WWP1 Gain-of-Function Inactivation of PTEN in Cancer Predisposition.

BACKGROUND: Patients with PTEN hamartoma tumor syndrome (PHTS) have germline mutations in the tumor-suppressor gene encoding phosphatase and tensin homologue (PTEN). Such mutations have been associated with a hereditary predisposition to multiple types of cancer, including the Cowden syndrome. However, a majority of patients who have PHTS-related phenotypes have tested negative for PTEN mutations. In a previous study, we found that the E3 ubiquitin ligase WWP1 negatively regulates the function of PTEN. METHODS: In a prospective cohort study conducted from 2005 through 2015, we enrolled 431 patients with wild-type PTEN who met at least the relaxed diagnostic criteria of the International Cowden Consortium. Patients were scanned for WWP1 germline variants. We used the Cancer Genome Atlas (TCGA) data set as representative of apparently sporadic cancers and the Exome Aggregation Consortium data set excluding TCGA (non-TCGA ExAC) and the noncancer Genome Aggregation Database (gnomAD) as representative of population controls without a reported cancer diagnosis. We established both in vitro and murine in vivo models to functionally characterize representative WWP1 variants. RESULTS: The existence of germline WWP1 variants was first established in a family with wild-type PTEN who had oligopolyposis and early-onset colon cancers. A validation series indicated that WWP1 germline variants occurred in 5 of 126 unrelated patients (4%) with oligopolyposis as a predominant phenotype. Germline WWP1 variants, particularly the WWP1 K740N and N745S alleles, were enriched in patients who did not have PHTS but had prevalent sporadic cancers, including PTEN-related cancer types in TCGA (odds ratio, 1.5; 95% confidence interval, 1.1 to 2.1; P = 0.01). The prioritized WWP1 variants resulted in gain-of-function effects, which led to aberrant enzymatic activation with consequent PTEN inactivation, thereby triggering hyperactive growth-promoting PI3K signaling in cellular and murine models. CONCLUSIONS: In this study involving patients with disorders resulting in a predisposition to the development of multiple malignant neoplasms without PTEN germline mutations, we confirmed the function of WWP1 as a cancer-susceptibility gene through direct aberrant regulation of the PTEN-PI3K signaling axis. (Funded by the National Institutes of Health and others.).

IPAA Is More "Desmoidogenic" Than Ileorectal Anastomosis in Familial Adenomatous Polyposis.

