Germ-line
RB
-
1
mutations predispose to pineoblastoma (PinB), but other predisposing genetic factors are not well established. We recently identified a germ-line
DICER1
mutation in a child with a ...PinB. This was accompanied by loss of heterozygosity (LOH) of the wild-type allele within the tumour. We set out to establish the prevalence of
DICER1
mutations in an opportunistically ascertained series of PinBs. Twenty-one PinB cases were studied: Eighteen cases had not undergone previous testing for
DICER1
mutations; three patients were known carriers of germ-line
DICER1
mutations. The eighteen PinBs were sequenced by Sanger and/or Fluidigm-based next-generation sequencing to identify
DICER1
mutations in blood gDNA and/or tumour gDNA. Testing for somatic
DICER1
mutations was also conducted on one case with a known germ-line
DICER1
mutation. From the eighteen PinBs, we identified four deleterious
DICER1
mutations, three of which were germ line in origin, and one for which a germ line versus somatic origin could not be determined; in all four, the second allele was also inactivated leading to complete loss of DICER1 protein. No somatic
DICER1
RNase IIIb mutations were identified. One PinB arising in a germ-line
DICER1
mutation carrier was found to have LOH. This study suggests that germ-line
DICER1
mutations make a clinically significant contribution to PinB, establishing
DICER1
as an important susceptibility gene for PinB and demonstrates PinB to be a manifestation of a germ-line
DICER1
mutation. The means by which the second allele is inactivated may differ from other
DICER1
-related tumours.
We describe a family severely affected by colorectal cancer (CRC) where whole‐exome sequencing identified the coinheritance of the germline variants encoding MSH6 p.Thr1100Met and MUTYH p.Tyr179Cys ...in, at least, three CRC patients diagnosed before 60 years of age. Digenic inheritance of monoallelic MSH6 variants of uncertain significance and MUTYH variants has been suggested to predispose to Lynch syndrome‐associated cancers; however, cosegregation with disease in the familial setting has not yet been established. The identification of individuals carrying multiple potential cancer risk variants is expected to rise with the increased application of whole‐genome sequencing and large multigene panel testing in clinical genetic counseling of familial cancer patients. Here we demonstrate the coinheritance of monoallelic variants in MSH6 and MUTYH consistent with cosegregation with CRC, further supporting a role for digenic inheritance in cancer predisposition.
Patients with hyperplastic polyposis syndrome (HPS) receive endoscopic surveillance to prevent malignant progression of polyps. However, the optimal treatment and surveillance protocol for these ...patients is unknown. The aim of this study was to describe the clinical and pathological features of a large HPS cohort during multiple years of endoscopic surveillance.
Databases were searched for patients with HPS, who were analysed retrospectively. Endoscopy reports and histopathology reports were collected to evaluate frequency of endoscopic surveillance and to obtain information regarding polyp and the presence of colorectal cancer (CRC).
In 77 patients with HPS, 1984 polyps were identified during a mean follow-up period of 5.6 years (range: 0.5-26.6). In 27 (35%) patients CRC was detected of which 22 (28.5%) at initial endoscopy. CRC was detected during surveillance in five patients (cumulative incidence: 6.5%) after a median follow-up time of 1.3 years and a median interval of 11 months. Of these interval CRCs, 4/5 were detected in diminutive serrated polyps (range: 4-16 mm). The cumulative risk of CRC under surveillance was 7% at 5 years. At multivariate logistic regression, an increasing number of hyperplastic polyps (OR 1.05, p=0.013) and serrated adenomas (OR 1.09, p=0.048) was significantly associated with CRC presence.
HPS patients undergoing endoscopic surveillance have an increased CRC risk. The number of serrated polyps is positively correlated with the presence of CRC in HPS, thus supporting a 'serrated pathway' to CRC. To prevent malignant progression, adequate detection and removal of all polyps seems advisable. If this is not feasible, surgical resection should be considered.
