High-resolution melting (HRM) re-analysis of a polyposis patients cohort reveals previously undetected heterozygous and mosaic APC gene mutations.

Familial adenomatous polyposis is most frequently caused by pathogenic variants in either the APC gene or the MUTYH gene. The detection rate of pathogenic variants depends on the severity of the phenotype and sensitivity of the screening method, including sensitivity for mosaic variants. For 171 patients with multiple colorectal polyps without previously detectable pathogenic variant, APC was reanalyzed in leukocyte DNA by one uniform technique: high-resolution melting (HRM) analysis. Serial dilution of heterozygous DNA resulted in a lowest detectable allelic fraction of 6% for the majority of variants. HRM analysis and subsequent sequencing detected pathogenic fully heterozygous APC variants in 10 (6%) of the patients and pathogenic mosaic variants in 2 (1%). All these variants were previously missed by various conventional scanning methods. In parallel, HRM APC scanning was applied to DNA isolated from polyp tissue of two additional patients with apparently sporadic polyposis and without detectable pathogenic APC variant in leukocyte DNA. In both patients a pathogenic mosaic APC variant was present in multiple polyps. The detection of pathogenic APC variants in 7% of the patients, including mosaics, illustrates the usefulness of a complete APC gene reanalysis of previously tested patients, by a supplementary scanning method. HRM is a sensitive and fast pre-screening method for reliable detection of heterozygous and mosaic variants, which can be applied to leukocyte and polyp derived DNA.

Identification of a Dutch founder mutation in MUSK causing fetal akinesia deformation sequence.

Fetal akinesia deformation sequence (FADS) refers to a clinically and genetically heterogeneous group of disorders with congenital malformations related to impaired fetal movement. FADS can result from mutations in CHRNG, CHRNA1, CHRND, DOK7 and RAPSN; however, these genes only account for a minority of cases. Here we identify MUSK as a novel cause of lethal FADS. Fourteen affected fetuses from a Dutch genetic isolate were traced back to common ancestors 11 generations ago. Homozygosity mapping in two fetuses revealed MUSK as a candidate gene. All tested cases carried an identical homozygous variant c.1724T>C; p.(Ile575Thr) in the intracellular domain of MUSK. The carrier frequency in the genetic isolate was 8%, exclusively found in heterozygous carriers. Consistent with the established role of MUSK as a tyrosine kinase that orchestrates neuromuscular synaptogenesis, the fetal myopathy was accompanied by impaired acetylcholine receptor clustering and reduced tyrosine kinase activity at motor nerve endings. A functional assay in myocytes derived from human fetuses confirmed that the variant blocks MUSK-dependent motor endplate formation. Taken together, the results strongly support a causal role of this founder mutation in MUSK, further expanding the gene set associated with FADS and offering new opportunities for prenatal genetic testing.

The efficacy of a standardized questionnaire in facilitating personalized communication about problems encountered in cancer genetic counseling: design of a randomized controlled trial.

BACKGROUND: Individuals with a personal or family history of cancer, can opt for genetic counseling and DNA-testing. Approximately 25% of these individuals experience clinically relevant levels of psychosocial distress, depression and/or anxiety after counseling. These problems are frequently left undetected by genetic counselors. The aim of this study is to evaluate the efficacy of a cancer genetics-specific screening questionnaire for psychosocial problems, the 'Psychosocial Aspects of Hereditary Cancer (PAHC) questionnaire' together with the Distress Thermometer, in: (1) facilitating personalized counselor-counselee communication; (2) increasing counselors' awareness of their counselees' psychosocial problems; and (3) facilitating the management of psychosocial problems during and after genetic counseling. METHODS: This multicenter, randomized controlled trial will include 264 individuals undergoing cancer genetic counseling in two family cancer clinics in the Netherlands. Participants will be randomized to either: (1) an intervention group that completes the PAHC questionnaire, the results of which are made available to the genetic counselor prior to the counseling session; or (2) a control group that completes the PAHC questionnaire, but without feedback being given to the genetic counselor. The genetic counseling sessions will be audiotaped for content analysis. Additionally, study participants will be asked to complete questionnaires at baseline, three weeks after the initial counseling session, and four months after a telephone follow-up counseling session. The genetic counselors will be asked to complete questionnaires at the start of and at completion of the study, as well as a checklist directly after each counseling session. The questionnaires/checklists of the study include items on communication during genetic counseling, counselor awareness of their clients' psychosocial problems, the (perceived) need for professional psychosocial support, cancer worries, general distress, specific psychosocial problems, satisfaction with care received, and experience using the PAHC questionnaire. DISCUSSION: This study will provide empirical evidence regarding the efficacy of a relatively brief psychosocial screening questionnaire in terms of facilitating personalized communication, increasing counselors' awareness, and optimizing management of psychosocial problems in the cancer genetic counseling setting. TRIAL REGISTRATION: This study is registered at the Netherlands Trial Register (NTR3205) and ClinicalTrials.gov (NCT01562431).