BACKGROUND: Desmoid disease is a leading cause of morbidity and mortality in patients with familial adenomatous polyposis. Abdominal desmoid disease usually follows total proctocolectomy with IPAA or total abdominal colectomy with ileorectal anastomosis. Sex, extraintestinal manifestations, and a 3'-mutation location have been identified as risk factors, but surgical risk factors are poorly understood. We hypothesized that pouch construction creates a higher risk of desmoid formation due to the increased stretch of the small-bowel mesentery. OBJECTIVE: This study aimed to investigate the surgical risk factors for desmoid formation. DESIGN: This was a retrospective, single-center, registry-based cohort study. SETTINGS: This study was conducted at a single academic institution with a prospectively maintained hereditary colorectal cancer database between 1995 and 2015. PATIENTS: All patients with familial polyposis (total 345) who underwent either proctocolectomy with a pouch or colectomy with an ileorectal anastomosis during the study period and met inclusion criteria were selected. MAIN OUTCOME MEASURES: The development of symptomatic abdominal desmoid disease was the primary end point. Associations between desmoid formation and resection type, surgical approach, and other patient factors were analyzed. RESULTS: A total of 172 (49%) patients underwent proctocolectomy/ileoanal pouch, whereas 173 (51%) underwent total colectomy/ileorectal anastomosis. Overall, 100 (28.9%) developed symptomatic desmoids after surgery. On univariable analysis, open surgery and pouch surgery were associated with desmoid development, along with extracolonic manifestations, family history of desmoids, mutation location, and a high desmoid risk score. On multivarible analysis, proctocolectomy with pouch was most strongly associated with desmoid disease ( p < 0.01). LIMITATIONS: This study was limited by its retrospective nature, the lack of uniform desmoid screening, and the variable duration of follow-up. Unanalyzed confounding factors include polyposis severity and number of surgeries. CONCLUSIONS: Patients with polyposis who underwent total proctocolectomy with pouch by any approach had significantly greater risk of developing desmoid disease than total colectomy with ileorectal anastomosis, even when accounting for other risk factors. See Video Abstract at http://links.lww.com/DCR/B822 .RESULTADOS DE LOS PACIENTES SOMETIDOS A RESECCIÓN INTESTINAL ELECTIVA ANTES Y DESPUÉS DE LA IMPLEMENTACIÓN DE UN PROGRAMA DE DETECCIÓN Y TRATAMIENTO DE ANEMIA. ANTECEDENTES: Se sabe que los pacientes anémicos que se someten a una cirugía electiva de cáncer colorrectal tienen tasas significativamente más altas de complicaciones posoperatorias y peores resultados. OBJETIVO: Mejorar las tasas de detección y tratamiento de la anemia en pacientes sometidos a resecciones electivas de colon y recto a través de una iniciativa de mejora de calidad. DISEO: Comparamos una cohorte histórica de pacientes antes de la implementación de nuestro programa de detección de anemia y mejora de la calidad del tratamiento con una cohorte prospectiva después de la implementación. ENTORNO CLINICO: Hospital de atención terciaria. PACIENTES: Todos los pacientes adultos con un nuevo diagnóstico de cáncer de colon o recto sin evidencia de enfermedad metastásica entre 2017 y 2019. INTERVENCIONES: Detección de anemia y programa de mejora de la calidad del tratamiento. PRINCIPALES MEDIDAS DE RESULTADO: El resultado primario fue el costo hospitalario por ingreso. RESULTADOS: Un total de 84 pacientes se sometieron a resección electiva de colon o recto antes de la implementación de nuestro proyecto de mejora de calidad de la anemia y 88 pacientes se sometieron a cirugía después. En la cohorte previa a la implementación, 44/84 (55,9 %) presentaban anemia en comparación con 47/99 (54,7 %) en la cohorte posterior a la implementación. Las tasas de detección (25 % a 86,4 %) y tratamiento (27,8 % a 63,8 %) aumentaron significativamente en la cohorte posterior a la implementación. El costo total medio por admisión se redujo significativamente en la cohorte posterior a la implementación (costo medio $16 827 vs. $25 796, p = 0,004); esta reducción significativa se observó incluso después de ajustar los factores de confusión relevantes (proporción de medias: 0,74, IC del 95 %: 0,65 a 0,85). El vínculo mecánico entre el tratamiento de la anemia y la reducción de costos sigue siendo desconocido. No hubo diferencias significativas en las tasas de transfusión de sangre, complicaciones o mortalidad entre los grupos. LIMITACIONES: El diseño de antes y después está sujeto a sesgos temporales y de selección. CONCLUSIONES: Demostramos la implementación exitosa de un programa de detección y tratamiento de anemia. Este programa se asoció con un costo por admisión significativamente reducido. Este trabajo demuestra el valor y los beneficios posibles de la implementación de un programa de detección y tratamiento de la anemia. Consulte Video Resumen en http://links.lww.com/DCR/C15 . (Traducción- Dr. Francisco M. Abarca-Rendon ).

Web-Based Model for Predicting Time to Surgery in Young Patients with Familial Adenomatous Polyposis: An Internally Validated Study.

INTRODUCTION: The timing of prophylactic colorectal surgery in patients with familial adenomatous polyposis (FAP) is based on the immediacy of the colorectal cancer risk. The ability to predict the need for surgery may help patients and their families plan in the context of life events and CRC risk. We created a model to predict the likelihood of surgery within 2 and 5 years of first colonoscopy at our institution. METHODS: A single institution hereditary colorectal syndrome (Cologene™) database was interrogated for all patients with FAP having a deleterious APC mutation. Patients with first colonoscopy after age 30 and before year 2000 were excluded. Cox regression analysis was done to assess multiple factors associated with surgery, followed by stepwise Cox regression analysis to select an optimal model. Receiver operator curve (ROC) analysis was performed to assess the model. RESULTS: A total of 211 (53% female) patients were included. Forty-five percent underwent surgery after an average of 3.8 years of surveillance. The final model was created based on initial clinical characteristics (age, gender, BMI, family history of desmoids, genotype-phenotype correlation), initial colonoscopic characteristics (number of polyps, polyp size, presence of high-grade dysplasia); and on clinical events (chemoprevention and polypectomy). AUC was 0.87 and 0.84 to predict surgery within 2 and 5 years, respectively. The final model can be accessed at this website: http://app.calculoid.com/#/calculator/29638 . CONCLUSION: This web-based tool allows clinicians to stratify patients' likelihood of colorectal surgery within 2 and 5 years of their initial examination, based on clinical and endoscopic features, and using the philosophy of care guiding practice at this institution.

