Surgical Oncologists and Nurses in Breast Cancer Care are Ready to Provide Pre-Test Genetic Counseling.

BACKGROUND: Pre-test genetic counseling for patients with breast cancer is increasingly being provided by nongenetic healthcare professionals. We evaluated the attitudes, knowledge, and self-efficacy of surgeons, oncologists, and nurses regarding mainstream genetic testing and the feasibility to incorporate pre-test genetic counseling into routine care. METHODS: We offered an online training to healthcare professionals from 13 hospitals and implemented a mainstream genetic testing pathway in 11/13 (85%) hospitals. Questionnaires were sent before (T0) and 6 months after (T1) completing the training. Those who did not complete the training received a questionnaire to assess their motivations. RESULTS: In 11 hospitals, 80 (65%) healthcare professionals completed the training, of whom 70 (88%) completed both questionnaires. The attitudes, (perceived) knowledge and self-efficacy of healthcare professionals were high both at baseline and 6 months after completing the training. After 6 months, their perceived knowledge about the advantages and disadvantages of a genetic test and implications for family members had significantly improved (p = 0.012 and p = 0.021, respectively). For the majority (89%), the time investment for pre-test genetic counseling was less than 15 min per patient and as expected or better. Healthcare professionals considered the total time investment feasible to incorporate mainstream genetic testing into their daily practice. The main barrier to complete the training was lack of time. The online training was considered useful, with a rating of 8/10. CONCLUSION: Surgical oncologists and nurses in breast cancer care feel well-equipped and motivated to provide pre-test genetic counseling after completion of an online training module.

Characteristics of Lynch syndrome associated ovarian cancer.

OBJECTIVE: To describe clinical characteristics of Lynch syndrome associated ovarian cancer and the efficacy of surveillance in the early detection of these ovarian cancers. METHODS: All Lynch syndrome associated ovarian cancer cases identified in either the Dutch Lynch syndrome registry (DLSR) between 1987 and 2016, and/or the cohort at the University Medical Center Groningen (UMCG) between 1993 and 2016 were included. Clinical data on age at diagnosis, mutation type, histological type, FIGO stage, treatment, follow-up and gynecological surveillance were collected. RESULTS: A total of 46/798 (6%) women in the DLSR and 7/80 (9%) in the UMCG cohort were identified as LS associated ovarian cancer patients. The median age at ovarian cancer diagnosis was 46.0 years (range 20-75 years). The most frequently reported histological type was endometrioid adenocarcinoma (40%; n = 21) and serous carcinoma (36%; n = 19). Most tumors (87%; n = 46) were detected at an early stage (FIGO I/II). Forty-one of 53 (77%) patients were diagnosed with ovarian cancer before LS was diagnosed. In the other 12/53 (23%) women, ovarian cancer developed after starting annual gynecological surveillance for LS; three ovarian cancers were screen-detected in asymptomatic women. Overall survival was 83%. CONCLUSION: Ovarian cancer in women with LS has a wide age-range of onset, is usually diagnosed at an early stage with predominantly endometrioid type histology and a good overall survival. The early stage at diagnosis could not be attributed to annual gynecological surveillance.

A multicentre comparative prospective blinded analysis of EUS and MRI for screening of pancreatic cancer in high-risk individuals.

OBJECTIVE: Endoscopic ultrasonography (EUS) and MRI are promising tests to detect precursors and early-stage pancreatic ductal adenocarcinoma (PDAC) in high-risk individuals (HRIs). It is unclear which screening technique is to be preferred. We aimed to compare the efficacy of EUS and MRI in their ability to detect clinically relevant lesions in HRI. DESIGN: Multicentre prospective study. The results of 139 asymptomatic HRI (>10-fold increased risk) undergoing first-time screening by EUS and MRI are described. Clinically relevant lesions were defined as solid lesions, main duct intraductal papillary mucinous neoplasms and cysts ≥10 mm. Results were compared in a blinded, independent fashion. RESULTS: Two solid lesions (mean size 9 mm) and nine cysts ≥10 mm (mean size 17 mm) were detected in nine HRI (6%). Both solid lesions were detected by EUS only and proved to be a stage I PDAC and a multifocal pancreatic intraepithelial neoplasia 2. Of the nine cysts ≥10 mm, six were detected by both imaging techniques and three were detected by MRI only. The agreement between EUS and MRI for the detection of clinically relevant lesions was 55%. Of these clinically relevant lesions detected by both techniques, there was a good agreement for location and size. CONCLUSIONS: EUS and/or MRI detected clinically relevant pancreatic lesions in 6% of HRI. Both imaging techniques were complementary rather than interchangeable: contrary to EUS, MRI was found to be very sensitive for the detection of cystic lesions of any size; MRI, however, might have some important limitations with regard to the timely detection of solid lesions.

