateUite instability are diagnosed but in which there is no vertical transmission of an altered DNA mismatch repair （MMR） gene. A term that has multiple, mutually incompatible meanings is highly problematic, particularly when it may influence the management of an individual family. The Lynch syndrome is best understood as a hereditary predisposition to malignancy that is explained by a germline mutation in a DNA MMR gene. The diagnosis does not depend in an absolute sense on any particular family pedigree structure or age of onset of malignancy. Families with a strong family history of colorectal cancer that do not have Lynch syndrome have been grouped as ‘Familial Colorectal Cancer Type-X＇. The first step in characterizing these cancer families is to distinguish them from Lynch syndrome. The term HNPCC no longer serves any useful purpose and should be phased out.

Clinical phenotype and prevalence of hereditary nonpolyposis colorectal cancer syndrome in Chinese population

AIM: To describe systematically the clinical characteristics and phenotype of HNPCC families and the prevalence of HNPCC in the general population of CRC patients in China. METHODS: HNPCC kindreds and CRC patients were from two sources. One was that we consecutively investigated kindreds and patients by ourselves. And the other was the published Chinese and foreign literature related to Chinese HNPCC syndrome. There were 142 HNPCC families fulfilling AC I and/or AC II including 57 families with detailed data, and 3874 general primary CRC patients in all. All statistical tests were two-sided. RESULTS: In AC I families, the number of Lynch syndrome I and II families were 25 (47.2%) and 28 (52.8%) respectively. There were 215 patients (82.4%) with CRC, 67 patients (25.7%) with extracolonic cancer and 50 patients (19.2%) with multiple primary cancers. In all CRC patients, multiple primary CRC were in 41 patients (19.1%), and the first-CRC was right-sided colorectal cancer in 143 patients (66.5%) and rectal cancer in 44 patients (20.5%). 8.8% and 19.2% of the first cancer were CRC and extracolonic cancers. Among those patients whose first cancer was CRC, 66.8% and 19.9% were right-sided colorectal cancer and rectal cancer, respectively. The similar results were found in AC II families. Normal distribution was only found in the distribution of the age of diagnosis of the first cancer in both AC I families (coefficient of skewness: u = 0.81, 0.20<0.40<P<0.50; coefficient of kurtosis: u = 1.13, 0.20<P<0.40,α=0.20) and AC II families (coefficient of skewness: u=0.63, P>0.5> 0.20; coefficient of kurtosis: u = 0.84, 0.20<0.40<P<0.50, α=0.20), but not found in the distribution of the age of diagnosis of the first CRC. When patients with HNPCC-associated cancer suffered from the first malignant tumor in HNPCC families diagnosed by AC I and AC II, the mean age and median age were 45.1±12.7 years and 44.0 years, 45.2±12.7 years and 44.5 years, respectively. The median age of diagnosis of the first tumor of the patients in the later generation was younger than that in the previous generation. Many extracolonic cancers were found to be associated with HNPCC syndrome. Gastric cancer was the most frequent extracolonic cancer followed by endometrial cancer and hepatocarcinoma. In general population of CRC patients, the prevalence of HNPCC diagnosed by AC I and AC II were 1.3% and 2.2%, respectively. CONCLUSION: The clinical phenotype and prevalence of Chinese HNPCC syndrome are similar to those of Europeans and Americans. Gastric cancer is the most common extracolonic malignant tumor. The age of diagnosis of the first malignant tumor tends to be increasingly younger in patients with HNPCC-related tumors.

Germline MLH1 and MSH2 mutational spectrum including frequent large genomic aberrations in Hungarian hereditary non-polyposis colorectal cancer families:Implications for genetic testing