Recognition of individuals with a genetic predisposition to gastric cancer (GC) enables preventive measures. However, the underlying cause of genetic susceptibility to gastric cancer remains largely ...unexplained. We performed germline whole-exome sequencing on leukocyte DNA of 54 patients from 53 families with genetically unexplained diffuse-type and intestinal-type GC to identify novel GC-predisposing candidate genes. As young age at diagnosis and familial clustering are hallmarks of genetic tumor susceptibility, we selected patients that were diagnosed below the age of 35, patients from families with two cases of GC at or below age 60 and patients from families with three GC cases at or below age 70. All included individuals were tested negative for germline CDH1 mutations before or during the study. Variants that were possibly deleterious according to in silico predictions were filtered using several independent approaches that were based on gene function and gene mutation burden in controls. Despite a rigorous search, no obvious candidate GC predisposition genes were identified. This negative result stresses the importance of future research studies in large, homogeneous cohorts.
Background & Aims Germline mutations in the cadherin 1, type 1, E-cadherin gene ( CDH1 ) cause a predisposition to gastric cancer. We evaluated the ability of the internationally accepted hereditary ...diffuse gastric cancer (HDGC) criteria to identify individuals with pathogenic mutations in CDH1 , and assessed their outcomes. The criteria were as follows: families with 2 or more cases of gastric cancer, with at least 1 patient diagnosed with diffuse gastric cancer (DGC) before age 50; families with 3 or more cases of DGC; families with 1 DGC before the age of 40; and families with a history of DGC and lobular breast cancer, with 1 diagnosis before the age of 50. Methods We collected results of a CDH1 mutation analysis of 578 individuals from 499 families tested in The Netherlands between 1999 and 2014 (118 families met the HDGC criteria for testing and 236 did not; there were 145 families with incomplete data and/or availability of only first-degree relatives). Data were linked with family histories and findings from clinical and pathology analyses. The Kaplan–Meier method and Cox regression analysis were used to evaluate the overall survival of patients with and without CDH1 mutations. Results In a cohort study in The Netherlands, the HDGC criteria identified individuals with a germline CDH1 mutation with a positive predictive value of 14% and 89% sensitivity. There were 18 pathogenic CDH1 mutations in 499 families (4%); 16 of these mutations were detected in the 118 families who met the HDGC criteria for testing. One pathogenic CDH1 mutation was detected in the 236 families who did not meet HDGC criteria and 1 in the 145 families with incomplete data and/or availability of only first-degree relatives. No CDH1 mutations were found in the 67 families whose members developed intestinal-type gastric cancer, or in the 22 families whose families developed lobular breast cancer. Among patients who fulfilled the HDGC criteria and had pathogenic CDH1 mutations, 36% survived for 1 year and 4% survived for 5 years; among patients who fulfilled the HDGC criteria but did not carry pathogenic CDH1 mutations, 48% survived for 1 year and 13% survived for 5 years ( P = .014 for comparative survival analysis between patients with and without a CDH1 mutation). Conclusions All individuals with a CDH1 mutation had a personal or family history of diffuse gastric cancer. Patients with gastric cancer and germline CDH1 mutations had shorter survival times than patients who met the HDGC criteria but did not have CDH1 mutations.
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.