The additional value of endometrial sampling in the early detection of endometrial cancer in women with Lynch syndrome.

OBJECTIVE: Based on previous studies, standard gynecological screening consisting of annual transvaginal ultrasonography (TVU) was added with endometrial sampling in women with Lynch syndrome (LS). The aim of this study was to evaluate the additional value of endometrial sampling in detecting (pre)malignancies of the endometrial tissue in women with LS or first-degree relatives. METHODS: All women above 30 years of age with LS or first-degree relatives at 50% risk of LS are offered annual gynecological screening in our family cancer clinic. Endometrial screening results from January 2003-December 2007 (period I: standard screening by transvaginal sonography and serum CA125) were compared with screening results from January 2008-June 2012 (period II: standard screening added with endometrial sampling). RESULTS: Seventy five women (300 patient years) were screened annually. There were 266 screening visits, 117 in period I and 149 in period II. In period I, four premalignant endometrial lesions were detected and one endometrial carcinoma (FIGO stage IB). In period II, two premalignancies were found. None of the lesions would have been missed without standard endometrial sampling. No interval endometrial cancers were detected in this study. CONCLUSION: In this study, annual endometrial screening seems an effective screening tool in the detection of premalignancies and early endometrial cancer in women with LS. Adding standard endometrial sampling to annual TVU has no additional value in the early detection of (pre)malignant endometrial lesions in women with LS in this study.

A role for MLH3 in hereditary nonpolyposis colorectal cancer.

We investigated a possible role of the mismatch-repair gene MLH3 in hereditary nonpolyposis colorectal cancer by scanning for mutations in 39 HNPCC families and in 288 patients suspected of having HNPCC. We identified ten different germline MLH3 variants, one frameshift and nine missense mutations, in 12 patients suspected of HNPCC. Three of the 12 also carried a mutation in MSH6.

The introduction of a choice to learn pre-symptomatic DNA test results for BRCA or Lynch syndrome either face-to-face or by letter.

In predictive DNA testing for hereditary cancer, test results should traditionally be disclosed face-to-face. Increasingly, however, counselees ask to receive their test result at home by letter. To compare the quality of genetic counselling in the traditional way to a procedure in which counselees are offered a choice on how to get their test result. Counselees from families with a known BRCA1/2 or Lynch syndrome mutation were randomised into two groups. The control group was given the DNA test result in a face-to-face consultation. In the intervention group people could choose to learn their test result face-to-face or by letter. The quality of genetic counselling was assessed through questionnaires at three different moments. Data of 198 counselees were analysed. The quality of genetic counselling and psychological functioning were equally good in both groups. The majority of cases chose for disclosure by letter. The counselees with a good test result in the intervention group were the most satisfied. Our results indicate that in predictive DNA testing for BRCA1/2 and Lynch syndrome, a choice protocol is equally safe and more satisfying. Moreover, it is more efficient for both counsellor and counselee.

Distress in partners of individuals diagnosed with or at high risk of developing tumors due to rare hereditary cancer syndromes.

OBJECTIVE: Li Fraumeni syndrome (LFS) and Von Hippel-Lindau disease (VHL) are two rare hereditary tumor syndromes, characterized by a high risk of developing multiple tumors at various sites and ages for which preventive and treatment options are limited. For partners, it may be difficult to deal with the on-going threat of tumors in both their spouse and children. Therefore, this study aims to evaluate the prevalence of and factors associated with psychological distress among partners of individuals with or at high risk of LFS or VHL. METHODS: As part of a nationwide, cross-sectional study, partners of individuals diagnosed with or at high risk of LFS or VHL were invited to complete a self-report questionnaire assessing distress, worries, and health-related quality of life. RESULTS: Fifty-five (58%) of those high-risk individuals with a partner consented to having their partner approached for the study. In total, 50 partners (91%) completed the questionnaire, of whom 28% reported clinically relevant levels of syndrome-related distress. Levels of distress and worries of the partners and their high-risk spouse were significantly correlated. Younger age and a lack of social support were also associated significantly with heightened levels of distress and worries. The majority of partners (76%) believed that professional psychosocial support should be routinely offered to them. CONCLUSIONS: Approximately one-quarter of the partners exhibit clinically relevant levels of distress that warrant psychological support. The distress levels of the 'patient' could potentially be used to identify partners at risk of developing clinically relevant levels of distress.