Natural history of colonic polyposis in young patients with familial adenomatous polyposis.

BACKGROUND AND AIMS: Proctocolectomy prevents colorectal cancer in familial adenomatous polyposis (FAP). Colorectal polyp progression is one of the indications for surgery. No data exist regarding the natural history of colorectal polyposis in young patients with FAP. This study examined the rate of polyposis progression and factors associated with it. METHODS: Patients with FAP <30 years old who had undergone ≥2 colonoscopies since 2000 were identified. Rate of polyposis progression was calculated by review of polyp counts obtained from baseline and last colonoscopy, accounting for any polyps removed during the observation period. Endoscopic and non-endoscopic factors affecting the rate of polyposis progression were evaluated. Multivariate analysis was performed to identify factors associated with rate of polyposis progression. RESULTS: One hundred sixty-eight patients (52% female; median age, 13.5 years) were included. Median rate of polyposis progression was 25.4 polyps/year (interquartile range, 9.5-69.8). Highest median rate of polyposis progression (89 polyps/year) was associated with mutation in codon 1309. The rate of polyposis progression was independently associated with the location of mutation in the adenomatous polyposis coli gene, the number of polyps at the initial colonoscopy, and exposure to chemoprevention. Of the 39.9% of patients who underwent surgery, an increase in polyp number was the most common indication (53.7%). CONCLUSIONS: The rate of polyposis progression in young patients with FAP varies with a median of about 25 new polyps per year. Progression is associated with distinct factors, which can be used in discussion with patients regarding the need for and timing of prophylactic colorectal surgery.

Hereditary colorectal cancer syndromes and genetic testing.

Colorectal cancer (CRC) is a leading cause of cancer and cancer deaths in the Western world. Approximately 5-10% of CRC are hereditary, due to a defined genetic cause. Individuals and families affected with a hereditary CRC syndrome exhibit benign and malignant extra-intestinal tumors, require aggressive cancer screening and benefit from management by a multi-disciplinary team of professionals. The clinical manifestations, genetic causes and current management of patients with hereditary colon cancer syndrome is provided.

Compound heterozygous MSH3 germline variants and associated tumor somatic DNA mismatch repair dysfunction.

We describe here an individual from a fourth family with germline compound heterozygous MSH3 germline variants and its observed biological consequences. The patient was initially diagnosed with invasive moderately-differentiated adenocarcinoma of the colon at the age of 43. Germline multigene panel testing revealed a pathogenic variant MSH3 c.2436-1 G > A and a variant of (initial) uncertain significance MSH3 c.3265 A > T (p.Lys1089*). Germline genetic testing of family members confirm the variants are in trans with the c.2436-1 G > A variant of paternal and the c.3265 A > T variant of maternal origin. Tumor DNA exhibits low levels of microsatellite instability and elevated microsatellite alterations at selected tetranucleotide repeats (EMAST). Tissue immunohistochemical staining for MSH3 demonstrated variant MSH3 protein is present in the cytoplasm and cell membrane but not in the nucleus of normal and tumor epithelial cells. Furthermore, variant MSH3 is accompanied by loss of nuclear MSH6 and a reduced level of nuclear MSH2 in some tumor cells, suggesting that the variant MSH3 protein may inhibit binding of MSH6 to MSH2.

Genomic Microsatellite Signatures Identify Germline Mismatch Repair Deficiency and Risk of Cancer Onset.

