Familial pancreatic cancer with PALB2 and NBN pathogenic variants: a case report

Abstract Background Family history is one of the risk factors for pancreatic cancer. It is suggested that patients with pancreatic cancer who have a familial history harbor germline pathogenic variants of BRCA1 and/or BRCA2 (BRCA1/2), PALB2, or ATM. Recently, some germline variants of familial pancreatic cancers (FPCs), including PALB2, have been detected. Several countries, including Japan, perform screening workups and genetic analysis for pancreatic cancers. We have been carrying out active surveillance for FPC through epidemiological surveys, imaging analyses, and genetic analysis. Case presentation Here, we present the case of a female patient harboring pathogenic variants of PALB2 and NBN, with a family history of multiple pancreatic cancer in her younger brother, her aunt, and her father. Moreover, her father harbored a PALB2 pathogenic variant and her daughter harbored the same NBN pathogenic variant. Given the PALB2 and NBN variants, we designed surveillance strategies for the pancreas, breast, and ovary. Conclusions Further studies are required to develop strategies for managing FPCs to facilitate prompt diagnosis before their progression.

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Surveillance of Individuals with a Family History of Pancreatic Cancer and Inherited Cancer Syndromes: A Strategy for Detecting Early Pancreatic Cancers

Diagnostics ◽

10.3390/diagnostics9040169 ◽

2019 ◽

Vol 9 (4) ◽

pp. 169

Author(s):

Matsubayashi ◽

Kiyozumi ◽

Ishiwatari ◽

Uesaka ◽

Kikuyama ◽

...

Keyword(s):

Pancreatic Cancer ◽

Family History ◽

Early Stage ◽

Developed Countries ◽

Familial Pancreatic Cancer ◽

Cancer Syndrome ◽

Inherited Cancer ◽

Clinicopathological Findings ◽

History Of ◽

Cancer Syndromes

A family history of pancreatic cancer (PC) is a risk factor of PC, and risk levels increase as affected families grow in number and/or develop PC at younger ages. Familial pancreatic cancer (FPC) is defined as a client having at least two PC cases in a first degree relatives. In the narrow sense, FPC does not include some inherited cancer syndromes that are known to increase the risks of PC, such as Peutz–Jeghers syndrome (PJS), hereditary pancreatitis (HP), hereditary breast ovarian cancer syndrome (HBOC), and so on. FPC accounts for 5%–10% of total PC diagnoses and is marked by several features in genetic, epidemiological, and clinicopathological findings that are similar to or distinct from conventional PC. Recent advances in genetic medicine have led to an increased ability to identify germline variants of cancer-associated genes. To date, high-risk individuals (HRIs) in many developed countries, including FPC kindreds and inherited cancer syndromes, are screened clinically to detect and treat early-stage PC. This article highlights the concept of FPC and the most recent data on its detection.

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Germline mutations in Brazilian pancreatic carcinoma patients.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e16749 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e16749-e16749

Author(s):

Livia Munhoz Rodrigues ◽

Simone Maistro ◽

Maria Lucia Hirata Katayama ◽

Luiz A.Senna Leite ◽

Joao Glasberg ◽

...

Keyword(s):

Pancreatic Cancer ◽

Genetic Testing ◽

Family History ◽

Pancreatic Carcinoma ◽

Germline Mutations ◽

Family History Of Cancer ◽

First Degree Relatives ◽

Pathogenic Variants ◽

History Of ◽

History Of Cancer

e16749 Background: Pancreatic cancer has the prospect of becoming the second leading cause of cancer death by 2030. The NCCN Guidelines recommend genetic testing for all patients with pancreatic cancer, however, the spectrum of germline mutations has not been extensively evaluated because recent studies with genetic testing have explored only a limited number of genes and have focused predominantly on Caucasian populations. Therefore, our objective is to evaluate the frequency and spectrum of germline mutations in unselected patients with pancreatic cancer in a multiethnic population. Methods: Patients from Instituto do Câncer do Estado de São Paulo (Brazil) with histopathological diagnosis of non-endocrine pancreatic carcinoma were included, regardless of the family history of cancer. These patients answered a life habits and family history of cancer questionnaire and supplied blood for the Next Generation Sequencing (MiSeq platform) with the TruSight Hereditary Cancer panel (Illumina), which includes 115 cancer predisposing genes. Variant analysis was performed with the VarStation, a Brazilian tool that offers post-sequencing computational support and aid for clinical interpretation. Results: To the present moment, 77 patients were evaluated. The mean age of the patients was 62 years (27-83), among whom, 13% with young age (≤50 years) and 47 women (61%). Thirty-eight patients (49%) reported cases of cancer in first-degree relatives. Regarding risk factors, 41 patients (53%) reported smoking, 19 (25%) alcohol ingestion and 20 (26%) had obesity. Seven out of 77 patients presented pathogenic variants in ATM (n = 2) , CHEK2, FANCM (n = 2) or PALB2 (n = 2) genes. Two of these patients ( CHEK2 and FANCM) had early onset pancreatic cancer (≤45 years), both denied smoking habit and family history of cancer in 1st degree relatives. Two patients, who were ATM mutation carriers, reported 1st or 2nd degree relatives with cancer and are alive after 4 and 8 years of diagnosis. Conclusions: In this unselected group of pancreatic cancer patients, 15% were young, almost half reported first-degree relatives with cancer and 9% were carriers of pathogenic variants in genes related with the homologous recombination DNA repair.

