bims-lifras 2019-11-03 papers

bims-lifras

Biomed News

on Li-Fraumeni syndrome

Issue of 2019–11–03
twenty-two papers selected by
Joanna Zawacka-Pankau

Management of patients with increased risk for familial pancreatic cancer: updated recommendations from the International Cancer of the Pancreas Screening (CAPS) Consortium.
Germline mutations in cancer-predisposition genes in patients with biliary tract cancer.
Genetic counselling and personalised risk assessment in the Australian pancreatic cancer screening program.
ATM whole gene deletion in an Italian family with hereditary pancreatic cancer: Challenges to cancer risk prediction associated with an 11q22.3 microdeletion.
Identification of a novel large EPCAM-MSH2 duplication, concurrently with LOHs in chromosome 20 and X, in a family with Lynch syndrome.
Hereditary or Not? Understanding Serrated Polyposis Syndrome.
Landscape of Germline Mutations in DNA Repair Genes for Breast Cancer in Latin America: Opportunities for PARP-Like Inhibitors and Immunotherapy.
Recent advances in genetic predisposition to pediatric acute lymphoblastic leukemia.
Quantitative and qualitative impairments in GATA2 and myeloid neoplasms.
Outcomes of women at high familial risk for breast cancer: An 8-year single-center experience.
Regarding the Yin and Yang of Precision Cancer- Screening and Treatment: Are We Creating a Neglected Majority?
Prevalence and spectrum of MLH1, MSH2, and MSH6 pathogenic germline variants in Pakistani colorectal cancer patients.
Prevalence of Lynch syndrome among patients with upper urinary tract carcinoma in a Japanese hospital-based population.
Metachronous ovarian endometrioid carcinomas in a patient with a PTEN variant: case report of incidentally detected Cowden syndrome.
Review: Ewing Sarcoma Predisposition.
Practical management of polyposis syndromes.
GENETICS IN ENDOCRINOLOGY: Somatic and germline mutations in the pathogenesis of pituitary adenomas.
Hereditary Leiomyomatosis and Renal Cell Cancer.
A novel splice site variant in ANOS1 gene leads to Kallmann syndrome in three siblings.
Germline missense mutation of Deleted in malignant brain tumor 1 (DMBT1) in familial mediastinal neuroendocrine cancer and in vitro effects in thyroid cancer cells.
Clinical and pathologic characteristics of familial prostate cancer in Asian population.
Do we know enough about the genetic involvement in laryngeal cancer susceptibility and prognostic outcome?

Gut. 2019 Oct 31. pii: gutjnl-2019-319352. [Epub ahead of print]

Management of patients with increased risk for familial pancreatic cancer: updated recommendations from the International Cancer of the Pancreas Screening (CAPS) Consortium.

International Cancer of the Pancreas Screening (CAPS) consortium

   BACKGROUND AND AIM: The International Cancer of the Pancreas Screening Consortium met in 2018 to update its consensus recommendations for the management of individuals with increased risk of pancreatic cancer based on family history or germline mutation status (high-risk individuals).
METHODS: A modified Delphi approach was employed to reach consensus among a multidisciplinary group of experts who voted on consensus statements. Consensus was considered reached if ≥75% agreed or disagreed.
RESULTS: Consensus was reached on 55 statements. The main goals of surveillance (to identify high-grade dysplastic precursor lesions and T1N0M0 pancreatic cancer) remained unchanged. Experts agreed that for those with familial risk, surveillance should start no earlier than age 50 or 10 years earlier than the youngest relative with pancreatic cancer, but were split on whether to start at age 50 or 55. Germline ATM mutation carriers with one affected first-degree relative are now considered eligible for surveillance. Experts agreed that preferred surveillance tests are endoscopic ultrasound and MRI/magnetic retrograde cholangiopancreatography, but no consensus was reached on how to alternate these modalities. Annual surveillance is recommended in the absence of concerning lesions. Main areas of disagreement included if and how surveillance should be performed for hereditary pancreatitis, and the management of indeterminate lesions.
CONCLUSIONS: Pancreatic surveillance is recommended for selected high-risk individuals to detect early pancreatic cancer and its high-grade precursors, but should be performed in a research setting by multidisciplinary teams in centres with appropriate expertise. Until more evidence supporting these recommendations is available, the benefits, risks and costs of surveillance of pancreatic surveillance need additional evaluation.

Keywords:  early detection; familial pancreatic cancer; genetic predisposition; pancreatic ductal adenocarcinoma; surveillance

DOI:  https://doi.org/10.1136/gutjnl-2019-319352
Oncotarget. 2019 Oct 15. 10(57): 5949-5957

Germline mutations in cancer-predisposition genes in patients with biliary tract cancer.

Takeshi Terashima, Kumiko Umemoto, Hideaki Takahashi, Hiroko Hosoi, Erina Takai, Shunsuke Kondo, Yasunari Sakamoto, Shuichi Mitsunaga, Izumi Ohno, Yusuke Hashimoto, Mitsuhito Sasaki, Masafumi Ikeda, Kazuaki Shimada, Shuichi Kaneko, Shinichi Yachida, Kokichi Sugano, Takuji Okusaka, Chigusa Morizane.

