|Pediatric craniopharyngioma in association with familial adenomatous polyposis|
Familial adenomatous polyposis (FAP) is a cancer predisposition syndrome driven by germline loss-of-function of the APC gene and phenotypically manifests with intestinal polyposis and a variety of extra-intestinal bone and soft tissue tumors. Craniopharyngioma is not a well-described FAP-associated tumor, however, six cases have been reported in adults, all demonstrating ectopic location and adamantinomatous histology. We report the first case of craniopharyngioma associated with FAP in a pediatric patient. A seven-year-old girl who presented with headache and vomiting was found on magnetic resonance imaging to have a suprasellar mass with cystic extension to the pre-pontine space. The tumor represented an adamantinomatous craniopharyngioma (aCP) with nuclear β-catenin expression. Whole exome sequencing confirmed a CTNNB1 activating point mutation and a germline APC frameshift variant. This case represents the first FAP-associated craniopharyngioma in childhood…. expanding our understanding of the molecular underpinnings driving tumorigenesis in this unique patient.
|Phenotypic confirmation of oligodontia, colorectal polyposis and cancer in a family carrying an exon 7 nonsense variant in the AXIN2 gene|
The AXIN2 gene, like APC, plays a role in the Wnt signalling pathway involved in colorectal tumour formation. Heterozygous mutations in AXIN2 have been shown to cause ectodermal dysplasia (including tooth agenesis, or more specifically, oligodontia), and, in some carriers, colorectal cancer and/or adenomatous polyposis develops. There is a paucity of published AXIN2 families making genotype-phenotype (polyposis, colorectal cancer and oligodontia) correlations challenging. In this case report we describe a family with c.1972delA, p.Ser658Alafs*31 nonsense variant in AXIN2 where the three confirmed carriers presented with both oligodontia and colorectal adenomatous polyposis; mean number of teeth missing in carriers was 16.5 (range 11–22) and mean number of polyps in carriers was 49 (range 5->100, polyps were predominantly adenomatous). This highlights the importance of confirming phenotypic information in familial polyposis, to guide appropriate genetic investigations, as well as providing additional phenotypic and penetrance data to aid in clinical risk management recommendations. Our experience supports the inclusion of AXIN2 on panels for testing of patients with polyposis.
|Endoscopic full thickness resection for early colon cancer in Lynch syndrome|
Subtotal colectomy is usually the therapy of choice in Lynch syndrome patients diagnosed with colon cancer. In patients who develop cancer after the age of 50–60 years, segmental colectomy is considered a good alternative. Although the endoscopic treatment of early colorectal cancer in non-Lynch patients has increased in the last decades, almost all patients with a Lynch syndrome-associated colorectal malignancy undergo surgery, even if the tumour is diagnosed in a (very) early stage. One of the endoscopic treatment options for early colorectal cancer is an endoscopic full thickness resection (eFTR). This treatment modality allows optimal pathological examination of the resection specimen, as a transmural resection is performed with optimal T-staging of the tumour. We report a case of a 62 year old man, diagnosed with MSH2-Lynch syndrome, who underwent successful eFTR treatment of an early (pT1) colon cancer located in the ascending colon, with no signs of recurrence 12 months after treatment. We discuss the pros and cons of endoscopic resection of early colorectal carcinoma in Lynch syndrome patients.
|Progress report: familial pancreatic cancer|
A hereditary predisposition to pancreatic ductal adenocarcinoma (PDAC) is reported in approximately 5% of patients. Familial pancreatic cancer (FPC) accounts for the vast majority of hereditary PDAC cases. FPC defines families with two or more affected first-degree relatives with PDAC that do not fulfil the criteria of any other inherited tumor syndrome or families with PDAC in three or more relatives of any degree. The current progress report focuses on the knowledge of FPC with regard to molecular pathogenesis, clinical and molecular diagnosis, surveillance and novel treatment options reported in the last 5 years.