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Correlation between Family RB1 Gene Pathogenic Variant with Clinical Features and Prognosis of Retinoblastoma under 5 Years Old

Disease Markers ◽

10.1155/2021/9981028 ◽

2021 ◽

Vol 2021 ◽

pp. 1-10

Author(s):

Yi Zhang ◽

Yizhuo Wang ◽

Dongsheng Huang ◽

Jianmin Ma ◽

Weiling Zhang ◽

...

Keyword(s):

Family History ◽

Clinical Phenotype ◽

Acid Sites ◽

Pathogenic Variant ◽

Rb1 Gene ◽

Genetic History ◽

High Risk Factors ◽

Pathogenic Variants ◽

History Of ◽

Hereditary Tumors

Retinoblastoma (RB) is the most common primary intraocular malignant tumor in infants and the prototype of human hereditary tumors. Its occurrence and development are closely related to the pathogenic variant of tumor suppressor RB1 gene. We aim to analyze the characteristics of RB1 gene pathogenic variant and clinical phenotype in retinoblastoma patients and their relatives. Children with RB were recruited from August 2007 to November 2017. QT-PCR, probing, and gene sequencing were used to analyze the sequence of RB1 gene in RB children, their parents, or grandparents with a clear history of illness. The SPSS20.0 software was used to analyze the correlation between polymorphisms of RB1 gene and the incidence and prognosis of the enrolled children and relatives. 40 RB children (20 males and 20 females) were recruited, unilateral RB accounted for 52.5% (21/40), bilateral RB accounted for 42.5% (17/40), and trilateral RB accounted for 5.0% (2/40). 6 patients had a clear family history (15.0%, 6/40). It had been verified that 19 probands (47.5%) have RB1 gene pathogenic variants (11 frameshift and 8 missense pathogenic variants), of which germline inheritance accounted for 47.4% (9/19) and nongermline heredity accounted for 52.6% (10/19). Pathogenic variants of 10 nucleic acid sites without reported were found, among which c.2455C>G (p.L819V) was confirmed to have heterozygous pathogenic variants in both a bilateral RB patient and his mother with unilateral RB. Family genetic high-risk factors, bilateral/trilateral RB, >12-month-onset RB have a higher proportion of RB1 gene pathogenic variant than children with no family history, unilateral RB, and ≤12-month ( P = 0.021 , 0.001,0.034). The proportion of pedigree inheritance of infantile retinoblastoma with bilateral disease is high. There was a certain proportion of RB1 gene pathogenic variant in 3-5-year-old children with bilateral RB, even if they had no family genetic history. Therefore, the detection of RB1 gene pathogenic variant should not only focus on infants but also on the phenotype of RB1 gene pathogenic variant in children over 3 years old with bilateral eye disease.

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Coffin-Lowry preprint 2018

10.31219/osf.io/6scqn ◽

2018 ◽

Author(s):

Paolo Moretti

Keyword(s):

Family History ◽

Clinical Features ◽

De Novo ◽

Severe Disease ◽

Immunosuppressive Treatment ◽

Pathogenic Variant ◽

First Degree Relatives ◽

Pathogenic Variants ◽

History Of ◽

Psychiatric Manifestations

Coffin-Lowry syndrome is an X-linked disease caused by pathogenic variants in RPS6KA3. The disease generally causes severe neurologic and non-neurologic abnormalities in males, and more variable phenotypes in females, including psychiatric manifestations. The majority of cases occur in the absence of known family history of the disease, and women carrying a de novo pathogenic variant may be undiagnosed due to the absence of severe disease manifestations or typically affected first-degree relatives. We describe the clinical features of a woman of normal intellect carrying a novel RPS6KA3 pathogenic variant in whom psychiatric manifestations and encephalopathy responded to immunosuppressive treatment.