Psychosocial impact of Von Hippel-Lindau disease: levels and sources of distress.

Von Hippel-Lindau disease (VHL) is a hereditary tumor susceptibility syndrome, characterized by an increased risk of developing multiple benign and malignant tumors at various sites and ages with limited preventive options. This study evaluates the prevalence of distress among VHL family members and factors associated significantly with such distress. Forty-eight families with a VHL mutation were identified via the nine family cancer clinics in the Netherlands. In total, 171 family members (carriers, 50% at-risk, non-carriers) were approached, of whom 123 (72%) completed a self-report questionnaire. Approximately 40% of the VHL family members reported clinically relevant levels of distress, approaching 50% among the carriers and, possibly even more striking, 36% among the non-carriers. Having lost a first degree relative due to VHL during adolescence (OR 11.2; 95% CI 1.4-86.9) was related significantly to heightened levels of distress. Approximately, only one-third of those who reported heightened levels of distress had received professional psychosocial support. A substantial percentage of family members experience clinically relevant levels of distress. We would recommend the introduction of a procedure for screening for distress in this vulnerable population. Special attention should be paid to those individuals who have lost a close relative due to VHL during adolescence.

Novel Algorithms for Improved Sensitivity in Non-Invasive Prenatal Testing.

Non-invasive prenatal testing (NIPT) of cell-free DNA in maternal plasma, which is a mixture of maternal DNA and a low percentage of fetal DNA, can detect fetal aneuploidies using massively parallel sequencing. Because of the low percentage of fetal DNA, methods with high sensitivity and precision are required. However, sequencing variation lowers sensitivity and hampers detection of trisomy samples. Therefore, we have developed three algorithms to improve sensitivity and specificity: the chi-squared-based variation reduction (χ2VR), the regression-based Z-score (RBZ) and the Match QC score. The χ2VR reduces variability in sequence read counts per chromosome between samples, the RBZ allows for more precise trisomy prediction, and the Match QC score shows if the control group used is representative for a specific sample. We compared the performance of χ2VR to that of existing variation reduction algorithms (peak and GC correction) and that of RBZ to trisomy prediction algorithms (standard Z-score, normalized chromosome value and median-absolute-deviation-based Z-score). χ2VR and the RBZ both reduce variability more than existing methods, and thereby increase the sensitivity of the NIPT analysis. We found the optimal combination of algorithms was to use both GC correction and χ2VR for pre-processing and to use RBZ as the trisomy prediction method.

Re-analysis of the Xq27-Xq28 region suggests a weak association of an X-linked gene with sporadic testicular germ cell tumour without cryptorchidism.

BACKGROUND: A testicular germ cell tumour (TGCT) predisposing gene has been mapped to the Xq27 region on the X chromosome. These linkage findings remain to be confirmed by other studies. METHODS: In 276 patients and 169 unaffected first-degree male relatives, 12 microsatellite markers covering the candidate region were genotyped and used to study possible association of TGCT with Xq27. RESULTS: In contrast to previously reported linkage of familial TGCT and cryptorchidism with Xq27, we observed an association between the subset of TGCT cases without a family history of TGCT or cryptorchism and marker DXS1193 (p=0.014). Carriers of minor alleles were at increased risk (odds ratio (OR) 4.7, confidence interval (CI) 1.1-19.6) CONCLUSION: We found an association on Xq27 in a subset of TGCT cases, which suggests the presence of an X-linked gene that slightly or moderately increases risk to develop sporadic TGCT but not cryptorchidism.

Multiplicity in polyp count and extracolonic manifestations in 40 Dutch patients with MYH associated polyposis coli (MAP).