AIM: To analyze the prevalence of germline MLH1 and MSH2 gene mutations and evaluate the clinical characteristics of Hungarian hereditary non-polyposis colorectal cancer (HNPCC) families. METHODS: Thirty-six kindreds were tested for mutations using conformation sensitive gel electrophoreses, direct sequencing and also screening for genomic rearrangements applying multiplex ligation-dependent probe amplifi cation (MLPA). RESULTS: Eighteen germline mutations (50%) were identifi ed, 9 in MLH1 and 9 in MSH2. Sixteen of these sequence alterations were considered pathogenic, the remaining two were non-conservative missense alterations occurring at highly conserved functional motifs. The majority of the defi nite pathogenic mutations (81%, 13/16) were found in families fulfilling the stringent Amsterdam Ⅰ/Ⅱ criteria, including three rearrangements revealed by MLPA (two in MSH2 and one in MLH1). However, in three out of sixteen HNPCC-suspected families (19%), a disease-causing alteration could be revealed. Furthermore, nine mutations described here are novel, and none of the sequence changes were found in more than one family.CONCLUSION: Our study describes for the f irst time the prevalence and spectrum of germline mismatch repair gene mutations in Hungarian HNPCC and suspected-HNPCC families. The results presented here suggest that clinical selection criteria should be relaxed and detection of genomic rearrangements should be included in genetic screening in this population.

Role of detection of microsatellite instability in Chinese with hereditary nonpolyposis colorectal cancer or ordinary hereditary colorectal cancer

AIM： To detect microsatellite instability （MSI） in patients with hereditary nonpolyposis colorectal cancer or ordinary hereditary colorectal cancer and to provide criteria for screening the kindreds with hereditary nonpolyposis colorectal cancer at molecular level.METHODS： MSI was detected in the specimens from 20 cases with HNPCC, 20 cases with ordinary hereditary colorectal cancer and 20 cases with sporadic colorectal cancer by means of polymerase chain reaction-single strand conformation polymorphism. RESULTS： The positive rate of MSI was 85% （17/20） in HNPCC group, 40% （8/20） in ordinary hereditary colorectal cancer group and 10% （2/20） in the sporadic colorectal cancer group respectively. The differences were significant. The mean ages of the three groups were 43.6, 52.2, and 61.8 years respectively, which increased gradually. The incidence of right hemicolon cancer was 64.7%, 37.5%, and 0% respectively, which decreased gradually and had significant difference. The expression ratio of BAT26 and BAT25 was 94.1% respectively, which was highest in the 5 gene sites studied. The incidence of poorly differentiated adenocarcinoma was 70.6% in HNPCC group among high frequency microsatellite instability （MSI-H）, which was higher than the other two groups, which had 50% and 50% respectively. CONCLUSION： The incidence of MSI-H is higher in HNPCC group. The detection of MSI is simple and economical and has high correlation with the clinicopathologic feature of HNPCC and can be used as a screening method to detect the germ line mutation of the mismatch repair gene.

Clinical and molecular analysis of hereditary non-polyposis colorectal cancer in Chinese colorectal cancer patients

AIM： To analyze the frequency of hereditary non-polyposis colorectal cancer （HNPCC） in Chinese colorectal cancer （CRC） patients, and to discuss the value of microsatellite instability （MSI） and/or immunohistochemistry （IHC） for MSH2/MLH1 protein analysis as pre-screening tests in China. METHODS： The Amsterdam criteria Ⅰ and Ⅱ （clinical diagnosis） and/or germline hMLHI/hMSH2 mutations （genetic diagnosis） were used to classify HNPCC families. Genetic tests, including microsatellite instability, immunohistochemistry for MSH2/MLH1 proteins and hMSH2/hMLH1 genes, were performed in each proband. RESULTS： From July 2000 to June 2004, 1988 patients with colorectal cancer were analysed and 114 CRC patients （5.7%） from 48 families were categorized as having HNPCC, including 76 from 26 families diagnosed clinically and 38 from the other 22 families diagnosed genetically. The sensitivity and specificity of high MSI and IHC for predicting mutations were 100% and 54%, and 79% and 77%, respectively. CONCLUSION： The frequency of HNPCC is approximately 10% among all Chinese CRC cases. The MSI and IHC detections for hMSH2/hMLH1 proteins are reliable prescreening tests for hMLHI/hMSH2 germline mutations in families suspected of having HNPCC.

