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Comparison of universal screening in major lynch-associated tumors: a systematic review of literature Fam. Cancer (IF 1.76) Pub Date : 2021-01-11 George Kunnackal John, Vipin Das Villgran, Christine Caufield-Noll, Francis M. Giardiello
Lynch syndrome (LS) is associated with an increased lifetime risk of several cancers including colorectal (CRC), endometrial (EC), ovarian (OC), urinary (UT) and sebaceous tumors (ST). The benefit for universal screening in CRC and EC is well known. However, this benefit in other major lynch-associated tumors is unclear. We performed a systematic review of all published articles in the MEDLINE database
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Genetic evaluation of patients and families with concern for hereditary endocrine tumor syndromes Fam. Cancer (IF 1.76) Pub Date : 2021-01-07 Jennifer L. Anderson, Robert Pilarski, Lawrence Kirschner, Pamela Brock
Hereditary endocrine tumor syndromes are rare conditions with overlapping features. It is imperative that healthcare providers differentiate between these syndromes for proper patient care. Advances in genetic testing technologies have increased utilization of genetic counseling and testing in this field; however, few endocrine cancer genetics clinics exist. Two years ago, a genetic counselor (GC)
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Correction to: Infantile fibrosarcoma with TPN3-NTRK3 fusion in a boy with Bloom Syndrome Fam. Cancer (IF 1.76) Pub Date : 2021-01-06 Sue M. Huson, Timo Staab, Marta Pereira, Heather Ward, Roberto Paredes, D. Gareth Evans, Daniel Baumhoer, James O’Sullivan, Ed Cheesman, Detlev Schindler, Stefan Meyer
In the original article it was not clear that the senior authorship of this report is shared by D Schindler and S Meyer, reflecting the contributions made. The senior authorship should now be recognised as being shared.
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Atypical choroidal nevus in a subject with a germline PALB2 pathogenic variant Fam. Cancer (IF 1.76) Pub Date : 2021-01-06 Timothy W. Grosel, Matthew Karl, Robert T. Pilarski, Frederick H. Davidorf, Mohamed H. Abdel-Rahman, Colleen M. Cebulla
Recent evidence suggests that PALB2 variants may increase risk for the development of uveal melanoma and uveal melanocytic neoplasms. Here we report a case of an atypical choroidal nevus in a patient with a personal history of cancer and pathogenic PALB2 germline variant. A 75-year-old white female presented with an elevated predominantly amelanotic choroidal lesion OS. On examination and ophthalmic
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Hereditary medullary thyroid carcinoma syndromes: experience from western India Fam. Cancer (IF 1.76) Pub Date : 2021-01-04 Chakra Diwaker, Vijaya Sarathi, Sanjeet Kumar Jaiswal, Ravikumar Shah, Anuja Deshmukh, Anand Ebin Thomas, Gagan Prakash, Gaurav Malhotra, Virendra Patil, Anurag Lila, Nalini Shah, Tushar Bandgar
The data from the Indian subcontinent on Medullary thyroid carcinoma (MTC) and associated endocrinopathies in hereditary MTC (HMTC) syndromes are limited. Hence, we analyzed clinical and biochemical characteristics, management, and outcomes of HMTC and other associated endocrinopathies [Pheochromocytoma (PCC) and Primary hyperparathyroidism (PHPT)] and compared with apparently sporadic MTC. The records
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Infantile fibrosarcoma with TPM3-NTRK1 fusion in a boy with Bloom syndrome Fam. Cancer (IF 1.76) Pub Date : 2020-11-21 Sue M. Huson, Timo Staab, Marta Pereira, Heather Ward, Roberto Paredes, D. Gareth Evans, Daniel Baumhoer, James O’Sullivan, Ed Cheesman, Detlev Schindler, Stefan Meyer
Bloom syndrome (BS) is a genomic and chromosomal instability disorder with prodigious cancer predisposition caused by pathogenic variants in BLM. We report the clinical and genetic details of a boy who first presented with infantile fibrosarcoma (IFS) at the age of 6 months and subsequently was diagnosed with BS at the age of 9 years. Molecular analysis identified the pathogenic germline BLM sequence
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Efficacy of paired tumor and germline testing in evaluation of patients with Lynch-like syndrome in a large integrated healthcare setting Fam. Cancer (IF 1.76) Pub Date : 2020-11-20 Holly Carwana, Elizabeth Hoodfar, JoAnn Bergoffen, Dan Li
Patients with mismatch repair (MMR) deficient colorectal cancer (CRC) without detectable germline pathogenic variants (PVs) or likely pathogenic variants (LPVs) in MMR genes are often labeled as Lynch-like syndrome (LLS). We sought to evaluate the efficacy of paired tumor and germline testing in risk stratification of patients with LLS in a large, community-based, integrated healthcare setting. Through
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Early-onset malignant phyllodes breast tumor in a patient with germline pathogenic variants in NF1 and BRCA1 genes Fam. Cancer (IF 1.76) Pub Date : 2020-11-19 Francesca Gensini, Roberta Sestini, Alessandro De Luca, Valentina Pinna, Paola Daniele, Lorenzo Orzalesi, Maria Cristina Petrella, Berardino Porfirio, Laura Papi