  The prevalence of germline mutations in patients with biliary tract carcinoma (BTC) remains unclear. Here, we investigated the prevalence and types of germline mutations in patients with BTC. We reviewed 269 patients with pathologically proven BTC and collected clinical characteristics, including medical and family histories. Additionally, we evaluated germline variants in 21 genes associated with hereditary predisposition for cancer by targeted sequencing in patients meeting ≥1 of the following criteria: 1) hereditary breast and/or ovarian cancer (HBOC) testing criteria modified for BTC, 2) Revised Bethesda Guidelines (RBGs) modified for BTC (modified RBG), 3) familial BTC criteria, or 4) young BTC criteria. Among the 269 patients, 80 met at least one criterion. Three pathogenic mutations in three patients were identified: two in BRCA2 and one in BRCA1. Among the 16 patients meeting modified HBOC testing criteria, 2 harbored germline BRCA2 mutations, and 1 harbored a germline BRCA1 mutation. However, no mutation in mismatch-repair genes were detected, despite 63 patients meeting modified RBG screening criteria and 18 qualifying as young BTC patients. We detected high prevalence of pathogenic germline mutations in BRCA1/2 and none in mismatch-repair genes in BTC patients following enrichment according to family or medical history in this study.

Keywords:  biliary tract cancer; cancer-predisposition genes; germline mutations; hereditary breast cancer syndrome; hereditary ovarian cancer syndrome

DOI:  https://doi.org/10.18632/oncotarget.27224
Hered Cancer Clin Pract. 2019 ;17 30

Genetic counselling and personalised risk assessment in the Australian pancreatic cancer screening program.

Tanya Dwarte, Skye McKay, Amber Johns, Katherine Tucker, Allan D Spigelman, David Williams, Alina Stoita.

   Background: Pancreatic cancer (PC) is an aggressive disease with a dismal 5-year survival rate. Surveillance of high-risk individuals is hoped to improve survival outcomes by detection of precursor lesions or early-stage malignancy.
Methods: Since 2011, a national high-risk cohort recruited through St Vincent's Hospital, Sydney, has undergone prospective PC screening incorporating annual endoscopic ultrasound, formal genetic counselling and mutation analysis as appropriate. PancPRO, a Bayesian PC risk assessment model, was used to estimate 5-year and lifetime PC risks for familial pancreatic cancer (FPC) participants and this was compared to their perceived chance of pancreatic and other cancers. Genetic counselling guidelines were developed to improve consistency. Follow-up questionnaires were used to assess the role of genetic counselling and testing.
Results: We describe the Australian PC screening program design and recruitment strategy and the results of the first 102 individuals who have completed at least one-year of follow-up. Seventy-nine participants met the FPC criteria (≥ two first-degree relatives affected), 22 individuals had both a BRCA2 pathogenic variant and a close relative with PC and one had a clinical diagnosis of Peutz-Jeghers syndrome. Participants reported a high perceived chance of developing PC regardless of their genetic testing status. PancPRO reported FPC participants' mean 5-year and lifetime PC risks as 1.81% (range 0.2-3.2%) and 10.17% (range 2.4-14.4%), respectively. Participants' perceived PC chance did not correlate with their PancPRO 5-year (r = - 0.17, p = 0.128) and lifetime PC risks (r = 0.19, p = 0.091). Two-thirds felt that current genetic testing would help them, and 91% of tested participants were glad to have undergone genetic testing. Overall, 79% of participants found genetic counselling to be helpful, and 88% reported they would recommend counselling to their relatives.
Conclusions: Participants reported multiple benefits of genetic counselling and testing but continue to seek greater clarification about their individual PC risk. Extension of PancPRO is required to enable personalised PC risk assessment for all high-risk sub-groups. More detailed discussion of PC risk for BRCA2 pathogenic variant carriers, providing a written summary in all cases and a plan for genetics review were identified as areas for improvement.

Keywords:  Endoscopic ultrasound; Genetic counselling; PancPRO; Pancreatic cancer screening; Personalised risk assessment

DOI:  https://doi.org/10.1186/s13053-019-0129-1
Cancer Genet. 2019 Oct 12. pii: S2210-7762(18)30559-3. [Epub ahead of print]240 1-4

ATM whole gene deletion in an Italian family with hereditary pancreatic cancer: Challenges to cancer risk prediction associated with an 11q22.3 microdeletion.

Heleen H Arts, Lorrie Lynch, Daria Grafodatskaya, Barry Eng, Lesley Malloy, John Duck, Robyn White, Crystal Woodside, Kathleen Bell, Kevin M Zbuk, Elizabeth McCready.

  Hereditary pancreatic cancer has been attributed to variants of several cancer predisposition genes including ATM. While heterozygous pathogenic variants in the ATM gene are implicated as a cause of familial breast and pancreatic cancers to our knowledge ATM whole gene deletions have not been previously reported. We describe a contiguous gene deletion of the ATM locus in a multi-generation family of Italian descent with a strong family history of pancreatic cancer. A deletion of one copy of the entire ATM gene was identified by routine panel testing and further characterized by chromosomal microarray analysis. An 11q22.3 microdeletion of approximately 960 kb was identified that is predicted to result in loss of 10 genes including ATM. The deletion was identified in two additional family members including a presymptomatic daughter and an affected sibling. A normal disomic complement of the 11q22.3 region was detected in a third family member with a history of prostate and pancreatic cancer. Additional family members were not available for testing. Given available evidence that ATM haploinsufficiency can increase cancer risk, we predict that the observed copy number loss has likely contributed to hereditary cancer in this family. However, absence of the familial microdeletion in at least one affected family member suggests that ATM deletions are unlikely the sole contributing factor influencing tumor development in affected individuals. This case highlights 11q22.3 microdeletions of the ATM gene region as a possible risk factor for hereditary cancer, including pancreatic cancer. The same case provides a further cautionary tale for over interpretation of cancer risk associated tumor suppressor microdeletions and suggests that the variant may not be sufficient for tumor development or may modify the cancer risks associated with other, yet unidentified hereditary cancer genes.