|Genetic counseling referral for ovarian cancer patients: a call to action|
The hereditary contribution to ovarian cancer has been increasingly recognized over the past decade, with a 2014 Society of Gynecologic Oncology (SGO) recommendation for all women with epithelial ovarian cancer to be considered for genetic testing. The objective of the study was to determine if disparities exist in genetic referrals and characterize referral patterns over time. A retrospective cohort study included all women diagnosed with invasive epithelial ovarian cancer at the University of Virginia from 2004 to 2015. Clinicopathologic data were abstracted from the electronic medical record and analyzed for association with genetic referral and testing. We identified 696 cases, with a median age of 62 years and a median follow up of 25.2 months (range 1–115). Thirty-four percent were referred for genetic counseling with an 80% genetic testing rate in those women. Referrals increased from a rate of 8% in 2004 to 68% in 2015. On multivariable analysis, papillary serous histology (OR 1.6, 95% CI 1.0–2.6), stage III disease (OR 3.4, 95% CI 1.6–7.5), ovarian cancer family history (OR 2.6, 95% CI 1.5–4.6), breast cancer family history (OR 1.7, 95% CI 1.1–2.5), and diagnosis after 2014 (OR 2.3, 95% CI 1.3–4.1) remained significantly associated with genetics referral. Older age and living > 100 miles away were associated with decreased referral (OR 0.97, 95% CI 0.95–0.99 per year and OR 0.49, 95% CI 0.28–0.86). As only 68% of women with epithelial ovarian cancer were referred in 2015 innovative strategies such as Medicare coverage for counseling are still needed to universalize testing.
|The incidence of consecutive manifestations in Von Hippel-Lindau disease|
Von Hippel-Lindau (VHL) disease is an autosomal dominant rare tumor syndrome characterized by high penetrance. VHL mutation carriers develop numerous manifestations in multiple organs during life. The natural course of development of new and growth of existing VHL-related manifestations is still unclear. In this study we aimed to gain insight into the development of subsequent manifestations in VHL disease. We retrospectively scored each new VHL-related manifestation as detected by standard follow-up (retina, central nervous system, kidneys and pancreas, excluding adrenal and endolymfatic sac manifestations) in 75 VHL mutation carriers. The Kaplan–Meier method was used to plot the cumulative proportions of all consecutive manifestations in each organ against age. The cumulative average number of manifestations in all organs during life was calculated by summating these cumulative proportions. Poisson model parameters were used to calculate average time to the detection of consecutive VHL manifestations in each organ. Consecutive VHL-related kidney and retina manifestations during life occur linearly according to Poisson distribution model. The total number of VHL manifestations rises linearly, with an average of seven VHL-related lesions at age 60 years. The incidence of consecutive VHL-related manifestations is constant during life in VHL mutation carriers. Our data is consistent with the notion that somatic inactivation of the remaining allele (Knudson's "two-hit" hypothesis) is the determining factor in developing new VHL-related manifestations.
|Moving into the mainstream: healthcare professionals' views of implementing treatment focussed genetic testing in breast cancer care|
A proportion of breast cancers are attributable to BRCA1 or BRCA2 mutations. Technological advances has meant that mutation testing in newly diagnosed cancer patients can be used to inform treatment plans. Although oncologists increasingly deliver treatment-focused genetic testing (TFGT) as part of mainstream ovarian cancer care, we know little about non-genetics specialists' views about offering genetic testing to newly diagnosed breast cancer patients. This study sought to determine genetics and non-genetics specialists' views of a proposal to mainstream BRCA1 and 2 testing in newly diagnosed breast cancer patients. Qualitative interview study. Nineteen healthcare professionals currently responsible for offering TFGT in a standard (triage + referral) pathway (breast surgeons + clinical genetics team) and oncologists preparing to offer TFGT to breast cancer patients in a mainstreamed pathway participated in in-depth interviews. Genetics and non-genetics professionals' perceptions of mainstreaming are influenced by their views of: their clinical roles and responsibilities, the impact of TFGT on their workload and the patient pathway and the perceived relevance of genetic testing for patient care in the short-term. Perceived barriers to mainstreaming may be overcome by: more effective communication between specialities, clearer guidelines/patient pathways and the recruitment of mainstreaming champions.