Specific psychosocial issues of individuals undergoing genetic counseling for cancer - a literature review.

Approximately 25% of individuals undergoing genetic counseling for cancer experiences clinically relevant levels of distress, anxiety and/or depression. However, these general psychological outcomes that are used in many studies do not provide detailed information on the specific psychosocial problems experienced by counselees. The aim of this review was to investigate the specific psychosocial issues encountered by individuals undergoing genetic counseling for cancer, and to identify overarching themes across these issues. A literature search was performed, using four electronic databases (PubMed, PsychInfo, CINAHL and Embase). Papers published between January 2000 and January 2013 were selected using combinations, and related indexing terms of the keywords: 'genetic counseling', 'psychology' and 'cancer'. In total, 25 articles met our inclusion criteria. We identified the specific issues addressed by these papers, and used meta-ethnography to identify the following six overarching themes: coping with cancer risk, practical issues, family issues, children-related issues, living with cancer, and emotions. A large overlap in the specific issues and themes was found between these studies, suggesting that research on specific psychosocial problems within genetic counseling has reached a point of saturation. As a next step, efforts should be made to detect and monitor these problems of counselees at an early stage within the genetic counseling process.

An α-E-catenin (CTNNA1) mutation in hereditary diffuse gastric cancer.

Diffuse gastric cancers typically present as late-stage tumours and, as a result, the 5 year survival rate is poor. Some gastric cancers are hereditary and these tend to be of the diffuse type; 30-40% of hereditary diffuse gastric cancers (HDGCs) can be explained by defective germline alleles of E-cadherin (CDH1), but for the remaining families the factors driving susceptibility remain unknown. We had access to a large HDGC pedigree with no obvious mutation in CDH1, and applied exome sequencing to identify new genes involved in gastric cancer. We identified a germline truncating allele of α-E-catenin (CTNNA1) that was present in two family members with invasive diffuse gastric cancer and four in which intramucosal signet ring cells were detected as part of endoscopic surveillance. The remaining CTNNA1 allele was silenced in the two diffuse gastric cancers from the family that were available for screening, and this was also true for signet ring cells identified in endoscopic biopsies. Since α-E-catenin functions in the same complex as E-cadherin, our results call attention to the broader signalling network surrounding these proteins in HDGC. We also detected somatic mutations in one tumour and found substantial overlap with genes mutated in sporadic gastric cancer, including PIK3CA, ARID1A, MED12 and MED23.

International Cancer of the Pancreas Screening (CAPS) Consortium summit on the management of patients with increased risk for familial pancreatic cancer.