OBJECTIVE: To investigate the contribution of MYH associated polyposis coli (MAP) among polyposis families in the Netherlands, and the prevalence of colonic and extracolonic manifestations in MAP patients. METHODS: 170 patients with polyposis coli, who previously tested negative for APC mutations, were screened by denaturing gradient gel electrophoresis and direct sequencing to identify MYH germline mutations. RESULTS: Homozygous and compound heterozygous MYH mutations were identified in 40 patients (24%). No difference was found in the percentage of biallelic mutation carriers between patients with 10-99 polyps or 100-1000 polyps (29% in both groups). Colorectal cancer was found in 26 of the 40 patients with MAP (65%) within the age range 21 to 67 years (median 45). Complete endoscopic reports were available for 16 MAP patients and revealed five cases with gastro-duodenal polyps (31%), one of whom also presented with a duodenal carcinoma. Breast cancer occurred in 18% of female MAP patients, significantly more than expected from national statistics (standardised morbidity ratio = 3.75). CONCLUSIONS: Polyp numbers in MAP patients were equally associated with the attenuated and classical polyposis coli phenotypes. Two thirds of the MAP patients had colorectal cancer, 95% of whom were older than 35 years, and one third of a subset of patients had upper gastrointestinal lesions. Endoscopic screening of the whole intestine should be carried out every two years for all MAP patients, starting from age 25-30 years. The frequent occurrence of additional extraintestinal manifestations, such as breast cancer among female MAP patients, should be thoroughly investigated.

Colorectal cancer risk variants at 8q23.3 and 11q23.1 are associated with disease phenotype in APC mutation carriers.

Familial adenomatous polyposis (FAP) is a dominantly inherited syndrome caused by germline mutations in the APC gene and characterized by the development of multiple colorectal adenomas and a high risk of developing colorectal cancer (CRC). The severity of polyposis is correlated with the site of the APC mutation. However, there is also phenotypic variability within families with the same underlying APC mutation, suggesting that additional factors influence the severity of polyposis. Genome-wide association studies identified several single nucleotide polymorphisms (SNPs) that are associated with CRC. We assessed whether these SNPs are associated with polyp multiplicity in proven APC mutation carriers. Sixteen CRC-associated SNPs were analysed in a cohort of 419 APC germline mutation carriers from 182 families. Clinical data were retrieved from the Dutch Polyposis Registry. Allele frequencies of the SNPs were compared for patients with <100 colorectal adenomas versus patients with ≥100 adenomas, using generalized estimating equations with the APC genotype as a covariate. We found a trend of association of two of the tested SNPs with the ≥100 adenoma phenotype: the C alleles of rs16892766 at 8q23.3 (OR 1.71, 95 % CI 1.05-2.76, p = 0.03, dominant model) and rs3802842 at 11q23.1 (OR 1.51, 95 % CI 1.03-2.22, p = 0.04, dominant model). We identified two risk variants that are associated with a more severe phenotype in APC mutation carriers. These risk variants may partly explain the phenotypic variability in families with the same APC gene defect. Further studies with a larger sample size are recommended to evaluate and confirm the phenotypic effect of these SNPs in FAP.

[More hereditary intestinal cancer can be detected if patients with colorectal carcinoma that are selected by the pathologist are examined for microsatellite instability]. / Meer opsporing van erfelijke darmkanker met onderzoek op microsatellietinstabiliteit bij door de patholoog geselecteerde patiënten met een colon-rectumcarcinoom.

OBJECTIVE: To determine whether an investigation of microsatellite instability (MSI) in patients with colorectal carcinoma that have been selected by the pathologist could increase the number of detected families with hereditary non-polyposis colorectal carcinoma (HNPCC). DESIGN: Prospective inventory. METHOD: Pathologists selected patients with a newly diagnosed colorectal carcinoma for MSI analysis of their tumour tissue if they met one of the following four criteria: (a) colorectal carcinoma diagnosed below 50 years of age; (b) a second colorectal carcinoma; (c) a combination of colorectal carcinoma and another HNPCC-related cancer; (d) colorectal adenoma with high-grade dysplasia diagnosed below 40 years of age. Patients with a positive MSI-test were referred to a clinical geneticist. The new strategy was introduced and explored in 5 hospitals for a period of to months. RESULTS: The new strategy was adopted and implemented successfully by pathologists and surgeons and accepted with satisfaction by the patients. Of the 55 patients included, 10 had a positive MSI-test. In 8/10 patients, DNA-mutation analysis was started by the clinical geneticist and 3 germline mutations in the MSH2-gene were detected. In 2 of 3 families with a pathogenic mutation, the family history alone did not fulfil the clinical criteria for HNPCC. CONCLUSION: Selection by the pathologist for MSI investigation was feasible in daily practice and identified more HNPCC patients than selection based on family history alone.