Keywords:  ATM; Hereditary cancer; Microdeletion; Pancreatic adenocarcinoma; SNP chromosomal microarray

DOI:  https://doi.org/10.1016/j.cancergen.2019.10.003
Int J Colorectal Dis. 2019 Oct 26.

Identification of a novel large EPCAM-MSH2 duplication, concurrently with LOHs in chromosome 20 and X, in a family with Lynch syndrome.

Francesca Pirini, Gianluca Tedaldi, Rita Danesi, Ilaria Cangini, Maria Maddalena Tumedei, Anna Ferrari, Silvia Vitali, Giulia De Maio, Carolina Terragna, Vincenza Solli, Michela Tebaldi, Maurizio Puccetti, Valentina Zampiga, Mila Ravegnani, Paola Ulivi, Fabio Falcini, Giovanni Martinelli, Daniele Calistri.

   BACKGROUND: Lynch syndrome (LS) is associated with germline mutations in one of the mismatch repair genes or EPCAM. The majority of the causative alterations are point mutations. Large genomic rearrangements represent only 5-20%. Hypothetically, the allelic imbalance, like the loss of heterozygosity, may be another high penetrance risk factor.
CASE PRESENTATION: We describe the case of a patient who developed 5 tumors during her lifetime and with a family history characterized by a high frequency of tumors associated with LS. The proband was tested for mutations and copy number alterations with a panel of hereditary cancer genes and by SNP array. She showed a 187 Kb duplication including EPCAM and the first 7 exons of MSH2, plus two loss of heterozygosity (LOHs) in chromosome 20 and one in chromosome X which include many tumor suppressor genes.
CONCLUSION: We found a novel large EPCAM-MSH2 duplication associated with LS and the presence of LOHs in regions containing numerous tumor suppressors, raising the hypothesis that these alterations could contribute to cancer susceptibility. Our results underline the importance to deepen the knowledge of molecular mechanisms in order to determine the role in cancer predisposition of novel genetic alterations.

Keywords:  EPCAM-MSH2 duplication; Loss of heterozygosity; Lynch syndrome; Multiple gene panel; Next-generation sequencing

DOI:  https://doi.org/10.1007/s00384-019-03414-y
Curr Treat Options Gastroenterol. 2019 Oct 31.

Hereditary or Not? Understanding Serrated Polyposis Syndrome.

Peter P Stanich, Rachel Pearlman.

   PURPOSE OF REVIEW: To present the current understanding of the diagnosis, management, and potential genetic causes of serrated polyposis syndrome.
RECENT FINDINGS: The clinical criteria for serrated polyposis syndrome was recently updated and now includes individuals with five or more serrated polyps proximal to the rectum that are 5 mm in size or greater and at least two that are 10 mm in size of greater as well as individuals with 20 or more serrated polyps throughout the colon with at least five proximal to the rectum. There is a significant risk for colon cancer in first-degree relatives of individuals with serrated polyposis syndrome. However, less than 3% of serrated polyposis syndrome cases are explained by identifiable germline mutations, with mutations in RNF43 being the only currently validated genetic cause. Serrated polyposis syndrome is rarely explained by identifiable germline mutations, but there remains an increased risk for colorectal cancer in first-degree relatives. Referral for genetic counseling and testing is recommended for individuals with serrated polyposis syndrome and a personal history of coexisting adenomatous polyposis or with a concerning family history and can be considered for all individuals with serrated polyposis syndrome. Close endoscopic surveillance of those with serrated polyposis syndrome and their first-degree relatives is recommended. Continued efforts at identifying hereditary causes of serrated polyposis are needed.

Keywords:  Colonic polyps; Human Genetics; Hyperplastic polyposis syndrome; Serrated polyposis syndrome

DOI:  https://doi.org/10.1007/s11938-019-00256-z
Genes (Basel). 2019 Oct 10. pii: E786. [Epub ahead of print]10(10):

Landscape of Germline Mutations in DNA Repair Genes for Breast Cancer in Latin America: Opportunities for PARP-Like Inhibitors and Immunotherapy.

Laura Keren Urbina-Jara, Augusto Rojas-Martinez, Emmanuel Martinez-Ledesma, Dione Aguilar, Cynthia Villarreal-Garza, Rocio Ortiz-Lopez.

  Germline mutations in BRCA1 and BRCA2 (BRCA1/2) genes are present in about 50% of cases of hereditary breast cancer. Proteins encoded by these genes are key players in DNA repair by homologous recombination (HR). Advances in next generation sequencing and gene panels for breast cancer testing have generated a large amount of data on gene variants implicated in hereditary breast cancer, particularly in genes such as PALB2, ATM, CHEK2, RAD51, MSH2, and BARD1. These genes are involved in DNA repair. Most of these variants have been reported for Caucasian, Jewish, and Asian population, with few reports for other communities, like those in Latin American (LA) countries. We reviewed 81 studies from 11 LA countries published between 2000 and 2019 but most of these studies focused on BRCA1/2 genes. In addition to these genes, breast cancer-related variants have been reported for PALB2, ATM, CHEK2, BARD1, MLH1, BRIP1, MSH2, NBN, MSH6, and PMS2 genes. Some of these variants are unique to LA populations. This analysis may contribute to enhance breast cancer variant characterization, and thus to find therapies and implement precision medicine for LA communities.