|Hereditary gastric cancer: what's new? Update 2013–2018|
Around 10–20% of gastric cancer patients have relatives with a diagnosis of GC and in 1–3% of patients a genetic cause can be confirmed. Histopathologically, GC is classified into intestinal-type, with glandular growth, and diffuse-type with poorly cohesive growth pattern often with signet ring cells. Familial or hereditary GC is classified into hereditary diffuse GC (HDGC), familial intestinal GC (FIGC) and polyposis forms. This review focuses on recent research findings and new concepts of hereditary GC.
|Implementation of a Systematic Tumor Screening Program for Lynch Syndrome in an Integrated Health Care Setting|
A subset of colorectal cancer (CRC) cases are attributable to Lynch syndrome (LS), a hereditary form of CRC. Effective evaluation for LS can be done on CRC tumors to guide diagnostic testing. Increased diagnosis of LS allows for surveillance and risk reduction, which can mitigate CRC-related burden and prevent cancer-related deaths. We evaluated participation in LS screening among newly diagnosed adult CRC patients. Some cases were referred for genetics evaluation prior to study recruitment (selective screening). Those not referred directly were randomized to the intervention or control (usual care) arms. Control cases were observed for one year, then given information about LS screening. Patients who declined participation were followed through the medical record. Of 601 cases of CRC, 194 (32%) enrolled in our study and were offered LS screening, 43 (7%) were followed as a control group, 148 (25%) declined participation and 216 (36%) were ineligible [63 (10%) of which received prior selective screening]. Six and nine cases of LS were identified through the intervention and selective screening groups, respectively. Overall, a higher proportion of PMS2 variants were identified in the intervention (3/6, 50%) versus selective screening groups (2/9, 22%) (not statistically significant). Eighty-eight percent and 23% of intervention and control patients, respectively, received LS screening. No control patients were found to have LS. Systems-based approaches are needed to ensure we fully identify LS cases. The proportion of LS cases from this program was 4% of newly diagnosed cases of CRC, similar to other programs.
|Implication of DNA repair genes in Lynch-like syndrome|
Many colorectal cancers (CRCs) that exhibit microsatellite instability (MSI) are not explained by MLH1 promoter methylation or germline mutations in mismatch repair (MMR) genes, which cause Lynch syndrome (LS). Instead, these Lynch-like syndrome (LLS) patients have somatic mutations in MMR genes. However, many of these patients are young and have relatives with cancer, suggesting a hereditary entity. We performed germline sequence analysis in LLS patients and determined their tumor's mutational profiles using FFPE DNA. Six hundred and fifty-four consecutive CRC patients were screened for suspected LS using MSI and absence of MLH1methylation. Suspected LS cases were exome sequenced to identify germline and somatic mutations. Single nucleotide variants were used to characterize mutational signatures. We identified 23 suspected LS cases. Germline sequence analysis of 16 available samples identified five cases with LS mutations and 11 cases without LS mutations, LLS. Most LLS tumors had a combination of somatic MMR gene mutation and loss of heterozygosity. LLS patients were relatively young and had excess first-degree relatives with cancer. Four of the 11 LLS patients had rare likely pathogenic variants in genes that maintain genome integrity. Moreover, tumors from this group had a distinct mutational signature compared to tumors from LLS patients lacking germline mutations in these genes. In summary, more than a third of the LLS patients studied had germline mutations in genes that maintain genome integrity and their tumors had a distinct mutational signature. The possibility of hereditary factors in LLS warrants further studies so counseling can be properly informed.
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