RET mutation screening in familial cutaneous lichen amyloidosis and in skin amyloidosis associated with multiple endocrine neoplasia.

In several families, multiple endocrine neoplasia type 2A (MEN 2A) has been found in association with cutaneous lichen amyloidosis. It has been debated, however, whether the skin amyloidosis found in MEN 2A families, localized exclusively in the interscapular area, represents the same anomaly as that found in autosomal dominant familial cutaneous lichen amyloidosis, which is more generalized. We screened two MEN 2A families with associated skin amyloidosis for germline mutations in the RET gene responsible for the MEN 2A cancer syndrome, and found the same mutation characteristic of MEN 2A in both families. We also screened probands from three pedigrees with familial cutaneous lichen amyloidosis for RET mutations. In none of the RET coding and flanking intronic sequences was a mutation detected. This most probably indicates that skin amyloidosis found in some MEN 2A families and familial cutaneous lichen amyloidosis are different conditions. Consequently, patients with apparent familial cutaneous lichen amyloidosis do not appear to be at risk for MEN 2A.

Accuracy of family history of cancer: clinical genetic implications.

Family medical history is the cornerstone of clinical genetic diagnosis and management in cases of familial cancer. The soundness of medical decisions can be compromised if reports by the family on affected relatives are inaccurate. Although very time consuming, family medical histories are therefore routinely verified. To investigate whether such verification is clinically justified, we retrospectively analysed the accuracy of a consecutive series of 383 tumour reports from counsellees on 120 families in our clinic. We evaluated these families for the impact of verification on clinical genetic diagnosis and management. Accuracy according to cancer type showed marked variation, ranging from 93% and 89% for breast cancer and colorectal cancer, respectively, to 42% and 37% for extra-colorectal alimentary tract cancer and uterine cancer. Accuracy was related to the degree of kinship of the affected relative, but not to age and gender of the counsellee, nor to the reason for referral or personal history of cancer. Age at diagnosis and multiple primary tumours were reported accurately in 97% and 94% of cases, respectively. In six out of 120 families verification data changed clinical genetic management, in five of these the genetic risk was reduced. Although verification of all reported cancer cases in a family remains the 'gold standard' for clinical as well as research purposes, verification of reports on breast cancer can be limited without seriously compromising medical decision making. In cases where verification is impossible because medical records are unavailable, findings from studies such as ours may help in interpreting family histories.

Familial testicular cancer in a single-centre population.

Familial occurrence of testicular cancer suggests a genetic predisposition to the disease. A genetic susceptibility may also be reflected by the occurrence of bilateral testicular neoplasms and the high rates of urogenital developmental anomalies in families prone to testicular cancer. In this study, the proportion of familial testicular cancer cases was analyzed retrospectively in a single-centre population of 693 testicular cancer patients treated between 1977 and 1997 and the relative risk (RR) for first-degree relatives of patients was estimated. In addition, the existence of bilateral testicular neoplasms and urogenital developmental anomalies in familial testicular cancer patients was evaluated. 24 of the 693 patients (3.5%) had a first-degree relative with testicular cancer. These 24 cases belonged to 17 families; in 7 of these 17 families both affected first-degree family members were part of the study population of 693 patients. Consequently, the 693 studied patients belonged to a total of 686 families. Thus, the actual proportion of familial testicular cancer was 2.5% (17 of 686 families). The familial cases consisted of 11 brother pairs, including 2 pairs of identical twins and 1 pair which also had two affected cousins, and 6 father-son pairs (in total 36 cases, 12 treated elsewhere). Estimates of the RR to first-degree relatives showed a 9- to 13-fold increased RR to brothers (P < 0.001) and a 2-fold increased RR to fathers (P = non-significant (n.s)) of testicular cancer patients. Among the 36 patients with familial testicular cancer, 2 (5.6%) had bilateral testicular cancer, 4 (11.1%) had undescended testis, 3 (8.3%) had inguinal hernia, and 1 (2.8%) showed renal hypoplasia. The present data on familial occurrence of testicular cancer may lend support to a role of genetic factors in the aetiology of testicular cancer.