Keywords:  BRCA1; BRCA2; DNA repair; Latin America; PARP inhibitors therapy; breast cancer; germline

DOI:  https://doi.org/10.3390/genes10100786
Expert Rev Hematol. 2019 Oct 28.

Recent advances in genetic predisposition to pediatric acute lymphoblastic leukemia.

Mackenzie Bloom, Jamie L Maciaszek, Mary Egan Clark, Ching-Hon Pui, Kim E Nichols.

   INTRODUCTION: Historically, the majority of childhood cancers, including acute lymphoblastic leukemia (ALL), were not thought to have a hereditary basis. However, recent germline genomic studies have revealed that at least 5 - 10% of children with cancer (and approximately 3 - 4% of children with ALL) develop the disease due to an underlying genetic predisposition. Areas covered: This review discusses several recently identified ALL predisposing conditions and provides updates on other more well-established syndromes. It also covers topics related to the evaluation and management of children and family members at increased ALL risk. Expert opinion: Germline predisposition is gaining recognition as an important risk factor underlying the development of pediatric ALL. The challenge now lies in how best to capitalize on germline genetic information to improve ALL diagnosis, treatment, and perhaps even prevention.

Keywords:  Acute lymphoblastic leukemia (ALL); Familial studies; Genetic predisposition; Genome wide association studies (GWAS); Hematologic malignancy; Transcription factors

DOI:  https://doi.org/10.1080/17474086.2020.1685866
IUBMB Life. 2019 Nov 01.

Quantitative and qualitative impairments in GATA2 and myeloid neoplasms.

Ritsuko Shimizu, Masayuki Yamamoto.

  GATA2 is a key transcription factor critical for hematopoietic cell development. During the past decade, it became clear that heterozygous germline mutations in the GATA2 gene cause bone marrow failure and primary immunodeficiency syndrome, conditions that lead to a predisposition toward myeloid neoplasms, such as myelodysplastic syndrome, acute myeloid leukemia, and chronic myelomonocytic leukemia. Somatic mutations of the GATA2 gene are also involved in the pathogenesis of myeloid malignancies. Cases with GATA2 gene mutations are divided into two groups, resulting in either a quantitative deficiency or a qualitative defect in the GATA2 protein depending on the mutation position and type. In the former case, GATA2 mRNA expression from the mutant allele is markedly reduced or completely abrogated, and reduced GATA2 protein expression is involved in the pathogenesis. In the latter case, almost equal amounts of structurally abnormal and wildtype GATA2 proteins are predicted to be present and contribute to the pathogenesis. The development of mouse models of these human GATA2-related diseases has been undertaken, which naturally develop myeloid neoplasms.

Keywords:  GATA2; disease model mice; familial MDS/AML; quantitative or qualitative change

DOI:  https://doi.org/10.1002/iub.2188
Asia Pac J Clin Oncol. 2019 Oct 28.

Outcomes of women at high familial risk for breast cancer: An 8-year single-center experience.

Jacqueline Lammert, Anita R Skandarajah, Kylie Shackleton, Patricia Calder, Susan Thomas, Geoffrey J Lindeman, Gregory Bruce Mann.

   OBJECTIVES: The value of a high-risk surveillance program for mutation carriers and women at high familial breast cancer risk has not been extensively studied. A Breast and Ovarian Cancer Risk Management Clinic (BOCRMC) was established at the Royal Melbourne Hospital in 2010 to provide multimodality screening and risk management strategies for this group of women. The aims of this study were to evaluate the program and describe breast cancer diagnoses for BRCA1, BRCA2, and other germline mutation carriers as well as high-risk noncarriers attending the BOCRMC.
METHODS: Clinical data from mutation carriers and noncarriers with a ≥25% lifetime risk of developing breast cancer who attended between 2010 and 2018 were extracted from clinic records and compared. The pattern and mode of detection of cancer were determined.
RESULTS: A total of 206 mutation carriers and 305 noncarriers attended the BOCRMC and underwent screening on at least one occasion. Median age was 37 years. After a median follow-up of 34 months, 15 (seven invasive) breast cancers were identified in mutation carriers, with seven (six invasive) breast cancers identified in noncarriers. Of these, 20 (90.9%) were detected by annual screening, whereas two (9.1%) were detected as interval cancers (both in BRCA1 mutation carriers). Median size of the invasive breast cancers was 11 mm (range: 1.5-30 mm). The majority (76.9%) were axillary node negative. In women aged 25-49 years, the annualized cancer incidence was 1.6% in BRCA1, 1.4% in BRCA2 mutation carriers, and 0.5% in noncarriers. This compares to 0.06% annualized cancer incidence in the general Australian population.
CONCLUSIONS: Screening was effective at detecting early-stage cancers. The incidence of events in young noncarriers was substantially higher than in the general population. This potentially justifies ongoing management through a specialty clinic, although further research to better personalize risk assessment in noncarriers is required.