Diagnosis of Lynch syndrome (LS) caused by a pathogenic germline MSH6 variant may be complicated by discordant immunohistochemistry (IHC) and/or by a microsatellite stable (MSS) phenotype. This study ...aimed to identify the various causes of the discordant phenotypes of colorectal cancer (CRC) and endometrial cancer (EC) in MSH6-associated LS. Data were collected from Dutch family cancer clinics. Carriers of a (likely) pathogenic MSH6 variant diagnosed with CRC or EC were categorized based on an microsatellite instability (MSI)/IHC test outcome that might fail to result in a diagnosis of LS (eg, retained staining of all 4 mismatch repair proteins, with or without an MSS phenotype, and other staining patterns). When tumor tissue was available, MSI and/or IHC were repeated. Next-generation sequencing (NGS) was performed in cases with discordant staining patterns. Data were obtained from 360 families with 1763 (obligate) carriers. MSH6 variant carriers with CRC or EC (n = 590) were included, consisting of 418 CRCs and 232 ECs. Discordant staining was reported in 77 cases (36% of MSI/IHC results). Twelve patients gave informed consent for further analysis of tumor material. Upon revision, 2 out of 3 MSI/IHC cases were found to be concordant with the MSH6 variant, and NGS showed that 4 discordant IHC results were sporadic rather than LS-associated tumors. In 1 case, somatic events explained the discordant phenotype. The use of reflex IHC mismatch repair testing, the current standard in most Western countries, may lead to the misdiagnosis of germline MSH6 variant carriers. The pathologist should point out that further diagnostics for inheritable colon cancer, including LS, should be considered in case of a strong positive family history. Germline DNA analysis of the mismatch repair genes, preferably as part of a larger gene panel, should therefore be considered in potential LS patients.
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.
Screening for Lynch syndrome (LS) in colorectal cancer (CRC) and endometrial cancer patients generally involves immunohistochemical staining of the mismatch repair (MMR) proteins. In case of MLH1 ...protein loss, MLH1 promotor hypermethylation (MLH1-PM) testing is performed to indirectly distinguish the constitutional MLH1 variants from somatic epimutations. Recently, multiple studies have reported that MLH1-PM and pathogenic constitutional MMR variants are not mutually exclusive. This study describes 6 new and 86 previously reported MLH1-PM CRCs or endometrial cancers in LS patients. Of these, methylation of the MLH1 gene promotor C region was reported in 30 MLH1, 6 MSH2, 6 MSH6, and 3 PMS2 variant carriers at a median age at diagnosis of 48.5 years interquartile range (IQR), 39-56.75 years, 39 years (IQR, 29-51 years), 58 years (IQR, 53.5-67 years), and 68 years (IQR, 65.6-68.5 years), respectively. For 31 MLH1-PM CRCs in LS patients from the literature, only the B region of the MLH1 gene promotor was tested, whereas for 13 cases in the literature the tested region was not specified. Collectively, these data indicate that a diagnosis of LS should not be excluded when MLH1-PM is detected. Clinicians should carefully consider whether follow-up genetic MMR gene testing should be offered, with age <60 to 70 years and/or a positive family history among other factors being suggestive for a potential constitutional MMR gene defect.
Lynch syndrome, an autosomal-dominant disorder characterised by high colorectal and endometrial cancer risks, is caused by inherited mutations in DNA mismatch repair (MMR) genes. Mutations fully ...abrogating gene function are unambiguously disease causing. However, missense mutations often have unknown functional implications, hampering genetic counselling. We have applied a novel approach to study three MSH2 unclassified variants (UVs) found in Dutch families with suspected Lynch syndrome.
The three mutations were recreated in the endogenous Msh2 gene in mouse embryonic stem cells by oligonucleotide-directed gene modification. The effect of the UVs on MMR activity was then tested using a set of functional assays interrogating the main MMR functions.
We recreated and functionally tested three MSH2 UVs: MSH2-Y165D (c.493T>G), MSH2-Q690E (c.2068C>G) and MSH2-M813V (c.2437A>G). We observed reduced levels of MSH2-Y165D and MSH2-Q690E but not MSH2-M813V proteins. MSH2-M813V was able to support all MMR functions similar to wild-type MSH2, whereas MSH2-Y165D and MSH2-Q690E showed partial defects.
Based on the results from our functional assays, we conclude that the MSH2-M813V variant is not disease causing. The MSH2-Y165D and MSH2-Q690E variants affect MMR function and are therefore likely the underlying cause of familial cancer predisposition. Since the MMR defect is partial, these variants may represent low penetrance alleles.
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