BACKGROUND: Screening individuals at increased risk for pancreatic cancer (PC) detects early, potentially curable, pancreatic neoplasia. OBJECTIVE: To develop consortium statements on screening, surveillance and management of high-risk individuals with an inherited predisposition to PC. METHODS: A 49-expert multidisciplinary international consortium met to discuss pancreatic screening and vote on statements. Consensus was considered reached if ≥ 75% agreed or disagreed. RESULTS: There was excellent agreement that, to be successful, a screening programme should detect and treat T1N0M0 margin-negative PC and high-grade dysplastic precursor lesions (pancreatic intraepithelial neoplasia and intraductal papillary mucinous neoplasm). It was agreed that the following were candidates for screening: first-degree relatives (FDRs) of patients with PC from a familial PC kindred with at least two affected FDRs; patients with Peutz-Jeghers syndrome; and p16, BRCA2 and hereditary non-polyposis colorectal cancer (HNPCC) mutation carriers with ≥ 1 affected FDR. Consensus was not reached for the age to initiate screening or stop surveillance. It was agreed that initial screening should include endoscopic ultrasonography (EUS) and/or MRI/magnetic resonance cholangiopancreatography not CT or endoscopic retrograde cholangiopancreatography. There was no consensus on the need for EUS fine-needle aspiration to evaluate cysts. There was disagreement on optimal screening modalities and intervals for follow-up imaging. When surgery is recommended it should be performed at a high-volume centre. There was great disagreement as to which screening abnormalities were of sufficient concern to for surgery to be recommended. CONCLUSIONS: Screening is recommended for high-risk individuals, but more evidence is needed, particularly for how to manage patients with detected lesions. Screening and subsequent management should take place at high-volume centres with multidisciplinary teams, preferably within research protocols.

Risks of less common cancers in proven mutation carriers with lynch syndrome.

PURPOSE: Patients with Lynch syndrome are at high risk for colon and endometrial cancer, but also at an elevated risk for other less common cancers. The purpose of this retrospective cohort study was to provide risk estimates for these less common cancers in proven carriers of pathogenic mutations in the mismatch repair (MMR) genes MLH1, MSH2, and MSH6. PATIENTS AND METHODS: Data were pooled from the German and Dutch national Lynch syndrome registries. Seven different cancer types were analyzed: stomach, small bowel, urinary bladder, other urothelial, breast, ovarian, and prostate cancer. Age-, sex- and MMR gene-specific cumulative risks (CRs) were calculated using the Kaplan-Meier method. Sex-specific incidence rates were compared with general population incidence rates by calculating standardized incidence ratios (SIRs). Multivariate Cox regression analysis was used to estimate the impact of sex and mutated gene on cancer risk. RESULTS: The cohort comprised 2,118 MMR gene mutation carriers (MLH1, n = 806; MSH2, n = 1,004; MSH6, n = 308). All cancers were significantly more frequent than in the general population. The highest risks were found for male small bowel cancer (SIR, 251; 95% CI, 177 to 346; CR at 70 years, 12.0; 95% CI, 5.7 to 18.2). Breast cancer showed an SIR of 1.9 (95% CI, 1.4 to 2.4) and a CR of 14.4 (95% CI, 9.5 to 19.3). MSH2 mutation carriers had a considerably higher risk of developing urothelial cancer than MLH1 or MSH6 carriers. CONCLUSION: The sex- and gene-specific differences of less common cancer risks should be taken into account in cancer surveillance and prevention programs for patients with Lynch syndrome.

Indication for CDKN2A-mutation analysis in familial pancreatic cancer families without melanomas.