We present a 24-year-old female patient affected by neurofibromatosis type 1 (NF1) who developed a malignant phyllodes tumor of the breast. The molecular studies showed that the patient carried a heterozygous inactivating deleterious variant in BRCA1 inherited from the father associated with a germline de novo pathogenic alteration in NF1; the tumor presented a biallelic inactivation of both genes
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Age at diagnosis of cancer in 185delAG BRCA1 mutation carriers of diverse ethnicities: tentative evidence for modifier factors Fam. Cancer (IF 1.76) Pub Date : 2020-11-09 Yael Laitman, Rachel Michaelson-Cohen, Rakefet Chen-Shtoyerman, Yael Goldberg, Orit Reish, Rinat Bernstein-Molho, Ephrat Levy-Lahad, Noa Ephrat Ben Baruch, Inbal Kedar, D. Gareth Evans, Sara Haim, Shani Paluch-Shimon, Eitan Friedman
Germline pathogenic sequence variants (PSVs) in BRCA1 substantially increase risk for developing breast (BC) and ovarian cancer (OvC). Yet, incomplete penetrance suggests that modifier factors affect phenotypic expression of mutant BRCA1 alleles. Analysis of identical BRCA1 PSV carriers of diverse ethnicities may provide further evidence for modifier factors. Female carriers of the 185delAG BRCA1 PSV
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Identification and management of Lynch syndrome in the Middle East and North African countries: outcome of a survey in 12 countries Fam. Cancer (IF 1.76) Pub Date : 2020-10-24 Mohammad Sina, Zeinab Ghorbanoghli, Amal Abedrabbo, Fahd Al-Mulla, Rihab Ben Sghaier, Marie-Pierre Buisine, George Cortas, Ladan Goshayeshi, Andreas Hadjisavvas, Wail Hammoudeh, Waseem Hamoudi, Carol Jabari, Maria A. Loizidou, Keivan Majidzadeh-A, Makia J. Marafie, Gurbankhan Muslumov, Laila Rifai, Rania Abu Seir, Suzan M. Talaat, Berrin Tunca, Hadia Ziada-Bouchaar, Mary E. Velthuizen, Ala I. Sharara
Background Lynch syndrome (LS), the most common inherited form of colorectal cancer (CRC), is responsible for 3% of all cases of CRC. LS is caused by a mismatch repair gene defect and is characterized by a high risk for CRC, endometrial cancer and several other cancers. Identification of LS is of utmost importance because colonoscopic surveillance substantially improves a patient’s prognosis. Recently
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A novel germline variant in RET gene resulting in an additional cysteine in a family with familial medullary thyroid carcinoma Fam. Cancer (IF 1.76) Pub Date : 2020-10-21 Josep Oriola, Aurora Sanchez, Blanca Paniello, Jordi Puig de la Bellacasa, Josefina Biarnés
Multiple endocrine neoplasia type 2 (MEN 2) is an autosomal dominant inherited disease, characterized by germ-line variants in RET proto-oncogene. Variants are frequently located in the RET extracellular cysteine-rich region domain, mainly affecting cysteines which are replaced by an alternative amino acid, resulting in a mispaired cysteine and the generation of RET dimers. We describe a novel c.1765A > T
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Frequency and spectrum of mutations across 94 cancer predisposition genes in African American women with invasive breast cancer Fam. Cancer (IF 1.76) Pub Date : 2020-10-21 Leann A. Lovejoy, Seth K. Rummel, Clesson E. Turner, Craig D. Shriver, Rachel E. Ellsworth
African American women are at increased risk of being diagnosed at a young age and/or with triple negative breast cancer, both factors which are included in current guidelines for identifying women who may benefit from genetic testing. Commercial breast cancer predisposition genetic panels, based largely on data derived from women of European ancestry, may not capture the full spectrum of cancer predisposition
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The role of TP53 pathogenic variants in early-onset HER2-positive breast cancer Fam. Cancer (IF 1.76) Pub Date : 2020-10-14 Carla Escudeiro, Carla Pinto, Joana Vieira, Ana Peixoto, Pedro Pinto, Manuela Pinheiro, Catarina Santos, Joana Guerra, Susana Lisboa, Rui Santos, João Silva, Conceição Leal, Nuno Coimbra, Paula Lopes, Marco Ferreira, Ana B. Sousa, Manuel R. Teixeira
Breast cancer is the most frequent event in Li-Fraumeni syndrome associated with germline TP53 variants. Some studies have shown that breast cancers in women with Li-Fraumeni syndrome are commonly HER2-positive, suggesting that HER2 amplification or over-expression in a young woman may be a useful criterion to test for germline variants in the TP53 gene. We assessed the prevalence of germline TP53
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Discordant DNA mismatch repair protein status between synchronous or metachronous gastrointestinal carcinomas: frequency, patterns, and molecular etiologies Fam. Cancer (IF 1.76) Pub Date : 2020-10-09 Monika Vyas, Canan Firat, Jaclyn F. Hechtman, Martin R. Weiser, Rona Yaeger, Chad Vanderbilt, Jamal K. Benhamida, Ajaratu Keshinro, Liying Zhang, Peter Ntiamoah, Marco Gonzalez, Rebecca Andrade, Imane El Dika, Arnold J. Markowitz, J. Joshua Smith, Julio Garcia-Aguilar, Efsevia Vakiani, David S. Klimstra, Zsofia K. Stadler, Jinru Shia