Tetrasomy 5p mosaicism in a boy with delayed growth, hypotonia, minor anomalies, and an additional isochromosome 5p [46,XY/47,XY, + i(5p)].

We describe a 1-year-old boy with a rare de novo 46,XY/47,XY, + i(5p) mosaicism (ratios 28/3 in peripheral blood lymphocytes and 2/12 in skin fibroblasts). The boy, born after a pregnancy of 34 weeks, had lung hypoplasia, persistent hypotonia, and postnatal growth failure. Craniofacial anomalies were also present. His clinical manifestations correspond to those described in trisomy 5p patients. Prenatal diagnosis on maternal age indication had shown normal male chromosomes in 16 cells in the short term culture of a chorionic villus sampling. Retrospectively, 1 out of 217 cells in this culture showed the i(5p). Several mechanisms could have resulted in the formation of this 46/47, + i(5p) mosaic. Postzygotic local incorrect ligation during chromatid replication, followed by a second replication offers an attractive model on theoretical grounds since it needs only one step to explain both isochromosome formation and mosaicism. Differences between the various tissues in selection pressure on cells with the isochromosome might explain the different ratios of mosaicism found.

Familial cancer database: a clinical aide-mémoire.

Cancer is associated with a wide range of hereditary disorders. Recognizing these disorders in cancer patients may be of great importance for the medical management of both patients and their relatives. Conversely, recognizing the fact that cancer may develop in patients already diagnosed with a particular hereditary disorder may be important for the same reason. We have developed a stand-alone interactive computer program, Familial Cancer Database (FaCD), to assist the clinician in making a genetic differential diagnosis in cancer patients as well as in becoming aware of the tumour spectrum associated with a particular hereditary disorder. The program tries to match tumour and non-tumour features observed in patients and their families with any of the more than 300 disorders presently contained in its database and provides a clinical synopsis with literature references for each of these disorders. FaCD is offered free of charge in support of the Familial Cancer and Prevention project of the UICC Cancer Epidemiology and Prevention program. The software is primarily aimed at health care professionals with at least a basic knowledge of clinical cancer genetics, and can be downloaded from the internet at http://facd.uicc.org.

Adrenocortical adenocarcinoma in an MSH2 carrier: coincidence or causal relation?

A woman is described who developed an ovarian adenocarcinoma, 3 metachronous colorectal adenocarcinomas, and a primary adrenocortical adenocarcinoma. Genetic investigation of the mismatch repair genes MLH1 and MSH2 showed a germline mutation in MSH2. Colorectal and ovarian carcinoma belong to the tumor spectrum of hereditary nonpolyposis colorectal cancer (HNPCC). Adrenocortical adenocarcinoma, however, has never been described as 1 of the HNPCC-associated tumors. To investigate whether the adrenocortical adenocarcinoma in this patient was caused by the MSH2 germline mutation, determination of microsatellite instability (MSI) and immunohistochemical analysis were performed on 1 of the colorectal tumors and the adrenocortical adenocarcinoma. MSI and general loss of MSH2 protein expression could be seen in the colorectal tumor but not in the adrenocortical adenocarcinoma. Therefore, it is highly unlikely that the adrenocortical adenocarcinoma found in this patient was due to her genetic predisposition for HNPCC. HUM PATHOL 31:1522-1527.

Familial and hereditary non-polyposis colorectal cancer: issues relevant for surgical practice.

About 15% of patients with colorectal cancer report a family history of this disease. An estimated 1%-5% of patients have hereditary non-polyposis colorectal cancer (HNPCC). Recently, DNA mismatch repair genes associated with this syndrome were identified. For about 50% of families in which HNPCC occurs, DNA-based diagnosis and presymptomatic DNA testing are now feasible. Diagnosis of a hereditary tumour syndrome is relevant for both the patient with cancer and his or her close relatives. The complexities of family studies warrant the forming of a multidisciplinary team which may choose to work within a specialized cancer family clinic.