BACKGROUND: CDKN2A-mutation carriers run a high risk of developing melanomas and have an increased risk of developing pancreatic cancer (PC). Familial PC (FPC) patients with a personal history or family history of melanomas are therefore offered CDKN2A-mutation analysis. In contrast, CDKN2A testing in FPC families without a history of melanomas is not generally recommended. The aim of this study was to evaluate the frequency of CDKN2A-mutations in FPC families without melanomas. METHODS: Data were gathered from PC family registers. FPC families were defined as families with clustering of PC without meeting diagnostic criteria of familial cutaneous malignant melanoma (familial CMM) or other inherited cancer syndromes. Blood samples were obtained for DNA isolation from PC patients or first degree relatives and analysed for CDKN2A-mutations. RESULTS: Among 40 FPC families, DNA analyses were carried out in 28 families (70%), leading to identification of CDKN2A-mutations in six families (21%). None of the CDKN2A-mutation-positive families fulfilled the diagnostic criteria for familial CMM and in three CDKN2A families no melanomas were observed. Two CDKN2A-mutations were found; the Dutch founder mutation p16-Leiden (c.225_243del, p.Ala76fs) and the c.19_23dup, p.Ser8fs-mutation. After disclosure of the CDKN2A-mutation in one of the families, a curable melanoma was diagnosed at dermatological surveillance in a 17-year-old family member. CONCLUSION: CDKN2A-mutation can be found in a considerable proportion of families with FPC. CDKN2A-mutation analysis should therefore be included in genetic testing in FPC families, even in the absence of reported melanomas. This strategy will enhance the recognition of individuals at risk for PC and facilitate the early detection of melanomas.

Familial gastric cancer: guidelines for diagnosis, treatment and periodic surveillance.

Hereditary diffuse gastric cancer (HDGC) is a relatively rare disorder, with a mutated CDH1 gene as the only known cause. Carriers of a germline mutation in CDH1 have a lifetime risk of >80% of developing diffuse gastric cancer. As periodic gastric surveillance is of limited value in detecting early stages of HDGC, prophylactic gastrectomy is advised for this patient group. Little is known about other types of familial gastric cancer. The Dutch working group on hereditary gastric cancer has formulated guidelines for various aspects of medical management for families and individuals at high risk of developing gastric cancer, including criteria for referral, classification, diagnostics, and periodic gastric surveillance. These guidelines are not limited to HDGC and are therefore partially complementary to the guidelines on hereditary diffuse gastric cancer of the international gastric cancer linkage consortium (IGCLC 2010). In order to optimize the care and increase the knowledge on hereditary gastric cancer it is important to centralize medical care for these patients. National and international collaboration is warranted to improve the quality of research by increasing the size of study cohorts.

CDH1-related hereditary diffuse gastric cancer syndrome: clinical variations and implications for counseling.

CDH1 mutation carriers have a strongly increased risk of developing gastric cancer (GC) and lobular breast cancer (LBC). Clinical data of GC cases and surgical and histological data of prophylactic gastrectomies and mastectomies of all 10 Dutch CDH1 mutation families were collected. In vitro functional assays were performed to analyze the nature of the newly found missense mutation c.1748T>G (p.Leu583Arg). Ten different CDH1 mutations were found. Functional assays gave strong arguments for the pathogenic nature of the p.Leu583Arg mutation. The pedigrees comprised 36 GC cases (mean age 40 years, range 20-72 years) and one LBC case. Twenty-nine/37 carriers alive, aged 18-61 years, underwent prophylactic gastrectomy. Invasive GC-foci and premalignant abnormalities were detected in 2 and 25 patients, respectively. In four patients GC/signetring cell (SRC) foci were diagnosed at preoperative gastroscopy. Long-standing presence of SRCs without progression to invasive carcinoma was shown in two others. Multifocal LBC/LCIS was found in the two prophylactic mastectomy specimens. Clefts of lip and/or palate (CL/P) were reported in seven individuals from three families. The age at onset and aggressiveness of GC is highly variable, which has to be included in counseling on planning prophylactic gastrectomies. The incidence of LBC is expected to increase and prophylactic mastectomy needs to be considered. The relationship between CL/P and CDH1 needs further study to inform future parents from hereditary diffuse gastric cancer (HDGC) families adequately.

Routine testing for PALB2 mutations in familial pancreatic cancer families and breast cancer families with pancreatic cancer is not indicated.