The widespread use of tumor DNA mismatch repair (MMR) protein immunohistochemistry in gastrointestinal tract (GIT) carcinomas has unveiled cases where the MMR protein status differs between synchronous/metachronous tumors from the same patients. This study aims at examining the frequency, patterns and molecular etiologies of such inter-tumoral MMR discordances. We analyzed a cohort of 2159 colorectal
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FRAMe: Familial Risk Assessment of Melanoma—a risk prediction tool to guide CDKN2A germline mutation testing in Australian familial melanoma Fam. Cancer (IF 1.76) Pub Date : 2020-09-29 Elizabeth A. Holland, Serigne Lo, Blake Kelly, Helen Schmid, Anne E. Cust, Jane M. Palmer, Martin Drummond, Nicholas K. Hayward, Antonia L. Pritchard, Graham J. Mann
Germline mutations in CDKN2A greatly increase risk of developing cutaneous melanoma. We have constructed a risk prediction model, Familial Risk Assessment of Melanoma (FRAMe), for estimating the likelihood of carrying a heritable CDKN2A mutation among Australian families, where the prevalence of these mutations is low. Using logistic regression, we analysed characteristics of 299 Australian families
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New surveillance guidelines for Li-Fraumeni and hereditary TP53 related cancer syndrome: implications for germline TP53 testing in breast cancer. Fam. Cancer (IF 1.76) Pub Date : 2020-09-28 D Gareth Evans,Emma R Woodward
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Patient reported experiences following laparoscopic prophylactic bilateral salpingo-oophorectomy or salpingectomy in an ambulatory care hospital. Fam. Cancer (IF 1.76) Pub Date : 2020-09-23 Rachel Trister,Michelle Jacobson,Patricia Nguyen,Mara Sobel,Lisa Allen,Steven A Narod,Joanne Kotsopoulos
Women at risk of developing ovarian cancer because of a BRCA1 or BRCA2 pathogenic variant are candidates for prophylactic bilateral salpingo-oophorectomy (BSO). While BSO surgeries are routinely performed, to our knowledge there are no studies that have examined patient-reported experiences following laparoscopic BSO performed in an ambulatory care setting. The objective of this study was to examine
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Quantitative evaluation of MSI testing using NGS detects the imperceptible microsatellite changed caused by MSH6 deficiency. Fam. Cancer (IF 1.76) Pub Date : 2020-09-19 Gou Yamamoto,Takashi Takenoya,Akemi Takahashi,Yukiko Osanai,Miho Kakuta,Tetsuhiko Tachikawa,Takanori Washio,Masato Kamiyama,Michio Shiibashi,Shigeki Yamaguchi,Kiwamu Akagi
Microsatellite instability (MSI) is an effective biomarker for diagnosing Lynch syndrome (LS) and predicting the responsiveness of cancer therapy. MSI testing is conventionally performed by capillary electrophoresis, and MSI status is judged by visual assessment of allele size change. Here, we attempted to develop a quantitative evaluation model of MSI using next-generation sequencing (NGS). Microsatellite
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Prevalence of pancreaticobiliary cancers in Irish families with pathogenic BRCA1 and BRCA2 variants. Fam. Cancer (IF 1.76) Pub Date : 2020-09-12 Robert Power,Cristin Leavy,Carmel Nolan,Niamh White,Roisin Clarke,Karen A Cadoo,David James Gallagher,Maeve Aine Lowery
Pathogenic variants (PVs) in the BRCA1 and BRCA2 genes are associated with an increased lifetime risk of pancreatic ductal adenocarcinoma (PDAC), and more recently have been associated with increased risk of biliary tract cancers (BTC). This study assessed the prevalence, age and gender distribution of PDAC/BTC cases in families known to carry a BRCA1/2 PV compared to those of the Irish population
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Worldwide variation in lynch syndrome screening: case for universal screening in low colorectal cancer prevalence areas. Fam. Cancer (IF 1.76) Pub Date : 2020-09-11 George Kunnackal John,Vipin Das Villgran,Christine Caufield-Noll,Francis Giardiello
To perform a systematic assessment of universal Lynch syndrome (LS) screening yield in colorectal cancer (CRC) patients around the world. Universal screening for LS is recommended in all CRC patients. However, the variation in yield of LS screening in the setting of significant global variation in CRC prevalence is unknown. A systematic review of articles in the MEDLINE database was performed to identify
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Genetic testing and surveillance in infantile myofibromatosis: a report from the SIOPE Host Genome Working Group. Fam. Cancer (IF 1.76) Pub Date : 2020-09-05 Simone Hettmer,Guillaume Dachy,Guido Seitz,Abbas Agaimy,Catriona Duncan,Marjolijn Jongmans,Steffen Hirsch,Iris Kventsel,Uwe Kordes,Ronald R de Krijger,Markus Metzler,Orli Michaeli,Karolina Nemes,Anna Poluha,Tim Ripperger,Alexandra Russo,Stephanie Smetsers,Monika Sparber-Sauer,Eveline Stutz,Franck Bourdeaut,Christian P Kratz,Jean-Baptiste Demoulin
Infantile myofibromatosis (IM), which is typically diagnosed in young children, comprises a wide clinical spectrum ranging from inconspicuous solitary soft tissue nodules to multiple disseminated tumors resulting in life-threatening complications. Familial IM follows an autosomal dominant mode of inheritance and is linked to PDGFRB germline variants. Somatic PDGFRB variants were also detected in solitary