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Incidence of Pathogenic Variants in Those With a Family History of Pancreatic Cancer

Frontiers in Oncology ◽

10.3389/fonc.2018.00330 ◽

2018 ◽

Vol 8 ◽

Cited By ~ 1

Author(s):

Sarah K. Macklin ◽

Pashtoon M. Kasi ◽

Jessica L. Jackson ◽

Stephanie L. Hines

Keyword(s):

Pancreatic Cancer ◽

Family History ◽

Pathogenic Variants ◽

History Of

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Incidence of pathogenic variants in individuals with a personal or family history of pancreatic cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.15_suppl.1589 ◽

2018 ◽

Vol 36 (15_suppl) ◽

pp. 1589-1589

Author(s):

Pashtoon Murtaza Kasi ◽

Sarah K Macklin ◽

Stephanie L. Hines

Keyword(s):

Pancreatic Cancer ◽

Family History ◽

Pathogenic Variants ◽

History Of

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Case Report: The Role of Molecular Analysis of the MUTYH Gene in Asymptomatic Individuals

Frontiers in Genetics ◽

10.3389/fgene.2020.590486 ◽

2020 ◽

Vol 11 ◽

Author(s):

Katarína Fabišíková ◽

Olívia Hamidová ◽

Regína Lohajová Behulová ◽

Katarína Závodná ◽

Petra Priščáková ◽

...

Keyword(s):

Family History ◽

Molecular Analysis ◽

Excision Repair ◽

Dna Lesions ◽

Pathogenic Variant ◽

Sequencing Analysis ◽

Biallelic Mutation ◽

Pathogenic Variants ◽

Mutyh Gene ◽

History Of

MUTYH-associated polyposis (MAP) is a rare hereditary condition caused by the biallelic mutation in the MUTYH gene encoding MUTYH glycosylase. This enzyme is a key member of the base excision repair (BER) pathway responsible for the repair of DNA lesions formed by reactive oxygen species (ROS). We report two cases of MAP. In case 1, a 67-year-old woman who presented with a personal history of colorectal and endometrial cancer and a family history of cancer syndromes underwent multigene panel testing that revealed a germline homozygous (biallelic) pathogenic variant c.1187G > A (p.Gly396Asp) in the MUTYH gene. Subsequent sequencing analysis performed in the offspring of the proband identified all three asymptomatic offspring as carriers of this pathogenic variant. In case 2, a 40-year-old woman with a strong family history of colorectal cancer [the proband’s sister was a carrier of the pathogenic variant c.536A > G (p.Tyr179Cys) of the MUTYH gene] and renal cancer underwent sequencing analysis of the MUTYH gene. The pathogenic heterozygous (monoallelic) variant c.536A > G (p.Tyr179Cys) of the MUTYH gene was identified in the proband. We found another pathogenic variant of the MUTYH gene—heterozygous (monoallelic) mutation c.1187G > A (p.Gly396Asp) in the genome of the proband’s husband. Molecular analysis of their offspring revealed that they are compound heterozygotes for MUTYH pathogenic variants c.536A > G (p.Tyr179Cys)/c.1187G > A (p.Gly396Asp). This paper shows the importance of genetic testing of asymptomatic relatives of the proband to ensure an early surveillance and management of individuals positive for pathogenic variant (s) in the MUTYH gene.

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Clinical Implications of Identifying Pathogenic Variants in Individuals With Thoracic Aortic Dissection

Circulation Genomic and Precision Medicine ◽

10.1161/circgen.118.002476 ◽

2019 ◽

Vol 12 (6) ◽

Cited By ~ 10

Author(s):

Brooke N. Wolford ◽

Whitney E. Hornsby ◽

Dongchuan Guo ◽

Wei Zhou ◽

Maoxuan Lin ◽

...

Keyword(s):

Family History ◽

Aortic Dissection ◽

Age Of Onset ◽

Family Members ◽

Aortic Disease ◽

Pathogenic Variant ◽

Carrier Status ◽

Thoracic Aortic Dissection ◽

Pathogenic Variants ◽

History Of

Background: Thoracic aortic dissection is an emergent life-threatening condition. Routine screening for genetic variants causing thoracic aortic dissection is not currently performed for patients or family members. Methods: We performed whole exome sequencing of 240 patients with thoracic aortic dissection (n=235) or rupture (n=5) and 258 controls matched for age, sex, and ancestry. Blinded to case-control status, we annotated variants in 11 genes for pathogenicity. Results: Twenty-four pathogenic variants in 6 genes (COL3A1, FBN1, LOX, PRKG1, SMAD3, and TGFBR2) were identified in 26 individuals, representing 10.8% of aortic cases and 0% of controls. Among dissection cases, we compared those with pathogenic variants to those without and found that pathogenic variant carriers had significantly earlier onset of dissection (41 versus 57 years), higher rates of root aneurysm (54% versus 30%), less hypertension (15% versus 57%), lower rates of smoking (19% versus 45%), and greater incidence of aortic disease in family members. Multivariable logistic regression showed that pathogenic variant carrier status was significantly associated with age <50 (odds ratio [OR], 5.5; 95% CI, 1.6–19.7), no history of hypertension (OR, 5.6; 95% CI, 1.4–22.3), and family history of aortic disease (mother: OR, 5.7; 95% CI, 1.4–22.3, siblings: OR, 5.1; 95% CI, 1.1–23.9, children: OR, 6.0; 95% CI, 1.4–26.7). Conclusions: Clinical genetic testing of known hereditary thoracic aortic dissection genes should be considered in patients with a thoracic aortic dissection, followed by cascade screening of family members, especially in patients with age-of-onset <50 years, family history of thoracic aortic disease, and no history of hypertension.