PALB2-mutation carriers not only have an increased risk for breast cancer (BC) but also for pancreatic cancer (PC). Thus far, PALB2 mutations have been mainly found in PC patients from families affected by both PC and BC. As it is well known that the prevalence of gene mutations varies between different populations, we studied the prevalence of PALB2 mutations in a Dutch cohort of non-BRCA1/2 familial PC (FPC) families and in non-BRCA1/2 familial BC (FBC) families with at least one PC case. Mutation analysis included direct sequencing and multiplex ligation-dependent probe amplification (MLPA) and was performed in a total of 64 patients from 56 distinct families (28 FPC families, 28 FBC families). In total, 31 patients (48%) originated from FPC families; 24 were FPC patients (77%), 6 had a personal history of BC (19%) and 1 was a suspected carrier (3.2%). The remaining 33 patients (52%) were all female BC patients of whom 31 (94%) had a family history of PC and 2 (6.1%) had a personal history of PC. In none of these 64 patients a PALB2 mutation was found. Therefore, PALB2 does not have a major causal role in familial clustering of PC and BC in non-BRCA1/2 families in the Dutch population.

CHEK2*1100delC homozygosity is associated with a high breast cancer risk in women.

BACKGROUND: Mutations in the CHEK2 gene confer a moderately increased breast cancer risk. The risk for female carriers of the CHEK2*1100delC mutation is twofold increased. Breast cancer risk for carrier women is higher in a familial breast cancer setting which is due to coinheritance of additional genetic risk factors. This study investigated the occurrence of homozygosity for the CHEK2*1100delC allele among familial breast cancer cases and the associated breast cancer risk. METHODS AND RESULTS: Homozygosity for the CHEK2*1100delC allele was identified in 8/2554 Dutch independent familial non-BRCA1/2 breast cancer cases. The genotype relative risk for breast cancer of homozygous and heterozygous familial breast cancer cases was 101.34 (95% CI 4.47 to 121 000) and 4.04 (95% CI 0.88 to 21.0), respectively. Female homozygotes appeared to have a greater than twofold increased breast cancer risk compared to familial CHEK2*1100delC heterozygotes (p=0.044). These results and the occurrence of multiple primary tumours in 7/10 homozygotes indicate a high cancer risk in homozygous women from non-BRCA1/2 families. CONCLUSIONS: Intensive breast surveillance is therefore justified in these homozygous women. It is concluded that diagnostic testing for biallelic mutations in CHEK2 is indicated in non-BRCA1/2 breast cancer families, especially in populations with a relatively high prevalence of deleterious mutations in CHEK2.

Feasibility of a pancreatic cancer surveillance program from a psychological point of view.

PURPOSE: : The success of any surveillance program depends not solely on its technological aspects but also on the commitment of participants to adhere to follow-up investigations, which is influenced by the psychological impact of surveillance. This study investigates the psychological impact of participating in a pancreatic cancer surveillance program. METHODS: : High-risk individuals participating in an endoscopic ultrasonography-magnetic resonance imaging-based pancreatic cancer surveillance program received a questionnaire assessing experiences with endoscopic ultrasonography and magnetic resonance imaging, reasons to participate, psychological distress, and benefits and barriers of surveillance. High-risk individuals were individuals with a strong family history of pancreatic cancer or carriers of pancreatic cancer-prone gene mutations. RESULTS: : Sixty-nine participants (85%) completed the questionnaire. Surveillance was reported as "very to extremely uncomfortable" by 15% for magnetic resonance imaging and 14% for endoscopic ultrasonography. Most reported reason to participate was that pancreatic cancer might be detected in a curable stage. Abnormalities were detected in 27 respondents, resulting in surgical resection in one individual and a shorter follow-up interval in five individuals. Surveillance outcomes did not influence cancer worries. Overall, 29% was "often" or "almost always" concerned about developing cancer. Six respondents (9%) had clinical levels of depression and/or anxiety. According to 88% of respondents, advantages of surveillance outweighed disadvantages. CONCLUSIONS: : Although endoscopic ultrasonography is more invasive than magnetic resonance imaging, endoscopic ultrasonography was not perceived as more burdensome. Despite one third of respondents worrying frequently about cancer, this was not related to the surveillance outcomes. Anxiety and depression levels were comparable with the general population norms. Advantages of participation outweighed disadvantages according to the majority of respondents. From a psychological point of view, pancreatic cancer surveillance in high-risk individuals is feasible and justified.