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Clinical phenotypes combined with saturation genome editing identifying the pathogenicity of BRCA1 variants of uncertain significance in breast cancer. Fam. Cancer (IF 1.76) Pub Date : 2020-08-17 Qiting Wan,Li Hu,Tao Ouyang,Jinfeng Li,Tianfeng Wang,Zhaoqing Fan,Tie Fan,Benyao Lin,Ye Xu,Yuntao Xie
Characterizing the pathogenicity of BRCA1 variants of uncertain significance (VUSs) is a major bottleneck in clinical management of BRCA1-associated breast cancer. Saturation genome editing (SGE) was recently reported as an innovative laboratory-based approach to assess the pathogenicity of BRCA1 variants. We combined clinical phenotypes and SGE score to identify the pathogenicity of BRCA1 VUSs detected
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Is a colorectal neoplasm diagnosis a trigger to change dietary and other lifestyle habits for persons with Lynch syndrome? A prospective cohort study. Fam. Cancer (IF 1.76) Pub Date : 2020-08-08 Jesca G M Brouwer,Merel Snellen,Tanya M Bisseling,Jan Jacob Koornstra,Hans F A Vasen,Ellen Kampman,Fränzel J B van Duijnhoven
A cancer diagnosis is suggested to be associated with changes in dietary and lifestyle habits. Whether this applies to persons with familial cancer, such as Lynch syndrome (LS) is unknown. We investigated whether a colorectal neoplasm (CRN) diagnosis in persons with LS is associated with changes in dietary and lifestyle habits over time. We used data of confirmed LS mutation carriers from the GEOLynch
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Recent advances in Lynch syndrome. Fam. Cancer (IF 1.76) Pub Date : 2020-08-08 Pål Møller,Julian Sampson,Mev Dominguez-Valentin,John Burn,Lone Sunde,Gabriela Möslein,Jukka-Pekka Mecklin,Toni Seppälä
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Barriers and facilitators to CDH1 carriers contemplating or undergoing prophylactic total gastrectomy. Fam. Cancer (IF 1.76) Pub Date : 2020-08-05 Kaitlin M McGarragle,Tae L Hart,Carol Swallow,Savtaj Brar,Anand Govindarajan,Zane Cohen,Melyssa Aronson
Hereditary diffuse gastric cancer (HDGC) is an inherited cancer syndrome associated with high lifetime risk of diffuse-type gastric cancer. Current guidelines recommend individuals with HDGC undergo prophylactic total gastrectomy (PTG) to eliminate this risk. However, PTG is associated with significant lifestyle changes, post-surgical recovery, and symptom burden. This study examined factors related
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Characterizing germline APC and MUTYH variants in Ashkenazi Jews compared to other individuals. Fam. Cancer (IF 1.76) Pub Date : 2020-08-03 Chinedu Ukaegbu,Zohar Levi,Tara D Fehlmann,Hajime Uno,Anu Chittenden,Jennifer A Inra,Shilpa Grover,Fay Kastrinos,Sapna Syngal,Matthew B Yurgelun
Germline variants in the APC and MUTYH genes contribute to colorectal cancer (CRC) and adenoma risk, though may occur with varying frequencies in individuals of different ancestries. The aim of this study was to evaluate the prevalence of APC, monoallelic MUTYH and biallelic MUTYH germline variants in Ashkenazi Jewish (AJ) and Other Ancestry (OA) individuals with colorectal adenomas. We studied 7225
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Recent advances in Lynch syndrome: response to Møller et al. Fam. Cancer (IF 1.76) Pub Date : 2020-08-03 Leah H Biller,Sapna Syngal,Matthew B Yurgelun
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Multiple primary cancers (renal papillary, lymphoma and teratoma) and hepatic cysts in association with a pathogenic germline mutation in the MET gene. Fam. Cancer (IF 1.76) Pub Date : 2020-07-20 Julian Adlard
Activating germline mutations of the MET gene are associated with hereditary papillary renal cancer. This a very rare autosomal dominant condition, which is usually considered not to display a phenotype of multiple types of malignancy. However, this report describes the case of a man who has been affected with testicular teratoma, diffuse large B-cell lymphoma and multiple hepatic cysts, as well as
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Complete response of hereditary leiomyomatosis and renal cell cancer (HLRCC)-associated renal cell carcinoma to nivolumab and ipilimumab combination immunotherapy by: a case report. Fam. Cancer (IF 1.76) Pub Date : 2020-07-15 Yasuhiro Iribe,Mitsuko Furuya,Yousuke Shibata,Masato Yasui,Makoto Funahashi,Junichi Ota,Hiromichi Iwashita,Yoji Nagashima,Hisashi Hasumi,Narihiko Hayashi,Kazuhide Makiyama,Keiichi Kondo,Reiko Tanaka,Masahiro Yao,Noboru Nakaigawa
Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a rare autosomal dominant disorder that results from a germline mutation in the fumarate hydratase gene (FH). Individuals with FH mutations are at risk of developing renal cell carcinoma (RCC). Patients with HLRCC-associated RCC (HLRCC-RCC) have aggressive clinical courses, but there is as yet no standardized therapy for advanced HLRCC-RCC
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Report of the fifth meeting of the European Consortium 'Care for CMMRD' (C4CMMRD), Leiden, The Netherlands, July 6th 2019. Fam. Cancer (IF 1.76) Pub Date : 2020-07-02 M Suerink,K Wimmer,L Brugieres,C Colas,R Gallon,T Ripperger,P R Benusiglio,E M A Bleiker,Z Ghorbanoghli,Y Goldberg,J C H Hardwick,M Kloor,M le Mentec,M Muleris,M Pineda,C Ruiz-Ponte,H F A Vasen