Risk of colon cancer in hereditary non-polyposis colorectal cancer patients as predicted by fuzzy modeling:Influence of smoking

AIM： To investigate whether a fuzzy logic model could predict colorectal cancer （CRC） risk engendered by smoking in hereditary non-polyposis colorectal cancer （HNPCC） patients. METHODS： Three hundred and forty HNPCC mismatch repair （MMR） mutation carriers from the Creighton University Hereditary Cancer Institute Registry were selected for modeling. Age-dependent curves were generated to elucidate the joint effects between gene mutation （hMLH1 or hMSH2）, gender, and smoking status on the probability of developing CRC. RESULTS： Smoking significantly increased CRC risk in male hMSH2 mutation carriers （P 〈 0.05）. hMLH1 mutations augmented CRC risk relative to hMSH2 mutation carriers for males （P 〈 0.05）. Males had a significantly higher risk of CRC than females for hMLH1 non smokers （P 〈 0.05）, hMLH1 smokers （P 〈 0.1） and hMSH2 smokers （P 〈 0.1）. Smoking promoted CRC in a dose-dependent manner in hMSH2 in males （P 〈 0.05）. Females with hMSH2 mutations and both sexes with the hMLH1 groups only demonstrated a smoking effect after an extensive smoking history （P 〈 0.05）. CONCLUSION： CRC promotion by smoking in HNPCC patients is dependent on gene mutation, gender and age. These data demonstrate that fuzzy modeling may enable formulation of clinical risk scores, thereby allowing individualization of CRC prevention strategies.

MLH1 promoter germline-methylation in selected probands of Chinese hereditary non-polyposis colorectal cancer families

AIM： To detect the MLH1 gene promoter germline- methylation in probands of Chinese hereditary non- polyposis colorectal cancer （HNPCC）, and to evaluate the role of methylation in MLH1 gene promoter and molecular genetics in screening for HNPCC.METHODS： The promoter germline methylation of MLH1 gene was detected by methylation-specific PCR （MSP） in 18 probands from unrelated HNPCC families with high microsatellite-instability （MSI-H） phenotype but without germline mutations in MSH2, MLH1 and MSH6 genes. At the same time, 6 kindreds were col- lected with microsatellite-stability （MSS） phenotype but without germline mutations in MSH2, MIH1 and MSH6 genes as controls. The results of MSP were confirmed by clone sequencing. To ensure the reliability of the results, family H65 with nonsense germline mutation at c.2228C 〉 A in MSH2 gene was used as the negative control and the cell line sw48 was used as the known positive control along with water as the blank control. Immunochemical staining of MIH1 protein was performed with Envision two-step method in those patients with aberrant methylation to judge whether the status of MLH1 gene methylation affects the expression of MLH1 protein.RESULTS： Five probands with MIH1 gene promoter methylation were detected in 18 Chinese HNPCC families with MSI-H phenotype but without germline mutations in MSH2, MLH1 and MSH6 genes. Two of the five probands from families H10 and H29 displayed exhaustive-methylation, fulfilling the Japanese criteria （JC） and the Amsterdam criteria （AC）, respectively. The other 3 probands presented part-methylation fulfilling the AC. Of the 13 probands with unmethylation phenotype, 8 fulfilled the JC and the Bethesda guidelines （BG）, 5 fulfilled the AC. The rate of aberrant methylation in MLH1 gene in the AC group （22.2%, 4/18） was higher than that in the JC/BG groups （5.6%, 1/18） in all HNPCC families with MSI-H phenotype but without germline mutations in PISH2, PIIH1 and MSH6 genes. However, no proband with methylation in MLH1 gene was found in the families with MSS phenotype and without germline mutations in MSH2, MLH1 and MSH6 genes. No expression of MLH1 protein was found in tumor tissues from two patients with exhaustive-methylation phenotype, whereas positive expression of MLH1 protein was observed in tumor tissues from patients with partial methylation phenotype （excluding family H42 without tumor tissue）, indicating that exhaustive-methylation of MLH1 gene can cause defective expression of MLH1 protein.CONCLUSION： Methylation phenotype of MLH1 gene is correlated with microsatellite phenotype of MMR genes, especially with MSI-H. Exhaustive-methylation of MLH1 gene can silence the expression of MLH1 protein. MLH1 promoter methylation analysis is a promising tool for molecular genetics screening for HNPCC.

