Following the identification in a proband of a germline
BRCA1
/
BRCA2
mutation in hereditary breast-ovarian cancer (HBOC) or a DNA mismatch repair gene mutation in Lynch syndrome (LS) he or she will ...be asked to inform at-risk family members about the option for presymptomatic DNA testing. However, in clinical practice multiple factors may complicate the process of information sharing. We critically evaluated studies on the uptake of presymptomatic genetic testing in both syndromes. A search of relevant MeSH terms and key words in PubMed, Embase and PsycINFO yielded 795 articles published between 2001 and 2017. Thirty of these publications included outcome measures relevant for the current study. Based on information provided by the proband (15 studies) the uptake of presymptomatic genetic testing ranged from 15 to 57% in HBOC, while one study in LS kindreds reported an uptake of 70%. Based on information provided by genetics centres (the remaining 15 studies) the uptake ranged from 21 to 44% in HBOC and from 41 to 94% in LS. However, when genetics centres contacted relatives directly a substantial number of additional family members could be tested. Proband-mediated provision of information to at-risk relatives is a standard procedure in hereditary breast-ovarian cancer and Lynch syndrome. However, the resulting uptake of presymptomatic testing is disappointing—an issue that is now urgent due to the increased use of genetic testing in clinical oncology. We propose that additional strategies should be introduced including the geneticist directly contacting relatives. The outcomes of these strategies should be carefully monitored and evaluated.
With more than 70 different histological sarcoma subtypes, accurate classification can be challenging. Although characteristic genetic events can largely facilitate pathological assessment, ...large-scale molecular profiling generally is not part of regular diagnostic workflows for sarcoma patients. We hypothesized that whole genome sequencing (WGS) optimizes clinical care of sarcoma patients by detection of diagnostic and actionable genomic characteristics, and of underlying hereditary conditions. WGS of tumor and germline DNA was incorporated in the diagnostic work-up of 83 patients with a (presumed) sarcomas in a tertiary referral center. Clinical follow-up data were collected prospectively to assess impact of WGS on clinical decision making. In 12/83 patients (14%), the genomic profile led to revision of cancer diagnosis, with change of treatment plan in eight. All twelve patients had undergone multiple tissue retrieval procedures and immunohistopathological assessments by regional and expert pathologists prior to WGS analysis. Actionable biomarkers with therapeutic potential were identified for 30/83 patients. Pathogenic germline variants were present in seven patients. In conclusion, unbiased genomic characterization with WGS identifies genomic biomarkers with direct clinical implications for sarcoma patients. Given the diagnostic complexity and high unmet need for new treatment opportunities in sarcoma patients, WGS can be an important extension of the diagnostic arsenal of pathologists.
Pathogenic variants (PV) of
are found in families fulfilling criteria for hereditary diffuse gastric cancer (HDGC) but no risk estimates were available until now. The aim of this study is to evaluate ...diffuse gastric cancer (DGC) risks for carriers of germline
PV.
Data from published CTNNA1 families were updated and new families were identified through international collaborations. The cumulative risk of DGC by age for PV carriers was estimated with the genotype restricted likelihood (GRL) method, taking into account non-genotyped individuals and conditioning on all observed phenotypes and genotypes of the index case to obtain unbiased estimates. A non-parametric (NP) and the Weibull functions were used to model the shape of penetrance function with the GRL. Kaplan-Meier incidence curve and standardised incidence ratios were also computed. A 'leave-one-out' strategy was used to evaluate estimate uncertainty.
Thirteen families with 46 carriers of PV were included. The cumulative risks of DGC at 80 years for carriers of
PV are 49% and 57%, respectively with the Weibull GRL and NP GRL methods. Risk ratios to population incidence reach particularly high values at early ages and decrease with age. At 40 years, they are equal to 65 and 833, respectively with the Weibull GRL and NP GRL.
This is the largest series of
families that provides the first risk estimates of GC. These data will help to improve management and surveillance for these patients and support inclusion of
in germline testing panels.
As estrogen receptor-positive (ER
) breast cancer in
mutation carriers arises at an older age with less aggressive tumor characteristics than ER-negative (ER
)
-mutated breast cancer, it has been ...suggested that these tumors are "sporadic" and not
driven. With the introduction of targeted treatments specific for tumors with a nonfunctioning
or
gene, the question whether the
genes are impaired in the tumor is highly relevant. Therefore, we performed genomic profiling of
-mutated ER
tumors.
Genomic profiling,
promoter methylation assessment, and loss of heterozygosity analysis were done on 16
-mutated ER
tumors. Results were compared with 57
-mutated ER
tumors, 36
-mutated ER
-associated tumors, and 182 sporadic ER
tumors.
The genomic profile of
-mutated ER
tumors was different from
-mutated ER
breast tumors, but highly similar to
-mutated ER
tumors. In 83% of the
-mutated ER
tumors, loss of the wild-type
allele was observed. In addition, clinicopathologic variables in
-mutated ER
cancer were also more similar to
-mutated ER
and sporadic ER
breast cancer than to
-mutated ER
cancers.
As
-mutated ER
tumors show a BRCAness copy number profile and LOH, it is likely that the loss of a functional BRCA1 protein plays a role in tumorigenesis in
-mutated ER
tumors. Therefore, we hypothesize that these tumors are sensitive to drugs targeting the
gene defect, providing new targeted treatment modalities for advanced BRCA-deficient, ER
breast cancer.
.