PURPOSE: Diagnosis of Mismatch Repair Deficiency (MMRD) is crucial for tumor management and early detection in patients with the cancer predisposition syndrome constitutional mismatch repair deficiency (CMMRD). Current diagnostic tools are cumbersome and inconsistent both in childhood cancers and in determining germline MMRD. PATIENTS AND METHODS: We developed and analyzed a functional Low-pass Genomic Instability Characterization (LOGIC) assay to detect MMRD. The diagnostic performance of LOGIC was compared with that of current established assays including tumor mutational burden, immunohistochemistry, and the microsatellite instability panel. LOGIC was then applied to various normal tissues of patients with CMMRD with comprehensive clinical data including age of cancer presentation. RESULTS: Overall, LOGIC was 100% sensitive and specific in detecting MMRD in childhood cancers (N = 376). It was more sensitive than the microsatellite instability panel (14%, P = 4.3 × 10-12), immunohistochemistry (86%, P = 4.6 × 10-3), or tumor mutational burden (80%, P = 9.1 × 10-4). LOGIC was able to distinguish CMMRD from other cancer predisposition syndromes using blood and saliva DNA (P < .0001, n = 277). In normal cells, MMRDness scores differed between tissues (GI > blood > brain), increased over time in the same individual, and revealed genotype-phenotype associations within the mismatch repair genes. Importantly, increased MMRDness score was associated with younger age of first cancer presentation in individuals with CMMRD (P = 2.2 × 10-5). CONCLUSION: LOGIC was a robust tool for the diagnosis of MMRD in multiple cancer types and in normal tissues. LOGIC may inform therapeutic cancer decisions, provide rapid diagnosis of germline MMRD, and support tailored surveillance for individuals with CMMRD.

Proximal colon cancers and the serrated pathway: a systematic analysis of precursor histology and BRAF mutation status.

Although the serrated neoplasia pathway is thought to give rise to the majority of sporadic microsatellite instability-high (MSI-H) colon cancer, the exact proportion of these tumors that arise from serrated precursors has not been fully studied. Tubular and tubulovillous adenomas with features of the serrated neoplasia pathway have been described, and unlike sessile serrated adenomas, these lesions lack BRAF mutations. The contribution of these adenomas to sporadic MSI-H colon cancer is unclear. To this end, we conducted an analysis of right-sided sporadic MSI-H and microsatellite stable (MSS) colon cancer, with emphasis on precursor lesions. Overall 25% (19/75) of MSI-H colon cancer had a precursor, of which only 4 were recognized histologically as arising from a sessile serrated adenoma, and the remaining were best classified as adenomas. Of the 31 (of 89) MSS colon cancers with a precursor, only 1 was a sessile serrated adenoma (P=0.06). Histological analysis of the precursor adenomas to sporadic MSI-H colon cancer demonstrated a high frequency of crypt serrations compared with MSS colon cancer (93 vs 36%, P<0.001). BRAF mutations were found in 57/75 (76%) sporadic MSI-H and 10/89 (11%) MSS colon cancers (P<0.001). Molecular analysis demonstrated BRAF mutations in 11/12 adenoma and 3/3 sessile serrated adenoma precursors adjacent to BRAF-mutated MSI-H colon cancer. Similarly, all 4 precursors to BRAF-mutated MSS colon cancer were also BRAF mutated. The presence of BRAF mutations in these adenomatous precursors suggests that they represent sessile serrated adenomas with complete cytologic dysplasia. Finally, patients with sporadic MSI-H colon cancer were more likely to harbour synchronous sessile serrated adenomas (20 vs 8%; P=0.023). This is the largest study to rigorously evaluate the precursor and synchronous lesions in patients with right-sided colon cancer. Detailed molecular and histological analysis of these lesions confirms the importance of serrated precursors in the development of sporadic MSI-H colon cancer.

Association of cancer with comorbid inflammatory conditions and treatment in patients with Lynch syndrome.

BACKGROUND: Individuals with Lynch syndrome (LS) and hereditary non-polyposis colorectal cancer (HNPCC) are at increased risk of both colorectal cancer and other cancers. The interplay between immunosuppression, a comorbid inflammatory condition (CID), and HNPCC on cancer risk is unclear. AIM: To evaluate the impact of CIDs, and exposure to monoclonal antibodies and immunomodulators, on cancer risk in individuals with HNPCC. METHODS: Individuals prospectively followed in a hereditary cancer registry with LS/HNPCC with the diagnosis of inflammatory bowel disease or rheumatic disease were identified. We compared the proportion of patients with cancer in LS/HNPCC group with and without a CID. We also compared the proportion of patients who developed cancer following a CID diagnosis based upon exposure to immunosuppressive medications. RESULTS: A total of 21 patients with LS/HNPCC and a CID were compared to 43 patients with LS/HNPCC but no CID. Cancer occurred in 84.2% with a CID compared to 76.7% without a CID (P = 0.74) with no difference in age at first cancer diagnosis 45.5 ± 14.6 vs 43.8 ± 7.1 years (P = 0.67). LS specific cancers were diagnosed in 52.4% with a CID vs 44.2% without a CID (P = 0.54). Nine of 21 (42.9%) patients were exposed to biologics or immunomodulators for the treatment of their CID. Cancer after diagnosis of CID was seen in 7 (77.8%) of exposed individuals vs 5 (41.7%) individuals unexposed to biologics/immunomodulators (P = 0.18). All 7 exposed compared to 3/5 unexposed developed a LS specific cancer. The exposed and unexposed groups were followed for a median 10 years and 8.5 years, respectively. The hazard ratio for cancer with medication exposure was 1.59 (P = 0.43, 95%CI: 0.5-5.1). CONCLUSION: In patients with LS/HNPCC, the presence of a concurrent inflammatory condition, or use of immunosuppressive medication to treat the inflammatory condition, might not increase the rate of cancer occurrence in this limited study.