Three novel missense germline mutations in different exons of MSH6 gene in Chinese hereditary non-polyposis colorectal cancer families

AIM: To investigate the germline mutations of MSH6 gene in probands of Chinese hereditary non-polyposis colorectal cancer (HNPCC) families fulfilling different clinical criteria. METHODS: Germline mutations of MSH6 gene were detected by PCR-based DNA sequencing in 39 unrelated HNPCC probands fulfilling different clinical criteria in which MSH2 and MLH1 mutations were excluded. To further investigate the pathological effects of detected missense mutations, we analyzed the above related MSH6 exons using PCR-based sequencing in 137 healthy persons with no family history. The clinicopathological features were collected from the Archive Library of Cancer Hospital, Fudan University and analyzed. RESULTS: Four germline missense mutations distributed in the 4th, 6th and 9th exons were observed. Of them, three were not found in international HNPCC databases and did not occur in 137 healthy controls, indicating that they were novel missense mutations. The remaining mutation which is consistent with the case H14 at c.3488A>T of exon 6 of MSH6 gene was also found in the controls, the rate was approximately 3.65% (5/137) and the type of mutation was not found in the international HNPCC mutational and SNP databases, suggesting that this missense mutation was a new SNP unreported up to date. CONCLUSION: Three novel missense mutations and a new SNP observed in the probands of Chinese HNPCC families, may play an important role in the development of HNPCC.

Genetic diagnosis strategy of hereditary non-polyposis colorectal cancer

AIM: To study the characteristics of mismatch repair gene mutation of Chinese hereditary non-polyposis colorectal cancer (HNPCC) and hMLH1 gene promoter methylation, and to improve the screening strategy and explore the pertinent test methods. METHODS: A systematic analysis of 30 probands from HNPCC families in the north of China was performed by immunohistochemistry, microsatellite instability (MSI), gene mutation and methylation detection. RESULTS: High frequency microsatellite instability occurred in 25 probands (83.3%) of HNPCC family. Loss of hMLH1 and hMSH2 protein expression accounted for 88% of all microsatellite instability. Pathogenic muta-tion occurred in 14 samples and 3 novel mutational sites were discovered. Deletion of exons 1-6, 1-7 and 8 of hMSH2 was detected in 3 samples and no large fragment deletion was found in hMLH1. Of the 30 probands, hMLH1 gene promoter methylation occurred in 3 probands. The rate of gene micromutation detection combined with large fragment deletion detection was 46.7%-56.7%. The rate of the two methods in combination with methylation detection was 63.3%. CONCLUSION: Scientific and rational detection strategy can improve the detection rate of HNPCC. Based on traditional molecular genetics and combined with epigenetics, multiple detection methods can accurately diagnose HNPCC.

Hereditary gastric cancer:Three rules to reduce missed diagnoses

Gastric cancer remains one of the most lethal cancers.The incidence and mortality rates are quite similar.The main reason for the high mortality is diagnosis at advanced stages of disease,when treatment options are poor.One of the supposed strategies to overcome late-stage diagnosis is identifying people at high risk with the aim of establishing rigorous clinical control,including routine endoscopy and biopsies.Hereditary gastric cancer(HGC)syndromes,though representing a sizeable group to monitor for prevention or,at least,for early diagnosis,are apparently extremely rare.The low rate of HGC diagnosis might be related to the low rates of suspicion,insufficient familiarity about clinical diagnosis criteria,and the supposed conditional necessity of a molecular diagnosis.In this review,we will discuss simple measures to increase HGC diagnosis by applying three rules that might provide an opportunity for precision care to benefit the families affected by this disease.