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Evaluating Susceptibility to Pancreatic Cancer: ASCO Provisional Clinical Opinion

Journal of Clinical Oncology ◽

10.1200/jco.18.01489 ◽

2019 ◽

Vol 37 (2) ◽

pp. 153-164 ◽

Cited By ~ 35

Author(s):

Elena M. Stoffel ◽

Shannon E. McKernin ◽

Randall Brand ◽

Marcia Canto ◽

Michael Goggins ◽

...

Keyword(s):

Pancreatic Cancer ◽

Genetic Testing ◽

Family History ◽

Pancreatic Adenocarcinoma ◽

Health Care Providers ◽

Expert Panel ◽

Familial Pancreatic Cancer ◽

Care Providers ◽

Increased Risk ◽

History Of

Purpose An ASCO provisional clinical opinion (PCO) offers timely clinical direction to ASCO’s membership and other health care providers. This PCO addresses identification and management of patients and family members with possible predisposition to pancreatic adenocarcinoma. Methods ASCO convened an Expert Panel and conducted a systematic review of the literature published from January 1998 to June 2018. Results of the databases searched were supplemented with hand searching of the bibliographies of systematic reviews and selected seminal articles and contributions from Expert Panel members’ curated files. Provisional Clinical Opinion All patients diagnosed with pancreatic adenocarcinoma should undergo assessment of risk for hereditary syndromes known to be associated with an increased risk for pancreatic adenocarcinoma. Assessment of risk should include a comprehensive review of family history of cancer. Individuals with a family history of pancreatic cancer affecting two first-degree relatives meet criteria for familial pancreatic cancer (FPC). Individuals (cancer affected or unaffected) with a family history of pancreatic cancer meeting criteria for FPC, those with three or more diagnoses of pancreatic cancer in same side of the family, and individuals meeting criteria for other genetic syndromes associated with increased risk for pancreatic cancer have an increased risk for pancreatic cancer and are candidates for genetic testing. Germline genetic testing for cancer susceptibility may be discussed with individuals diagnosed with pancreatic cancer, even if family history is unremarkable. Benefits and limitations of pancreatic cancer screening should be discussed with individuals whose family history meets criteria for FPC and/or genetic susceptibility to pancreatic cancer. Additional information is available at www.asco.org/gastrointestinal-cancer-guidelines .

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Familial Pancreatic Cancer

Archives of Pathology & Laboratory Medicine ◽

10.5858/133.3.365 ◽

2009 ◽

Vol 133 (3) ◽

pp. 365-374 ◽

Cited By ~ 13

Author(s):

Chanjuan Shi ◽

Ralph H. Hruban ◽

Alison P. Klein

Keyword(s):

Pancreatic Cancer ◽

Family History ◽

Familial Aggregation ◽

Pancreatic Tumors ◽

Familial Pancreatic Cancer ◽

Genetic Syndromes ◽

Genetic Syndrome ◽

Close Family Member ◽

Pancreatic Cancers ◽

Increased Risk

Abstract Context.—Approximately 5% to 10% of individuals with pancreatic cancer report a history of pancreatic cancer in a close family member. In addition, several known genetic syndromes, such as familial breast cancer (BRCA2), the Peutz-Jeghers syndrome, and the familial atypical multiple mole melanoma syndrome, have been shown to be associated with an increased risk of pancreatic cancer. The known genes associated with these conditions can explain only a portion of the clustering of pancreatic cancer in families, and research to identify additional susceptibility genes is ongoing. Objective.—To provide an understanding of familial pancreatic cancer and the pathology of familial exocrine pancreatic cancers. Data Sources.—Published literature on familial aggregation of pancreatic cancer and familial exocrine pancreatic tumors. Conclusions.—Even in the absence of predictive genetic testing, the collection of a careful, detailed family history is an important step in the management of all patients with pancreatic cancer. While most pancreatic cancers that arise in patients with a family history are ductal adenocarcinomas, certain subtypes of pancreatic cancer have been associated with familial syndromes. Therefore, the histologic appearance of the pancreatic cancer itself, and/or the presence and appearance of precancerous changes in the pancreas, may increase the clinical index of suspicion for a genetic syndrome.

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