In approximately 10% of all gastric cancer (GC) cases, a heritable cause is suspected. A subset of these cases have a causative germline
mutation; however, in most cases the cause remains unknown. ...Our objective was to assess to what extent these remaining cases may be explained by germline mutations in the novel candidate GC predisposing genes
,
or
.
We sequenced a large cohort of unexplained young and/or familial patients with GC (n=286) without a
germline mutation for germline variants affecting
,
and
using a targeted next-generation sequencing approach based on single-molecule molecular inversion probes.
Predicted deleterious germline variants were not encountered in
, but recurrently observed in
(n=2) and
(n=3) in our cohort of patients with GC. In contrast to deleterious variants in
, deleterious variants in
also occur frequently in the general population.
Based on our results
should no longer be considered a GC predisposition gene, whereas deleterious
variants are confirmed as an infrequent cause of GC susceptibility. Biallelic
germline mutations are at most a very rare cause of GC susceptibility as no additional cases were identified.
Background and Aims The aim of this study was to determine the yield of endoscopic screening in first-degree relatives (FDRs) of CDH1 -negative hereditary diffuse-type gastric cancer (HDGC) patients. ...Methods In this retrospective observational cohort study, in 2 expert centers in the Netherlands data were collected on FDRs from families fulfilling the international HDGC criteria that underwent endoscopic screening. Extensive inspection of the stomach was performed by gastroscopy, taking random and/or targeted stomach biopsy specimens to identify diffuse-type gastric cancer. Results Between 2004 and 2016, 90 persons (40% men; mean age, 48 years) from 40 families were offered endoscopic screening. The mean number of endoscopies per person was 3. The mean follow-up time was 46 months and mean endoscopic interval 20 months. Signet ring cell carcinoma foci restricted to the mucosa (pT1a) were identified in 4 persons (4%) from 1 family, which afterward was diagnosed with a germline CTNNA1 mutation. Advanced poorly cohesive gastric carcinoma was diagnosed in 1 person from another family. Intestinal metaplasia was diagnosed in 38 persons (42%) and low-grade dysplasia in 4 persons (4%). Additionally, in 40 persons (44%) scar tissue was observed in the gastric mucosa, which can hinder the endoscopic detection of small white lesions typical for HDGC. Conclusions Endoscopic screening in HDGC families without a pathogenic CDH1 mutation may be reasonable, as we detected signet ring cell carcinomas in 6% of persons screened. However, the criteria and frequency of screening may have to be reconsidered.
When hereditary breast and ovarian cancer (HBOC) due to a BRCA1/BRCA2 germline pathogenic variant is diagnosed, the proband will be asked to inform other at-risk family members. In the Netherlands, a ...guideline was introduced in 2012 which provided detailed recommendations regarding this proband-mediated procedure. We now evaluated the uptake of predictive BRCA1/BRCA2 testing in 40 consecutive HBOC families diagnosed in our centre in 2014. We performed a retrospective observational study of all 40 families in which a pathogenic BRCA1/BRCA2 germline variant was identified during 2014. We scored the uptake of predictive and confirmatory testing by the end of 2018 and explored factors associated with the level of uptake. Two families were excluded. In the remaining 38 families, among 239 family members ≥18 years at 50% risk of being a mutation carrier or at 25% risk if the family member at 50% risk was deceased, 102 (43%) were tested. Among 108 females 25-75 years of age at 50% risk, 59 (55%) underwent predictive or confirmatory testing, and among 43 males at 50% risk with daughters ≥18 years, 22 (51%) were tested. Factors which complicated cascade screening included family members living abroad, probands not wanting to share information and limited pedigree information. In conclusion, the standard proband-mediated procedure of informing relatives seems to be far from optimal. We suggest a tailored approach for each family, including the option of a direct approach to at-risk family members by the geneticist. In addition, we suggest detailed monitoring and follow-up of families.
BACKGROUND : The International Gastric Cancer Linkage Consortium (IGCLC) consensus guideline advises prophylactic gastrectomy in early adulthood to prevent gastric cancer development in
germline ...mutation carriers; psychosocial reasons may postpone gastrectomy. We analyzed the yield of signet-ring cell carcinoma (SRCC) during surveillance gastroscopy in
mutation carriers. METHODS : A retrospective analysis on surveillance gastroscopies in
mutation carriers was performed. The yield of SRCC in both targeted and random biopsies was studied. Endoscopic (biopsy) results were compared with the histopathologic outcomes in gastrectomy specimens. RESULTS : 42
mutation carriers (18 men; mean age 43, range 20-82 years) underwent 96 surveillance gastroscopies. SRCC lesions were identified on surveillance gastroscopy in 21 patients (50 %), by either targeted biopsies only (n = 11), random biopsies only (n = 3), or both random and targeted biopsies (n = 7). SRCC was detected in 41 /377 targeted biopsies (11 %), whereas random biopsies revealed SRCC in 14/1563 biopsies (0.9 %). At least one SRCC lesion was found in 26 of 30 gastrectomy specimens. In 18 of these 26 specimens (69 %), SRCC had been identified by endoscopic biopsies. Missed lesions were all small superficial SRCC foci, mainly in the body of the stomach. CONCLUSION : In our cohort of
mutation carriers, SRCC lesions were identified by an extensive endoscopic surveillance protocol in 69 % of SRCC-positive patients who underwent a gastric resection. The low number of SRCC detected through random sampling demands a critical reappraisal of random biopsy sampling in the IGCLC guideline.
PDF