Novel MLH1 frameshift mutation in an extended hereditary nonpolyposis colorectal cancer family

AIM： To present novel frameshift mutation c.31delC [p.L11X] in the MLH1 gene identified in an extended Bulgarian hereditary non-polyposis colorectal cancer （HNPCC） family and to analyze the molecular and clinical findings within the pedigree concerning the proposal of adequate individual prophylactic strategy for all mutation carriers.METHODS： The pedigree of the family consists of 42 members in four generations. Search for mutations in the MLH1 and hMSH2 genes was performed in the proband. After PCR amplification of all exons including flanking intronic regions, amplicons were directly sequenced.RESULTS： The mutation was found in nine from the thirteen pedigree members who signed informed consent to participate in the study. In three adenocarcinomas, microsatellite instability and lack of the MLH1 protein expression were detected. The only one tubulovillous adenoma analyzed was microsatellite stable and the MLH1 protein showed an intact staining.CONCLUSION： The newly described mutation c.31delC is HNPCC causative. Besides the typical clinical features of the syndrome, we found a specific pathologic manifestation such as moderate to high differentiated adenocarcinomas of the colon. One of the mutation carriers developed a benign giant cell soft tissue tumor, The primary tumor Iocalizatlons were frequently extracolonic and detailed yearly gastrointestinal and gynecological examinations have been proposed to the mutation carriers. We emphasize the importance of including the HNPCC genetic counseling and testing as well in the following surveillance of all patients at risk in the services covered by the health insurance in Bulgaria.

Expression of Cyclooxygenase-2 and Its Relationship with Mismatch Repair and Microsatellite Instability in Hereditary Nonpolyposis Colorectal Cancer

Objective To investigate cyclooxygenase-2 (COX-2) expression and its relationship with mismatch repair (MMR) protein expression and microsatellite instability (MSI) in hereditary nonpolyposis colorectal cancer (HNPCC). Methods A total of 28 cases of colorectal adenoma and 14 cases of colorectal carcinoma were collected between July 2003 and July 2007 from 33 HNPCC families. Sporadic colorectal adenoma (n=32) and carcinoma patients (n=24) served as controls. With samples of tumor tissues and normal colonic mucosa collected from the patients, the protein expressions of COX-2 and MMR (hMLH1, hMSH2, and hMSH6) were examined with immunohistochemical assay. Frequency of MSI in five standard MSI loci BAT25, BAT26, D2S123, D5S346, and D17S250 were analyzed by means of polymerase chain reaction. Results The rate of COX-2 high-expression was 53.6% (15/28) and 42.9% (6/14) in HNPCC adenoma and carcinoma; 62.5% (20/32) and 91.7% (22/24) in sporadic adenoma and carcinoma, respectively. That rate was lower in HNPCC carcinoma than in sporadic carcinoma (P<0.05). MMR-deletion rate and percentage of high-frequency MSI (MSI-H) in HNPCC carcinoma were higher than those in sporadic colorectal carcinoma [both 71.4% (10/14) vs. 12.5% (3/24), both P<0.01]. Among the 10 MMR-deficient HNPCC carcinoma patients, COX-2 low-expression was observed in 8 cases (80.0%), while COX-2 high-expression was observed in all of the 4 MMR-positive HNPCC carcinoma cases (P<0.05). In comparison to MMR positive HNPCC carcinoma, HNPCC adenoma, and sporadic carcinoma, COX-2 expression was significantly lower in corresponding MMR-deficient cases (all P<0.05). The rates of COX-2 low-expression in HNPCC adenoma, HNPCC carcinoma, and sporadic carcinoma with MSI-H were significantly higher than those in the cases with microsatellite stability (all P<0.05). Conclusion COX-2 is expressed at a low level in HNPCC carcinoma, different from the high COX-2 expression in sporadic carcinoma.

Two novel germline mutations of MLH1 and investigation of their pathobiology in hereditary non-polyposis colorectal cancer families in China