[Familial gastric cancer: diagnosis, treatment and periodic surveillance]. / Familiaire maagkanker: diagnostiek, behandeling en periodieke controles.

The only known genetic causes of hereditary diffuse gastric cancer (HDGC) are germline mutations in the CDH1 gene.- CDH1 mutation carriers have a lifetime risk of 70-80% of developing diffuse gastric cancer. As periodic gastric surveillance is of limited value in detecting early stages of HDGC, prophylactic gastrectomy is advised for this patient group. This group is small and little is known about other types of familial gastric cancer. The Dutch Working Group on Hereditary Gastric Cancer has formulated criteria for various aspects of medical care for families and individuals at high risk of developing gastric cancer, including criteria for diagnostics and periodic gastric surveillance. In order to optimize the care and increase the knowledge on hereditary gastric cancer it is important to centralize medical care for these patients.

Body weight and risk of breast cancer in BRCA1/2 mutation carriers.

Obesity is an established risk factor for postmenopausal breast cancer in the general population. However, it is still unclear whether this association also exists in BRCA1/2 mutation carriers. We investigated the association between self-reported anthropometric measures and breast cancer risk in a nationwide retrospective cohort study, including 719 BRCA1/2 carriers, of whom 218 had been diagnosed with breast cancer within 10 years prior to questionnaire completion. All time-varying Cox proportional hazards analyses were stratified by menopausal status. For premenopausal breast cancer, no statistically significant associations were observed for any of the anthropometric measures. The association between body mass index (BMI) at age 18 and premenopausal breast cancer risk suggested a trend of decreasing risk with increasing BMI (HR(22.50-24.99 vs. 18.50-22.49) = 0.83, 95% CI = 0.47-1.44 and HR(≥ 25.00 vs. 18.50-22.49) = 0.41, 95% CI = 0.13-1.27). For postmenopausal breast cancer, being 1.67 m and taller increased the risk 1.7-fold (HR = 1.67, 95% CI = 1.01-2.74) when compared to a height <1.67 m. Compared with a current body weight < 72 kg, a current body weight of ≥ 72 kg increased the risk of postmenopausal breast cancer 2.1-fold (95% CI = 1.23-3.59). A current BMI of ≥ 25.0 kg/m², an adult weight gain of 5 kg or more, and a relative adult weight gain of 20% or more were all non-significantly associated with a 50-60% increased risk of postmenopausal breast cancer [HR = 1.46 (0.86-2.51), HR = 1.56 (95% CI = 0.85-2.87), and HR = 1.60 (95% CI = 0.97-2.63), respectively], when compared with having a healthy or stable weight. No associations for body weight or BMI at age 18 were observed. In conclusion, menopausal status seemed to modify the association between body weight and breast cancer risk among BRCA1/2 carriers. We observed no clear association between body weight and premenopausal breast cancer, while overweight and weight gain increased postmenopausal breast cancer risk. Carriers may reduce their risk of postmenopausal breast cancer by maintaining a healthy body weight throughout life.

Risk of colorectal and endometrial cancers in EPCAM deletion-positive Lynch syndrome: a cohort study.