Keywords:  BRCA1 gene; BRCA2 gene; breast cancer screening; early detection of cancer; hereditary breast and ovarian cancer syndrome

DOI:  https://doi.org/10.1111/ajco.13274
Int J Environ Res Public Health. 2019 Oct 29. pii: E4168. [Epub ahead of print]16(21):

Regarding the Yin and Yang of Precision Cancer- Screening and Treatment: Are We Creating a Neglected Majority?

Colleen M McBride, Yue Guan, Jennifer L Hay.

  In this commentary, we submit that the current emphasis of precision cancer screening and treatment (PCST) has been to provide and interpret the implications of "positive" screening results for those deemed to be at greatest risk for cancer or most likely to benefit from targeted treatments. This is an important, but proportionately small target group, regardless of the cancer context. Overlooked by this focus is the larger majority of those screened who receive "negative" results. We contend that for optimal dissemination of PCST, the complement of positive and negative results be viewed as an inseparable yin-yang duality with the needs of those who receive negative screening results viewed as important as those deemed to be at highest risk or derive targeted treatment benefit. We describe three areas where communication of negative PCST results warrant particular attention and research consideration: population-based family history screening, germline testing for hereditary cancer syndromes, and tumor testing for targeted cancer treatment decision-making. Without thoughtful consideration of the potential for negative results to have psychological and behavioral influences, there is a potential to create a "neglected majority". This majority may be inclined to misinterpret results, disseminate inaccurate information to family, dismiss the credibility of results, or become disillusioned with existing medical treatments.

Keywords:  germline testing for hereditary cancer syndromes; health communication; negative results; population-based family history screening; precision cancer screening and treatment; tumor testing for targeted cancer therapies

DOI:  https://doi.org/10.3390/ijerph16214168
Hered Cancer Clin Pract. 2019 ;17 29

Prevalence and spectrum of MLH1, MSH2, and MSH6 pathogenic germline variants in Pakistani colorectal cancer patients.

Muhammad Usman Rashid, Humaira Naeemi, Noor Muhammad, Asif Loya, Jan Lubiński, Anna Jakubowska, Muhammed Aasim Yusuf.

   Background: Pathogenic germline variants in MLH1, MSH2 and MSH6 genes account for the majority of Lynch syndrome (LS). In this first report from Pakistan, we investigated the prevalence of pathogenic MLH1/MSH2/MSH6 variants in colorectal cancer (CRC) patients.
Methods: Consecutive cases (n = 212) were recruited at the Shaukat Khanum Memorial Cancer Hospital and Research Centre (SKMCH&RC), between November 2007 to March 2011. Patients with a family history of > 3 or 2 HNPCC-associated cancers were classified as HNPCC (n = 9) or suspected-HNPCC (n = 20), respectively (group 1; n = 29). Cases with no family history were designated as non-HNPCC (group 2; n = 183). MLH1/MSH2/MSH6 genes were comprehensively screened in group 1. Pathogenic/likely pathogenic variants identified in group 1 were subsequently evaluated in group 2.
Results: Eight distinct pathogenic/likely pathogenic MLH1/MSH2 variants were found in group 1 (10/29; 34.5%), belonging to HNPCC (5/9; 55.6%) and suspected-HNPCC (5/20; 25%) families and in group 2 (2/183; 1.1%) belonging to non-HNPCC. Overall, three recurrent variants (MSH2 c.943-1G > C, MLH1 c.1358dup and c.2041G > A) accounted for 58.3% (7/12) of all families harboring pathogenic/likely pathogenic MLH1/MSH2 variants. Pathogenic MSH6 variants were not detected.
Conclusion: Pathogenic/likely pathogenic MLH1/MSH2 variants account for a substantial proportion of CRC patients with HNPCC/suspected-HNPCC in Pakistan. Our findings suggest that HNPCC/suspected-HNPCC families should be tested for these recurrent variants prior to comprehensive gene screening in this population.

Keywords:  HNPCC; Likely pathogenic variants; MMR genes; Pakistan; Pathogenic variants; Suspected-HNPCC

DOI:  https://doi.org/10.1186/s13053-019-0128-2
Jpn J Clin Oncol. 2019 Oct 30. pii: hyz140. [Epub ahead of print]

Prevalence of Lynch syndrome among patients with upper urinary tract carcinoma in a Japanese hospital-based population.

Tetsuya Ito, Koji Kono, Hidetaka Eguchi, Yasushi Okazaki, Gou Yamamoto, Tetsuhiko Tachikawa, Kiwamu Akagi, Yohei Okada, Satoru Kawakami, Makoto Morozumi, Jun-Ichi Tamaru, Hideyuki Ishida.

   BACKGROUND: The prevalence of Lynch syndrome and the use of universal tumor screening to identify Lynch syndrome among unselected patients with upper urinary tract urothelial carcinoma, which is associated with Lynch syndrome, have not been closely investigated yet.
METHODS: A total of 166 tumors from 164 upper urinary tract urothelial carcinoma patients were tested for microsatellite instability and expression of mismatch repair proteins (MLH1, MHS2, MSH6 and PMS2) by immunohistochemistry. Genetic testing was performed for patients suspected of having Lynch syndrome. Clinicopathological factors, including familial and personal cancer history associated with mismatch repair deficiency, were evaluated.
RESULTS: The frequency of high-level microsatellite instability and loss of at least one mismatch repair protein was 2.4% (4/164); the microsatellite instability and immunohistochemistry results showed complete concordance. Of these four patients, three were genetically proven to have Lynch syndrome, while the remaining one was highly suggestive for Lynch syndrome based on their personal cancer history. Univariate analysis showed that age<70 years (P = 0.04), ureter as the tumor location (P = 0.052), previous history/synchronous diagnosis of colorectal cancer (P < 0.01) and fulfillment of the criteria per the revised Bethesda guideline (P < 0.01) tended to be or were significantly associated with high-level microsatellite instability/mismatch repair loss.
CONCLUSIONS: The prevalence of Lynch syndrome among unselected upper urinary tract urothelial carcinoma patients was at least 1.8% in our study population. The screening efficacies of the microsatellite instability test and immunohistochemistry appear equivalent. Universal tumor screening may be a valid approach; however, selective screening methods that consider factors associated with mismatch repair loss/high-level microsatellite instability tumors require further investigation.