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Improving primary care identification of familial breast cancer risk using proactive invitation and decision support. Fam. Cancer (IF 1.76) Pub Date : 2020-06-11 Nadeem Qureshi,Brittany Dutton,Stephen Weng,Christina Sheehan,Wendy Chorley,John F R Robertson,Denise Kendrick,Joe Kai
Family history of breast cancer is a key risk factor, accounting for up to 10% of cancers. We evaluated the proactive assessment of familial breast cancer (FBC) risk in primary care. Eligible women (30 to 60 years) were recruited from eight English general practices. Practices were trained on FBC risk assessment. In four randomly-assigned practices, women were invited to complete a validated, postal
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Prospective observational data informs understanding and future management of Lynch syndrome: insights from the Prospective Lynch Syndrome Database (PLSD). Fam. Cancer (IF 1.76) Pub Date : 2020-06-08 Toni T Seppälä,Mev Dominguez-Valentin,Julian R Sampson,Pål Møller
The Prospective Lynch Syndrome Database (PLSD) has been developed as an international, multicentre, prospective, observational study that aims to provide age and organ-specific cancer risks according to gene and gender, estimates of survival after cancer and information on the effects of interventions. Recent reports from PLSD provided improved estimates of cancer risks and survival and showed that
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Chemoprevention in familial adenomatous polyposis: past, present and future. Fam. Cancer (IF 1.76) Pub Date : 2020-06-08 Phillip M Kemp Bohan,Gautam Mankaney,Timothy J Vreeland,Robert C Chick,Diane F Hale,Jessica L Cindass,Annelies T Hickerson,Daniel C Ensley,Vance Sohn,G Travis Clifton,George E Peoples,Carol A Burke
Familial adenomatous polyposis (FAP) is a hereditary colorectal cancer syndrome characterized by colorectal adenomas and a near 100% lifetime risk of colorectal cancer (CRC). Prophylactic colectomy, usually by age 40, is the gold-standard therapy to mitigate this risk. However, colectomy is associated with morbidity and fails to prevent extra-colonic disease manifestations, including gastric polyposis
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Two cases of somatic STK11 mosaicism in Danish patients with Peutz-Jeghers syndrome. Fam. Cancer (IF 1.76) Pub Date : 2020-06-06 Anne Marie Jelsig,Birgitte Bertelsen,Isabel Forss,John Gásdal Karstensen
Peutz–Jeghers syndrome (PJS) is a hereditary polyposis syndrome characterized by hamartomatous Peutz–Jeghers polyps in the gastrointestinal tract, mucocutaneous pigmentations, and increased risk for intestinal and extraintestinal cancer. In more than two-third of patients it is possible to detect pathogenic variants in the serine/threonine kinase 11 (STK11) gene, but so far is knowledge about genetic
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Germline variants discovered in lymphoma patients undergoing tumor profiling: a case series. Fam. Cancer (IF 1.76) Pub Date : 2020-06-06 Anthony J Scott,Molly C Tokaz,Michelle F Jacobs,Arul M Chinnaiyan,Tycel J Phillips,Ryan A Wilcox
Clinical tumor sequencing protocols often depend on obtaining germline DNA from patients to aid in the identification of de novo variants in the tumor, and therefore come with the possibility for the incidental discovery of germline variants. Ninety-one adult patients with lymphoma were consented and enrolled in MIONCOSEQ, an IRB-approved tumor profiling protocol that utilizes an exome sequencing platform
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Constitutional mosaicism for a BRCA2 mutation as a cause of early-onset breast cancer. Fam. Cancer (IF 1.76) Pub Date : 2020-05-28 Pia Alhopuro,Reetta Vainionpää,Anna-Kaisa Anttonen,Kristiina Aittomäki,Heli Nevanlinna,Minna Pöyhönen
Germline mutations in the BRCA1 and BRCA2 genes cause hereditary breast and ovarian cancer syndrome (HBOC). Mutations in these genes are usually inherited, and reports of de novo BRCA1/2 mutations are rare. To date, only one patient with low-level BRCA1 mutation mosaicism has been published. We report on a breast cancer patient with constitutional somatic mosaicism of a BRCA2 mutation. BRCA2 mutation
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Small fraction of testicular cancer cases may be causatively related to CHEK2 inactivating germ-line mutations: evidence for somatic loss of the remaining CHEK2 allele in the tumor tissue. Fam. Cancer (IF 1.76) Pub Date : 2020-05-26 Valeriya I Ni,Alexandr O Ivantsov,Mariya A Kotkova,Sofia V Baskina,Elena V Ponomareva,Rashida V Orlova,Eldar E Topuzov,Kirill K Kryukov,Kseniya V Shelekhova,Svetlana N Aleksakhina,Anna P Sokolenko,Evgeny N Imyanitov
A recent study suggested a role of CHEK2 loss-of-function germ-line pathogenic variants in the predisposition to testicular cancer (TC) (AlDubayan et al. JAMA Oncol 5:514–522, 2019). We attempted to validate this finding relying on the high population frequency of recurrent CHEK2 pathogenic variants in Slavic populations. CHEK2 pathogenic alleles (c.1100delC (p.Thr367Metfs); del5395 [del ex9-10]; IVS2 + 1G > A