Malignancy risk in individuals with familial adenomatous polyposis receiving biologics and immunomodulators.

Clinicians may be hesitant to prescribe biologics or immunomodulators to individuals with familial adenomatous polyposis (FAP) and comorbid inflammatory disease (CID) because of increased cancer risk. Our aim was to compare the risk of malignancy in FAP individuals with inflammatory bowel (IBD) and/or rheumatic disease that received biologics/immunomodulators to those who did not. Individuals with FAP and CID were included in the study. We compared the incidence of cancer between individuals exposed to biologics/immunomodulators compared to unexposed from the date of diagnosis of comorbid disease till last follow up or death. Hazard ratio (HR) for cancer was computed using Cox regression model and compared by exposure status to biologic/immunomodulators. 25 individuals with FAP and a comorbid inflammatory disease were identified including 9 (36%) with IBD and 16 (64%) with rheumatic disease. 14 (56%) were exposed to a biologic and or immunomodulator. Median duration of biologic/immunomodulator exposure was 48 (2-180) months. 3 (21.4%) in the exposed group compared to 1 (9.1%) in the unexposed group developed cancer with a HR for exposure of 1.92 (CI 0.2-18.5, p = 0.57). Median duration of follow up after the diagnosis of inflammatory disease was 10 (5.5-17.0) years in the exposed and 6 (3.0-15.0) years in the unexposed group. In the exposed group, 1 patient developed gastric and 2 developed colon cancer. One unexposed patient developed medullary thyroid cancer. There is a possible trend of more cancers in the group that received biologics/immunomodulators-but given the small number of patients and p-value, there may be no difference at all. This preliminary finding warrants study in a larger cohort.

Defining phenotypes and cancer risk in hyperplastic polyposis syndrome.

BACKGROUND: Hyperplastic polyposis syndrome is a rare syndrome of colorectal cancer predisposition. Patterns of inheritance of hyperplastic polyposis syndrome are not obvious and the clinical definition is relatively arbitrary. We hypothesize that there are multiple phenotypes included in what is currently called hyperplastic polyposis syndrome. We performed this review of a large series of patients who presented with multiple serrated polyps to look for clinical patterns that may confirm our hypothesis. METHODS: Hereditary colorectal cancer, colonoscopy, and clinical databases from a single institution were queried for patients meeting the following criteria: 1) ≥ 20 serrated colorectal polyps; 2) ≥ 5 serrated polyps proximal to the sigmoid; 3) ≥ 2 serrated polyps ≥ 10 mm in size; 4) any serrated polyps in a person with at least one first-degree relative who has hyperplastic polyposis syndrome. Records were reviewed for demographics, polyp details, and personal or family history of colorectal extracolonic malignancy. RESULTS: One-hundred fifteen patients were included. Median age at diagnosis was 62 years and 56% were male. Ninety-seven percent were white. Twenty-five percent of patients had a personal history and 38% had a family history of colorectal cancer. Twenty-eight percent of patients had a personal history and 54% had a family history of extracolonic cancer. Phenotype analysis identified 3 patterns: relatively few large, right-sided polyps (n = 55), many small left-sided polyps (n = 18), and a combination of both left- and right-sided polyps (n = 42). The right-sided phenotype had more sessile serrated polyps and tended to develop colorectal cancer at a younger age. CONCLUSIONS: There are at least 3 different but overlapping clinical phenotypes within hyperplastic polyposis. Recognizing this clinical heterogeneity is important in defining underlying genetic causes.