Keywords:  Lynch syndrome; immunohistochemistry; microsatellite instability; mismatch repair deficiency; universal tumor screening; upper urinary tract urothelial carcinoma

DOI:  https://doi.org/10.1093/jjco/hyz140
BMC Cancer. 2019 Oct 29. 19(1): 1014

Metachronous ovarian endometrioid carcinomas in a patient with a PTEN variant: case report of incidentally detected Cowden syndrome.

Hiroyuki Matsubayashi, Satomi Higashigawa, Yoshimi Kiyozumi, Yasue Horiuchi, Yasuyuki Hirashima, Nobuhiro Kado, Masato Abe, Takuma Ohishi, Sumiko Ohnami, Kenichi Urakami, Ken Yamaguchi.

   BACKGROUND: Somatic PTEN mutation occurs in a proportion of ovarian endometrioid carcinomas. However, these cancers have seldom been reported in diseases associated with germline PTEN variants, such as Cowden syndrome (CS).
CASE PRESENTATION: The present case was a 39-year-old woman with a left ovarian carcinoma who demonstrated a germline splice variant of PTEN (c.1026 + 1G > T) following genome-wide whole exome sequencing of her germline DNA. Histology of her resected tumor revealed endometrioid carcinoma of the same type as a right ovarian cancer resected eight years previously. These tumors showed null immunostaining for PTEN. She was genetically diagnosed with CS. Despite her clinical examinations had demonstrated several characteristic findings of CS, including mammary fibroma, esophageal and skin papilloma, colonic hamartoma, uterine myoma, and lipoma, the clinicians could not approach this diagnosis.
CONCLUSION: Ovarian endometrioid carcinoma is generally thought to develop from endometrial tissue menstruated from the uterus and implanted on the ovary. To date, ovarian cancers have not been listed as CS-related cancers; however, ovarian endometrioid cancer can have a potential association with CS in endometriosis cases.

Keywords:  Endometrioid carcinoma; Germline variant; Ovarian; PTEN

DOI:  https://doi.org/10.1186/s12885-019-6272-2
Pathol Oncol Res. 2019 Oct 26.

Review: Ewing Sarcoma Predisposition.

Pablo Gargallo, Yania Yáñez, Antonio Juan, Vanessa Segura, Julia Balaguer, Bárbara Torres, Silves Oltra, Victoria Castel, Adela Cañete.

  Ewing sarcoma is a rare tumor developed in bone and soft tissues of children and teenagers. This entity is biologically led by a chromosomal translocation, typically including EWS and FLI1 genes. Little is known about Ewing sarcoma predisposition, although the role of environmental factors, ethnicity and certain polymorphisms on Ewing sarcoma susceptibility has been studied during the last few years. Its prevalence among cancer predisposition syndromes has also been thoroughly examined. This review summarizes the available evidence on predisposing factors involved in Ewing sarcoma susceptibility. On the basis of these data, an integrated approach of the most influential factors on Ewing sarcoma predisposition is proposed.

Keywords:  Cancer predisposition; Ewing sarcoma; Genetic susceptibility; Polymorphism

DOI:  https://doi.org/10.1007/s12253-019-00765-3
Frontline Gastroenterol. 2019 Oct;10(4): 379-387

Practical management of polyposis syndromes.

Roshani Patel, Warren Hyer.

  Hereditary bowel tumours are usually part of a distinct syndrome which require management of both intestinal and extra-intestinal disease. Polyposis syndromes include: Familial adenomatous polyposis, MUTYH-associated polyposis, Serrated polyposis syndrome, Peutz-Jeghers syndrome, Juvenile polyposis syndrome and PTEN-hamartomatous syndromes. Of all colorectal cancers (CRC), 5%-10% will be due to an underlying hereditary CRC syndrome. Diagnosis and management of polyposis syndromes is constantly evolving as new scientific and technological advancements are made with respect to identifying causative genes and increased sophistication of endoscopic therapy to treat polyps. This, in addition to data yielded from meticulous record-keeping by polyposis registries has helped to guide management in what are otherwise relatively rare conditions. These data help guide clinical management of patients and their 'at-risk' relatives. Diagnosis is both genetic where possible but clinical recognition is key in the absence of an identifiable causative gene. Furthermore, some syndromes can overlap which can additionally complicate diagnosis. The principle goals of polyposis management are first to manage and treat the presenting patient and then to identify 'at-risk' patients, through screening and predictive genetic testing, endoscopic surveillance to allow therapy and guide surgical prophylaxis. Due to the complexity of diagnosis and management, patients and their families should be referred to a genetics centre or a polyposis registry where dedicated management can take place.