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Low accuracy of self-reported family history of melanoma in high-risk patients. Fam. Cancer (IF 1.76) Pub Date : 2020-05-21 Nicholas D Flint,Michael D Bishop,Tristan C Smart,Jennifer L Strunck,Kenneth M Boucher,Douglas Grossman,Aaron M Secrest
Family history of melanoma is a major melanoma risk factor. However, self-reported family histories for some cancers, including melanoma, are commonly inaccurate. We used a unique database, the Utah Population Database (UPDB), as well as the Utah Cancer Registry to determine the accuracy of self-reported family history of melanoma in a large cohort of high-risk patients. Patient charts were reviewed
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Women's responses and understanding of polygenic breast cancer risk information. Fam. Cancer (IF 1.76) Pub Date : 2020-05-20 T Yanes,R Kaur,B Meiser,M Scheepers-Joynt,S McInerny,K Barlow-Stewart,Y Antill,L Salmon,C Smyth,P A James,M A Young
It is estimated that polygenic factors can explain up to 18% of familial breast cancer. Clinical implementation of polygenic testing has begun, with several commercial laboratories now testing. Despite commercial implementation, there is little research investigating how women respond and understand polygenic risk information. This study aimed to explore women’s experience receiving their personalised
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Biallelic NF1 inactivation in high grade serous ovarian cancers from patients with neurofibromatosis type 1. Fam. Cancer (IF 1.76) Pub Date : 2020-05-13 Eliza Courtney,Sock Hoai Chan,Shao Tzu Li,Diana Ishak,Khurshid Merchant,Tarryn Shaw,Wen Yee Chay,Felicia Hui Xian Chin,Wai Loong Wong,Adele Wong,Joanne Ngeow
Neurofibromatosis type 1 (NF1) is a multisystem disorder caused by germline heterozygous NF1 loss-of-function variants. The NF1 gene encodes neurofibromin, a RAS GTPase-activating protein, which functions by down-regulating RAS/RAF/MAPK-signalling pathways. Somatic NF1 aberrations frequently occur in sporadic ovarian cancer (OC), but the incidence of OC in NF1 patients is rare. Here we report the germline
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Evaluation of implementation of risk management guidelines for carriers of pathogenic variants in mismatch repair genes: a nationwide audit of familial cancer clinics. Fam. Cancer (IF 1.76) Pub Date : 2020-05-09 B Meiser,R Kaur,J Kirk,A Morrow,M Peate,W K T Wong,E McPike,E Cops,C Dowson,R Austin,M Fine,L Thrupp,R Ward,F Macrae,J E Hiller,A H Trainer,G Mitchell,
IntroductionThis nationwide study assessed the impact of Lynch syndrome-related risk management guidelines on clinicians’ recommendations of risk management strategies to carriers of pathogenic variants in mismatch repair genes and the extent to which carriers took up strategies in concordance with guidelines. Materials and methodsClinic files of 464 carriers (with and without colorectal cancer) were
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MLH1 intronic variants mapping to + 5 position of splice donor sites lead to deleterious effects on RNA splicing. Fam. Cancer (IF 1.76) Pub Date : 2020-05-04 Tamara Alejandra Piñero,Omar Soukarieh,Marion Rolain,Karin Alvarez,Francisco López-Köstner,Giovana Tardin Torrezan,Dirce Maria Carraro,Ivana Lucia De Oliveira Nascimento,Thaís Ferreira Bomfim,Taísa Manuela Bonfim Machado-Lopes,Juliana Côrtes Freitas,Maria Betânia Toralles,Kiyoko Abe Sandes,Benedito Mauro Rossi,Samuel Aguiar Junior,Joanna Meira,Mev Dominguez-Valentin,Pål Møller,Carlos Alberto Vaccaro
Germline pathogenic variants in the DNA mismatch repair genes (MMR): MLH1, MSH2, MSH6, and PMS2, are causative of Lynch syndrome (LS). However, many of the variants mapping outside the invariant splice site positions (IVS ± 1, IVS ± 2) are classified as variants of unknown significance (VUS). Three such variants (MLH1 c.588+5G>C, c.588+5G>T and c.677+5G>A) were identified in 8 unrelated LS families
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Cumulative risk of skin cancer in patients with Li-Fraumeni syndrome. Fam. Cancer (IF 1.76) Pub Date : 2020-04-30 S A Nieuwenburg,F Adan,M W G Ruijs,G S Sonke,M E van Leerdam,M B Crijns
Li-Fraumeni syndrome (LFS) is an inherited cancer syndrome, characterized by an early onset of various types of cancers. LFS is associated with a germline mutation in the TP53 gene. The risk of developing skin cancer in patients with LFS is unknown. To evaluate the cumulative risk of skin cancer in patients with LFS and to compare this risk to the general Dutch population. In this retrospective cohort
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Characterization of a germline splice site variant MLH1 c.678-3T>A in a Lynch syndrome family. Fam. Cancer (IF 1.76) Pub Date : 2020-04-30 Ciyu Yang,Margaret Sheehan,Ester Borras,Karen Cadoo,Kenneth Offit,Liying Zhang
Germline mutations in the DNA mismatch repair (MMR) genes cause Lynch syndrome. Classification and interpretation of intronic variants, especially those outside the consensus ± 1 ~ 2 splice sites are challenging as it is uncertain whether such variants would affect splicing accuracy and efficiency. The assessment of the pathogenicity of splice site variants in MLH1 is further complicated by the various