Lynch syndrome screening in newly diagnosed colorectal cancer in general pathology practice: from the revised Bethesda guidelines to a universal approach.

OBJECTIVE: Lynch syndrome (LS) is the most common hereditary form of colorectal cancer (CRC). The revised 2004 Bethesda guidelines were developed to identify potential LS patients. This study aimed to retrospectively evaluate utilization and adequacy of the guidelines in general pathology practice and to determine if a universal LS screening approach increased the potential LS detection rate in newly diagnosed CRCs. MATERIAL AND METHODS: Included were 445 primary CRCs surgically resected from November 2006 to March 2009, when reflex microsatellite instability (MSI) testing was based on histomorphology and age as well as 145 CRCs resected from July 2009 to July 2010 when a universal LS testing paradigm was used. Reflex MSI testing rates and MSI testing results were determined. RESULTS: The overall LS screening rate from November 2006 to March 2009 was 34.8%, and the extrapolated microsatellite instability-high (MSI-H) rate was 8.5% (38/445). Strict adherence to the revised Bethesda guidelines, that is, without testing CRC diagnosed in patients ‡60 years, would have missed 26 (68.4%) MSI-H CRCs. The overall LS screening rate from July 2009 to July 2010 was 76.3% and the MSI-H rate was 20.6% (30/145). Compared with the MSI tested group, the untested group had more CRCs removed by local excision (22.2% vs. 4.8%, p = 0.00035). CONCLUSION: The revised Bethesda guidelines are inadequate for LS screening when personal and family cancer history is not available to the pathologist, a universal screening paradigm greatly increased the rate of MSI testing and MSI-H CRC detection and CRCs less likely to be screened for LS were those diagnosed in locally excised specimens.

The Second Allele: A Key to Understanding the Timing of Sporadic and Hereditary Colorectal Tumorigenesis.

Our understanding of the molecular basis of colorectal neoplasia is derived from Mendelian genetics, with tumor suppressor genes contributing more to the deregulation of growth than oncogenes. In patients with hereditary syndromes, expression of one allele of a key tumor suppressor gene is absent at birth. The loss of the expression of the second allele precipitates tumorigenesis. However, there are multiple ways in which the expression of the second allele of a tumor suppressor gene is lost. Here, we review these ways and their possible effect on phenotype.

SMAD4 mutation and the combined syndrome of juvenile polyposis syndrome and hereditary haemorrhagic telangiectasia.

Juvenile polyposis syndrome (JPS) and hereditary haemorrhagic telangiectasia (HHT) are autosomal dominant disorders with characteristic clinical phenotypes. Recently, reports of the combined syndrome of JPS and HHT have been described in individuals with mutations in the SMAD4 gene, whose product-SMAD4-is a critical intracellular effector in the signalling pathway of transforming growth factor beta (TGFbeta). This report describes a 24-year-old man who presented to the Respiratory Institute after colectomy for JPS with a SMAD4 mutation and who was subsequently diagnosed to have HHT with asymptomatic cerebral and pulmonary arteriovenous malformations (AVMs). Patients with JPS due to a SMAD4 mutation should be screened for the vascular lesions associated with HHT, especially occult AVMs in visceral organs, which may potentially present catastrophically with serious medical consequences.

A Multi-Institutional Cohort of Therapy-Associated Polyposis in Childhood and Young Adulthood Cancer Survivors.

Prior small reports have postulated a link between gastrointestinal polyposis and childhood and young adulthood cancer (CYAC) treatment (therapy-associated polyposis; TAP), but this remains a poorly understood phenomenon. The aim of this study was to describe the phenotypic spectrum of TAP in a multi-institutional cohort. TAP cases were identified from eight high-risk cancer centers. Cases were defined as patients with ≥10 gastrointestinal polyps without known causative germline alteration or hereditary colorectal cancer predisposition syndrome who had a history of prior treatment with chemotherapy and/or radiotherapy for CYAC. A total of 34 TAP cases were included (original CYAC: 27 Hodgkin lymphoma, three neuroblastoma, one acute myeloid leukemia, one medulloblastoma, one nephroblastoma, and one non-Hodgkin lymphoma). Gastrointestinal polyposis was first detected at a median of 27 years (interquartile range, 20-33) after CYAC treatment. A total of 12 of 34 (35%) TAP cases had ≥50 colorectal polyps. A total of 32 of 34 (94%) had >1 histologic polyp type. A total of 25 of 34 (74%) had clinical features suggestive of ≥1 colorectal cancer predisposition syndrome [e.g., attenuated familial adenomatous polyposis (FAP), serrated polyposis syndrome, extracolonic manifestations of FAP, mismatch repair-deficient colorectal cancer, or hamartomatous polyposis] including 8 of 34 (24%) with features of multiple such syndromes. TAP is an apparently acquired phenomenon that should be considered in patients who develop significant polyposis without known causative germline alteration but who have had prior treatment for a CYAC. Patients with TAP have features that may mimic various hereditary colorectal cancer syndromes, suggesting multiple concurrent biologic mechanisms, and recognition of this diagnosis may have implications for cancer risk and screening.