BACKGROUND: Lynch syndrome is caused by germline mutations in MSH2, MLH1, MSH6, and PMS2 mismatch-repair genes and leads to a high risk of colorectal and endometrial cancer. We previously showed that constitutional 3' end deletions of EPCAM can cause Lynch syndrome through epigenetic silencing of MSH2 in EPCAM-expressing tissues, resulting in tissue-specific MSH2 deficiency. We aim to establish the risk of cancer associated with such EPCAM deletions. METHODS: We obtained clinical data for 194 carriers of a 3' end EPCAM deletion from 41 families known to us at the Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands and compared cancer risk with data from a previously described cohort of 473 carriers from 91 families with mutations in MLH1, MSH2, MSH6, or a combined EPCAM-MSH2 deletion. FINDINGS: 93 of the 194 EPCAM deletion carriers were diagnosed with colorectal cancer; three of the 92 women with EPCAM deletions were diagnosed with endometrial cancer. Carriers of an EPCAM deletion had a 75% (95% CI 65-85) cumulative risk of colorectal cancer before the age of 70 years (mean age at diagnosis 43 years [SD 12]), which did not differ significantly from that of carriers of combined EPCAM-MSH2 deletion (69% [95% CI 47-91], p=0·8609) or mutations in MSH2 (77% [64-90], p=0·5892) or MLH1 (79% [68-90], p=0·5492), but was higher than noted for carriers of MSH6 mutation (50% [38-62], p<0·0001). By contrast, women with EPCAM deletions had a 12% [0-27] cumulative risk of endometrial cancer, which was lower than was that noted for carriers of a combined EPCAM-MSH2 deletion (55% [20-90], p<0·0001) or of a mutation in MSH2 (51% [33-69], p=0·0006) or MSH6 (34% [20-48], p=0·0309), but did not differ significantly from that noted for MLH1 (33% [15-51], p=0·1193) mutation carriers. This risk seems to be restricted to deletions that extend close to the MSH2 gene promoter. Of 194 carriers of an EPCAM deletion, three had duodenal cancer and four had pancreatic cancer. INTERPRETATION: EPCAM deletion carriers have a high risk of colorectal cancer; only those with deletions extending close to the MSH2 promoter have an increased risk of endometrial cancer. These results underscore the effect of mosaic MSH2 deficiency, leading to variable cancer risks, and could form the basis of an optimised protocol for the recognition and targeted prevention of cancer in EPCAM deletion carriers.

A novel pathogenic MLH1 missense mutation, c.112A > C, p.Asn38His, in six families with Lynch syndrome.

BACKGROUND: An unclassified variant (UV) in exon 1 of the MLH1 gene, c.112A > C, p.Asn38His, was found in six families who meet diagnostic criteria for Lynch syndrome. The pathogenicity of this variant was unknown. We aim to elucidate the pathogenicity of this MLH1 variant in order to counsel these families adequately and to enable predictive testing in healthy at-risk relatives. METHODS: We studied clinical data, microsatellite instability and immunohistochemical staining of MMR proteins, and performed genealogy, haplotype analysis and DNA testing of control samples. RESULTS: The UV showed co-segregation with the disease in all families. All investigated tumors showed a microsatellite instable pattern. Immunohistochemical data were variable among tested tumors. Three families had a common ancestor and all families originated from the same geographical area in The Netherlands. Haplotype analysis showed a common haplotype in all six families. CONCLUSIONS: We conclude that the MLH1 variant is a pathogenic mutation and genealogy and haplotype analysis results strongly suggest that it is a Dutch founder mutation. Our findings imply that predictive testing can be offered to healthy family members. The immunohistochemical data of MMR protein expression show that interpreting these results in case of a missense mutation should be done with caution.

Hereditary causes of kidney tumours.

BACKGROUND: In most cases of renal cell carcinoma there is no family history of renal cancer and no hereditary cause of the disease. Hereditary renal cancer accounts for about 2-4% of cases. Recognition of this subgroup by clinicians is important because of the possibility of severe medical consequences for patients and their relatives. MATERIALS AND METHODS: We review the latest data about different genetic conditions characterized by an increased risk of developing renal cancer and we formulate tools to recognize high-risk families. RESULTS: In general, a positive family history, young age at diagnosis of renal cancer, multiple and/or bilateral renal tumours and combined occurrence of different histological types of renal tumours should raise suspicion of a hereditary renal tumour syndrome. In addition, the presence of specific extrarenal symptoms in patients could assist in differentiating between tumour syndromes. CONCLUSIONS: A detailed medical and family history, along with physical examination are key factors to diagnose hereditary renal cancer syndromes. When a genetic predisposition for renal cancer is suspected, referral to a Family Cancer Clinic is warranted to initiate genetic examination and counselling on preventive options.