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Primary fallopian tube carcinoma (PFTC) in a BRIP-1 mutation carrier: the first case report. Fam. Cancer (IF 1.76) Pub Date : 2020-04-24 Giovanni Grandi,Martina Caroli,Carlo Alboni,Laura Cortesi,Angela Toss,Elena Barbieri,Laura Botticelli,Fabio Facchinetti
Some hereditary ovarian cancer cases can be associated with a mutation of a gene involved in the DNA double-strand break repair system other than BRCA, such as BRIP1. This mutation is an emerging indication for prophylactic risk-reducing salpingo-oophorectomy (RRSO): however, anomalous tubal pathologic lesions have not yet been reported during RRSO performed for this specific indication (BRIP1), as
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Systematic development of a training program for healthcare professionals to improve communication about breast cancer genetic counseling with low health literate patients. Fam. Cancer (IF 1.76) Pub Date : 2020-04-22 Jeanine A M van der Giessen,Margreet G E M Ausems,Maria E T C van den Muijsenbergh,Sandra van Dulmen,Mirjam P Fransen
There is a disproportionate underuse of genetic testing in breast cancer patients from lower education or migrant background. Within these groups, communication about referral to genetic counseling appears challenging due to limited health literacy and cultural barriers. Our aim was to develop and evaluate a training program for healthcare professionals (breast surgeons and specialized nurses), to
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Highly aggressive thoracic desmoid tumors in adolescent siblings with fatal outcomes in an FAP kindred: a need for increased vigilance and intervention in at-risk AYAs. Fam. Cancer (IF 1.76) Pub Date : 2020-04-13 Mohamed M Gad,Anne-Marie Langevin,Aaron J Sugalski,Gail E Tomlinson
Desmoid tumors are a manifestation of familial adenomatous polyposis (FAP), associated with mutation of the APC gene. Although considered benign tumors, desmoids can be aggressive and cause considerable morbidity. Known risk factors for desmoid tumor growth include location of mutations within the APC gene, family history of desmoid tumors, previous surgery, female gender, and pregnancy. Desmoids occur
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Waiting and "weighted down": the challenge of anticipatory loss for individuals and families with Li-Fraumeni Syndrome. Fam. Cancer (IF 1.76) Pub Date : 2020-03-28 Allison Werner-Lin,Jennifer L Young,Catherine Wilsnack,Shana L Merrill,Victoria Groner,Mark H Greene,Payal P Khincha
Li-Fraumeni Syndrome (LFS) is characterized by risk of multiple primary malignancies in diverse sites, pediatric onset, near complete penetrance by age 70 years, limited options for prevention, and substantial uncertainty regarding disease manifestation and prognosis. Forty-five families, including 117 individuals aged 13–81 years, enrolled in the US National Cancer Institute’s Li-Fraumeni Syndrome
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De novo SDHB gene mutation in a family with extra-adrenal paraganglioma. Fam. Cancer (IF 1.76) Pub Date : 2020-03-21 Caitlin B Mauer,Brian Reys,Jonathan Wickiser
A 14-year-old male presented with abdominal pain. Imaging illustrated a left-sided adrenal mass; he underwent a left nephrectomy, confirming an extra-adrenal PGL. Germline genetic testing revealed a heterozygous, likely pathogenic mutation in the SDHB gene. The patient’s family subsequently underwent genetic testing; his mother and sister were both positive for the familial SDHB mutation. Cascade testing
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Analysis of 3297 individuals suggests that the pathogenic germline 5'-UTR variant BRCA1 c.-107A > T is not common in south-east Germany. Fam. Cancer (IF 1.76) Pub Date : 2020-03-21 A Laner,A Benet-Pages,B Neitzel,E Holinski-Feder
In this study we aim to determine the prevalence of the recently identified pathogenic BRCA1 variant c.-107A > T in the south-east German population. This variant causes the epigenetic silencing of the BRCA1 promotor and has been detected in two independent families from the UK without a germline BRCA1 or BRCA2 pathogenic variant. A total of 3297 individuals with suspicion of hereditary breast and
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Genetic health professionals' experiences with initiating reanalysis of genomic sequence data. Fam. Cancer (IF 1.76) Pub Date : 2020-03-21 Danya F Vears,Karine Sénécal,Pascal Borry
Despite the increased diagnostic yield associated with genomic sequencing (GS), a sizable proportion of patients do not receive a genetic diagnosis at the time of the initial GS analysis. Systematic data reanalysis leads to considerable increases in genetic diagnosis rates yet is time intensive and leads to questions of feasibility. Few policies address whether laboratories have a duty to reanalyse
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Patient-reported burden of intensified surveillance and surgery in high-risk individuals under pancreatic cancer surveillance. Fam. Cancer (IF 1.76) Pub Date : 2020-03-19 Kasper A Overbeek,Djuna L Cahen,Anne Kamps,Ingrid C A W Konings,Femme Harinck,Marianne A Kuenen,Bas Groot Koerkamp,Marc G Besselink,Casper H van Eijck,Anja Wagner,Margreet G E Ausems,Manon van der Vlugt,Paul Fockens,Frank P Vleggaar,Jan-Werner Poley,Jeanin E van Hooft,Eveline M A Bleiker,Marco J Bruno,