AIM： To detect germline mutations of MLH1, and investigate microsatellite instability and expression of MLH1 in tumor tissues of hereditary non-polyposis colorectal cancer （HNPCC） with two novel germline mutations, and further investigate the pathobiology of the two novel mutations of MLH1. METHODS： RNA was extracted from the peripheral blood of 12 patients from 12 different families that fulfilled the Amsterdam 11 Criteria for HNPCC. Germline mutations of MLH1 were determined by RT-PCR, followed by cDNA sequencing analysis. PCR-GeneScan analysis was used to investigate microsatellite instability with a panel of five microsatellite markers （BAT26, BAT25, D5S346, D2S123 and mfd15）, along with immunohistochemical staining to detect the expression of MLH1 protein in two patients＇ tumor tissues with novel mutations. RESULTS： Three germline mutations were found in four patients, one of the mutations has previously been reported, but the other two, CGC→TGC at codon 217 of exon 8 and CCG→CTG at codon 581 of exon 16, have not been reported. The two patients＇ tumor tissues with novel mutations had high-frequency microsatellite instability that showed more than two unstable loci, and both tumors lost their MLH1 protein expression. CONCLUSION： The two novel germline mutations of MLH1 in HNPCC families i.e. CGC→TGC at codon 217 of exon 8 and CCG→CTG at codon 581 of exon 16, are very likely to have pathological significance.

Implications of multigene testing for hereditary breast cancer in primary care

Approximately 1 in 8 women will develop breast cancer during their lifetime and the risk factors include age, family history, and reproductive factors. In women with a family history of breast cancer, there is a proportion in which a gene mutation can be the cause of the predisposition for breast cancer. A careful assessment of family and clinical history should be performed in these women in order to determine if a genetic counseling referral is indicated. In cases of hereditary breast cancer, genetic testing with a multigene panel can identify specific genetic mutations in over 100 genes. The most common genes mutated in hereditary breast cancer are the high-penetrance BRCA1 and BRCA2 genes. In addition, other mutations in high-penetrance genes in familial cancer syndromes and mutations in DNA repair genes can cause hereditary breast cancer. Mutations in low-penetrance genes and variants of uncertain signifcance may play a role in breast cancer development, but the magnitude and scope of risk in these cases remain unclear, thus the clinical utility of testing for these mutations is uncertain. In women with high-penetrance genetic mutations or lifetime risk of breast cancer 〉 20%, risk-reducing interventions, such as intensive screening, surgery, and chemoprevention, can decrease the incidence and mortality of breast cancer.

Germline mutations in hereditary diffuse gastric cancer

Gastric cancer is one of the leading causes of cancer-related deaths worldwide. Among which, about 1%–3% of gastric cancer patients were characterized by inherited gastric cancer predisposition syndromes, knowing as hereditary diffuse gastric cancer（HDGC）. Studies reported that CDH1 germline mutations are the main cause of HDGC. With the help of rapid development of genetic testing technologies and data analysis tools, more and more researchers focus on seeking candidate susceptibility genes for hereditary cancer syndromes. In addition, National Comprehensive Cancer Network（NCCN） guidelines recommend that the patients of HDGC carrying CDH1 mutations should undergo prophylactic gastrectomy or routine endoscopic surveillances. Therefore, genetic counseling plays a key role in helping individuals with pathogenic mutations make appropriate risk management plans. Moreover, experienced and professional genetic counselors as well as a systematic multidisciplinary team（MDT） are also required to facilitate the development of genetic counseling and benefit pathogenic mutation carriers who are in need of regular and standardized risk management solutions. In this review, we provided an overview about the germline mutations of several genes identified in HDGC, suggesting that these genes may potentially act as susceptibility genes for this malignant cancer syndrome. Furthermore, we introduced information for prevention, diagnosis and risk management of HDGC. Investigations on key factors that may have effect on risk management decision-making and genetic data collection of more cancer syndrome family pedigrees are required for the development of HDGC therapeutic strategies.

Review:BRCA1/2 associated hereditary breast cancer

Breast cancer is one of the leading causes of death in women today. Some of the patients are hereditary, with a large proportion characterized by mutation in BRCAI and/or BRCA2 genes. In this review, we provide an overview of these two genes, focusing on their relationship with hereditary breast cancers. BRCA1/2 associated hereditary breast cancers have unique features that differ from the general breast cancers, including alterations in cellular molecules, pathological bases, biological behavior, and a different prevention strategy. But the outcome of BRCA1/2 associated hereditary breast cancers still remains controversial; further studies are needed to elucidate the nature of BRCA 1/2 associated hereditary breast cancers.