Keywords:  familial adenomatous polyposis; polyposis

DOI:  https://doi.org/10.1136/flgastro-2018-101053
Eur J Endocrinol. 2019 Oct 01. pii: EJE-19-0602.R1. [Epub ahead of print]

GENETICS IN ENDOCRINOLOGY: Somatic and germline mutations in the pathogenesis of pituitary adenomas.

Silvia Vandeva, Adrian F Daly, Patrick Petrossians, Sabina Zacharieva, Albert Beckers.

Pituitary adenomas are frequently occurring neoplasms that produce clinically significant disease in 1:1000 of the general population. The pathogenesis of pituitary tumors has been a matter of interest as it could help to improve diagnosis and treatment. Until recently, however, disruptions in relatively few genes had been shown to predispose to pituitary tumor formation. In the last decade several more genes and pathways have been described. Germline pathogenic variants in the aryl hydrocarbon receptor- interacting protein (AIP) gene were found in familial or sporadic pituitary adenomas, usually with an aggressive clinical course. Cyclin-dependent kinase inhibitor 1B (CDKN1B) pathogenic variants lead to multiple endocrine neoplasia type 4 (MEN4) syndrome, in which pituitary adenomas can occur. Xq26.3 duplications involving the gene GPR101 cause X-linked acrogigantism. The pheochomocytoma and/or paraganglioma with pituitary adenoma association (3PAs) syndrome suggest that pathogenic variants in the genes of the succinate dehydrogenase complex or MYC-associated factor X (MAX) might be involved in pituitary tumorigenesis. New recurrent somatic alterations were also discovered in pituitary adenomas, such as, ubiquitin specific protease 8 (USP8) and USP48 pathogenic variants in corticotropinomas. The aim of the present review is to provide an overview on the genetic pathophysiology of pituitary adenomas and their clinical relevance.

DOI: https://doi.org/10.1530/EJE-19-0602
Acta Derm Venereol. 2019 Oct 30.

Hereditary Leiomyomatosis and Renal Cell Cancer.

Anders Würgler Hansen, Zahràa Riyadh Abed Chayed, Kristine Pallesen, Ileana Codruta Vasilescu, Anette Bygum.

  Hereditary leiomyomatosis and renal cell cancer is a genodermatosis with an autosomal dominant inheritance pattern. It is a tumour predisposition syndrome characterized by cutaneous and uterine leiomyomas, and increased susceptibility to develop renal cell cancer. There are 200-300 families with hereditary leiomyomatosis and renal cell cancer reported worldwide, but the syndrome is believed to be underdiagnosed. Cutaneous leiomyomas are small smooth muscle tumours that tend to grow over time. Larger lesions, in particular, can cause pain or itching. Uterine leiomyomas are highly penetrant feature in women with hereditary leiomyomatosis and renal cell cancer. They frequently cause symptoms and surgical intervention is often necessary. Hereditary leiomyomatosis and renal cell cancer-associated renal cell cancer has a high potential to metastasize. Patients are diagnosed by genetic testing if a pathogenic mutation is demonstrated in the gene encoding fumarate hydratase. Immunohistochemistry may be a useful diagnostic approach in patients without a detectable pathogenic mutation. Diagnosed patients should be monitored for renal tumours in a lifelong surveillance programme.

Keywords:   cancer surveillance; cutaneous leiomyomas; renal cell cancer; uterine leiomyomas; hereditary leiomyomatosis

DOI:  https://doi.org/10.2340/00015555-3366
Gene. 2019 Oct 26. pii: S0378-1119(19)30836-4. [Epub ahead of print] 144177

A novel splice site variant in ANOS1 gene leads to Kallmann syndrome in three siblings.

Xiaohui Jiang, Dingming Li, Yanzi Gao, Xueguang Zhang, Xiang Wang, Yihong Yang, Ying Shen.

  Idiopathic hypogonadotropic hypogonadism (IHH) is a rare genetic disease caused by low doses of hypothalamic gonadotropin-releasing hormone (GnRH), leading to absence or delayed sexual development. Kallmann syndrome (KS) is characterized by IHH with anosmia or hyposmia. Here, we identified a novel splice site variant (c. 726+2T>G) of ANOS1 gene in three siblings with KS from a Chinese Han family by whole-exome sequencing (WES). In this family, KS is classified as an X-linked recessive inheritance pattern. This mutation was inherited from the mother by Sanger sequencing. An in vitro functional experiment has identified the deleterious effect of this mutation on the transcriptional level of ANOS1 gene. Importantly, the effectiveness of timely hormone replacement therapy was evaluated on the three siblings. Hence, finding genetic causes could be helpful in the early diagnosis and timely treatment of KS.

Keywords:  ANOS1 gene; Kallmann syndrome; idiopathic hypogonadotropic hypogonadism; mutation; whole exome sequencing

DOI:  https://doi.org/10.1016/j.gene.2019.144177
Neuroendocrinology. 2019 Oct 28.

Germline missense mutation of Deleted in malignant brain tumor 1 (DMBT1) in familial mediastinal neuroendocrine cancer and in vitro effects in thyroid cancer cells.

Ning Qu, Rong-Liang Shi, Tian Liao, Sheng-Lin Huang, Duo Wen, Jia-Qian Hu, Ting-Ting Zhang, Li-Tao Han, Ben Ma, Jian Wang, Yu-Long Wang, Yu Wang, Qing-Hai Ji.