Primer on Hereditary Cancer Predisposition Genes Included Within Somatic Next-Generation Sequencing Panels.

PURPOSE: It has been estimated that 5% to 10% of cancers are due to hereditary causes. Recent data sets indicate that the incidence of hereditary cancer may be as high as 17.5% in patients with cancer, and a notable subset is missed if screening is solely by family history and current syndrome-based testing guidelines. Identification of germline variants has implications for both patients and their families. There is currently no comprehensive overview of cancer susceptibility genes or inclusion of these genes in commercially available somatic testing. We aimed to summarize genes linked to hereditary cancer and the somatic and germline panels that include such genes. METHODS: Germline predisposition genes were chosen if commercially available for testing. Penetrance was defined as low, moderate, or high according to whether the gene conferred a 0% to 20%, 20% to 50%, or 50% to 100% lifetime risk of developing the cancer or, when percentages were not available, was estimated on the basis of existing literature descriptions. RESULTS: We identified a total of 89 genes linked to hereditary cancer predisposition, and we summarized these genes alphabetically and by organ system. We considered four germline and six somatic commercially available panel tests and quantified the coverage of germline genes across them. Comparison between the number of genes that had germline importance and the number of genes included in somatic testing showed that many but not all germline genes are tested by frequently used somatic panels. CONCLUSION: The inclusion of cancer-predisposing genes in somatic variant testing panels makes incidental germline findings likely. Although somatic testing can be used to screen for germline variants, this strategy is inadequate for comprehensive screening. Access to genetic counseling is essential for interpretation of germline implications of somatic testing and implementation of appropriate screening and follow-up.

Upper and Lower Gastrointestinal Findings in PTEN Mutation-Positive Cowden Syndrome Patients Participating in an Active Surveillance Program.

OBJECTIVES: Cowden syndrome (CS), associated with germline PTEN mutations, is an autosomal-dominant disorder with increased frequencies of thyroid and breast cancers. Recent reports document the occurrence of gastrointestinal (GI) polyps and increased risk of colon cancer in PTEN mutation carriers. Studies to date, however, have not been based on mutation carriers undergoing active, systematic, routine-interval GI surveillance. Our objective is to document the upper and lower GI findings in CS patients undergoing such an active GI surveillance program. METHODS: In a 5-year period, 3,000 consecutive patients were referred to our high-risk GI cancer clinic for various reasons. Of these 3,000, 10 met full-blown clinical criteria for the diagnosis of CS. Individuals with identified PTEN mutations underwent annual upper and lower endoscopy surveillance programs using dual white light and narrow-band imaging. All biopsies including archived materials were reviewed by a single dedicated GI pathologist. RESULTS: Ten PTEN mutation carriers from different ethnic backgrounds were invited and all participated in the active GI surveillance program. Eight patients had colonic polyps, mostly hyperplastic (eight patients) and hamartomatous (five patients), but also adenomatous (three patients), ganglioneuromatous (three patients), and juvenile polyps (two patients). One patient (10%) had an early-onset rectal cancer (aged 44 years), which was null for PTEN expression on immunohistochemistry. All patients had gastric polyps and nine (90%) had duodenal polyps, mostly hyperplastic and hamartomatous. Additional three patients (30%) had adenomatous duodenal polyps. CONCLUSIONS: PTEN mutation-positive CS patients have a higher frequency of upper GI polyps than previously believed. They appear prone to develop adenomatous upper and lower tract dysplastic polyps and cancer. Thus, the polyps encountered during upper or lower endoscopy in these patients should not be automatically considered innocent hamartomas without malignant potential. Active surveillance programs in specialized centers should be considered in these patients.