In high-risk individuals participating in a pancreatic cancer surveillance program, worrisome features warrant for intensified surveillance or, occasionally, surgery. Our objectives were to determine the patient-reported burden of intensified surveillance and/or surgery, and to assess post-operative quality of life and opinion of surgery. Participants in our pancreatic cancer surveillance program completed
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Collaborative Group of the Americas on Inherited Gastrointestinal Cancer Position statement on multigene panel testing for patients with colorectal cancer and/or polyposis. Fam. Cancer (IF 1.76) Pub Date : 2020-03-14 Brandie Heald,Heather Hampel,James Church,Beth Dudley,Michael J Hall,Maureen E Mork,Aparajita Singh,Elena Stoffel,Jessica Stoll,Y Nancy You,Matthew B Yurgelun,Sonia S Kupfer,
Multigene panel tests for hereditary cancer syndromes are increasingly utilized in the care of colorectal cancer (CRC) and polyposis patients. However, widespread availability of panels raises a number of questions including which patients should undergo testing, which genes should be included on panels, and the settings in which panels should be ordered and interpreted. To address this knowledge gap
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Lack of evidence for CDK12 as an ovarian cancer predisposing gene. Fam. Cancer (IF 1.76) Pub Date : 2020-03-14 Alexandre Eeckhoutte,Mathilde Saint-Ghislain,Manon Reverdy,Virginie Raynal,Sylvain Baulande,Guillaume Bataillon,Lisa Golmard,Dominique Stoppa-Lyonnet,Tatiana Popova,Claude Houdayer,Elodie Manié,Marc-Henri Stern
CDK12 variants were investigated as a genetic susceptibility to ovarian cancer in a series of 416 unrelated and consecutive patients with ovarian carcinoma and who carry neither germline BRCA1 nor BRCA2 pathogenic variant. The presence of CDK12 variants was searched in germline DNA by massive parallel sequencing on pooled DNAs. The lack of detection of deleterious variants and the observed proportion
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Do the risks of Lynch syndrome-related cancers depend on the parent of origin of the mutation? Fam. Cancer (IF 1.76) Pub Date : 2020-02-27 Shimelis Dejene Gemechu,Christine M van Vliet,Aung Ko Win,Jane C Figueiredo,Loic Le Marchand,Steven Gallinger,Polly A Newcomb,John L Hopper,Noralane M Lindor,Mark A Jenkins,James G Dowty
Individuals who carry pathogenic mutations in DNA mismatch repair (MMR) genes have high risks of cancer, and small studies have suggested that these risks depend on the sex of the parent from whom the mutation was inherited. We have conducted the first large study of such a parent-of-origin effect (POE). Our study was based on all MMR gene mutation carriers and their relatives in the Colon Cancer Family
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Perceptions of risk and reward in BRCA1 and BRCA2 mutation carriers choosing salpingectomy for ovarian cancer prevention. Fam. Cancer (IF 1.76) Pub Date : 2020-02-24 Talayeh S Ghezelayagh,Lauren E Stewart,Barbara M Norquist,Deborah J Bowen,Vivian Yu,Kathy J Agnew,Kathryn P Pennington,Elizabeth M Swisher
Salpingectomy with interval oophorectomy has gained traction as an ovarian cancer prevention strategy, but is not currently recommended for high risk women. Nevertheless, some choose this approach. We aimed to understand risk perception and plans for oophorectomy in BRCA1 and BRCA2 (BRCA) mutation carriers choosing salpingectomy for ovarian cancer prevention. This was a longitudinal survey study of
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Increased prevalence of Barrett's esophagus in patients with MUTYH-associated polyposis (MAP). Fam. Cancer (IF 1.76) Pub Date : 2020-02-22 Ceranza G Daans,Zeinab Ghorbanoghli,Mary E Velthuizen,Hans F A Vasen,George J A Offerhaus,Miangela M Lacle,Peter D Siersema,Margreet G E M Ausems,Jurjen J Boonstra
Barrett’s oesophagus (BE) has been associated with an increased risk of both colorectal adenomas and colorectal cancer. A recent investigation reported a high frequency of BE in patients with adenomatous polyposis coli (APC)-associated polyposis (FAP). The aim of the present study is to evaluate the prevalence of BE in a large cohort of patients with MUTYH-associated polyposis (MAP) and APC-associated
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Mismatch repair gene pathogenic germline variants in a population-based cohort of breast cancer. Fam. Cancer (IF 1.76) Pub Date : 2020-02-14 Tu Nguyen-Dumont,Jason A Steen,Ingrid Winship,Daniel J Park,Bernard J Pope,Fleur Hammet,Maryam Mahmoodi,Helen Tsimiklis,Derrick Theys,Mark Clendenning,Graham G Giles,John L Hopper,Melissa C Southey
The advent of gene panel testing is challenging the previous practice of using clinically defined cancer family syndromes to inform single-gene genetic screening. Individual and family cancer histories that would have previously indicated testing of a single gene or a small number of related genes are now, increasingly, leading to screening across gene panels that contain larger numbers of genes. We