BACKGROUND: Neuroendocrine tumor (NET) rarely occurs in the mediastinum and the etiology and pathogenesis are still unclear.
OBJECTIVES: This study assessed inherited or de novo mutations in familial mediastinal NETs.
METHOD: DNA samples from four persons were subjected to the whole-exome sequencing, and Sanger sequencing was used to identify Deleted in malignant brain tumor 1 (DMBT1) mutations in all 45 family members.
RESULTS: All patients showed a germline DMBT1 mutation at 4971C. Sanger sequencing data showed that four NETs and two carriers in the first patient family had this DMBT1 mutation, and two NETs and four carriers in the second patient family had this DMBT1 mutation. The in vitro data showed that ectopic expression of DMBT1 reduced tumor cell viability and migration by arresting the G1/S phase of cell cycle.
CONCLUSIONS: The data from current study identified a germline missense mutation in DMBT1D1657E as a susceptibility gene for familial mediastinal NETs.

DOI: https://doi.org/10.1159/000504369
Prostate. 2019 Oct 30.

Clinical and pathologic characteristics of familial prostate cancer in Asian population.

Myong Kim, Jung Kwon Kim, Changhee Ye, Hakmin Lee, Jong Jin Oh, Sangchul Lee, Seong Jin Jeong, Sang Eun Lee, Sung Kyu Hong, Seok-Soo Byun.

   BACKGROUND: We investigated prevalence of familial and hereditary prostate cancer (PCa) in Asian population, and compared clinical characteristics between familial and sporadic disease.
METHODS: Pedigrees of 1102 patients who were treated for PCa were prospectively acquired. Clinical and pathologic characteristics and biochemical recurrence (BCR)-free survival were compared between familial PCa and sporadic PCa in patients who underwent radical prostatectomy (RP; n = 751).
RESULTS: The prevalence of familial, first-degree familial, and hereditary PCa was found to be 8.4%, 6.7%, and 0.9%, respectively; similar result was obtained in patients who underwent RP (8.4%, 6.4%, and 0.9%). Patients with familial PCa were significantly younger than those with sporadic PCa (63.3 vs 65.6 years; P = .015). However, preoperative variables (prostate-specific antigen, clinical stage, biopsy Gleason score [GS], and percentage of positive biopsy cores) and postoperative variables (surgical GS, upgrading rate, pathologic stage, and percentage of tumor volume) did not correlate with family history (P range: .114-.982). Kaplan-Meier analysis of 5-year BCR-free survival revealed no significant difference between sporadic (82.7%), familial (89.4%; P = .594), and first-degree familial (87.1%; P = .774) PCa. Analysis of p53, Bcl-2, Ki67, and other immunohistochemistry biomarkers revealed that only increasing p53 expression and first-degree familial PCa approached significance (P = .059).
CONCLUSION: The prevalence of familial PCa was somewhat lower in the Asian population than in other ethnic groups. Clinical and pathologic variables and selected histologic biomarker abnormalities were not significantly different in patients with and without a family history of PCa. BCR-free survival following RP was also unaffected by family history.

Keywords:  clinical characteristics; familial; hereditary; pathologic characteristics; prostate cancer

DOI:  https://doi.org/10.1002/pros.23917
Rom J Morphol Embryol. 2019 ;60(2): 353-367

Do we know enough about the genetic involvement in laryngeal cancer susceptibility and prognostic outcome?

Corina Iulia Cornean, Marcel Cosgarea, Andreea Cătană, Carmen Aurelia Mogoantă, Violeta Necula, Alma Aurelia Maniu.

INTRODUCTION: Advances in molecular biology have opened the door to a wide range of research material through the usage of genetic testing on certain variables within the human genome known as single-nucleotide polymorphisms (SNPs).The purpose of this article is to present a review on the influence variants within SNPs have on the outcome of laryngeal cancer when associated with different variables, such as external toxins or survival rate. Amongst these toxins, the most frequent and most studied have been alcohol and tobacco consumption, with a proven increased rate of overall cancer risk within the aero-digestive tract.
MATERIALS AND METHODS: The review was realized utilizing available studies on the subject of genetic polymorphisms analysis of deoxyribonucleic acid (DNA) samples using polymerase chain reaction (PCR) assays and laryngeal cancer published in the PubMed database.
RESULTS: Statistical analysis of 262 polymorphisms shows a predominantly positive association between two genetic variants of the human genome (mutant homozygote and heterozygote) and cancer risk with significant influence on patient outcome and survival. Genotype combinations were divided into two categories depending on the individual 'at risk' and 'protective' allele within the loci of each inherited gene block. Amongst the genes involved with aero-digestive cancers, the most studied were those belonging to the xenobiotic metabolism, nucleotide excision repair (NER) and DNA repair pathways. The presence of toxins has a distinct cumulative effect within the genotype-phenotype relationship, which further influences the presence of malignancy depending on the adaptability of each individual genome.
CONCLUSIONS: Laryngeal cancer evolution is linked to inherited risk factors found within the genetic code. Most studied were the genes belonging to NER pathways, DNA repair and xenobiotic metabolism, which all favored mutant homozygote and heterozygote variants, as high risk factors. Only five articles focused on overall survival rates with insufficient results to undisputedly predict the risk variants. The consumption of external toxins has a positive effect on the overall cancer risk in consumers. Most articles affirmed further evaluation or replication was needed in a larger scale population to conclusively validate their results.