bims-lifras 2023-02-26 papers

bims-lifras

Biomed News

on Li-Fraumeni syndrome

Issue of 2023‒02‒26
fourteen papers selected by
Joanna Zawacka-Pankau
Karolinska Institutet

Li-Fraumeni-associated pancreatic neuroendocrine tumour and XAF1 p.Glu134Ter risk modifier variant.
Germline pathogenic SMARCA4 variants in neuroblastoma.
Germline RUNX1 variants in paediatric patients in a French specialised centre.
Functional Analyses of Rare Germline Missense BRCA1 Variants Located within and outside Protein Domains with Known Functions.
Primary Care Implications of the Expanded National Guidelines for Germline Testing of Patients Previously Diagnosed with Colorectal Cancer.
Germline Testing of Mismatch Repair Genes Is Needed in the Initial Evaluation of Patients With Muir-Torre Syndrome-Associated Cutaneous Sebaceous Neoplasms: A Case Series.
Identification of germline cancer predisposition variants in pediatric sarcoma patients from somatic tumor testing.
Analysis of clinical and genomic profiles of therapy-related myeloid neoplasm in Korea.
A case of unresectable intrahepatic cholangiocarcinoma with a germline BRCA1 mutation.
A Rare PDGFRA Exon 15 Germline Mutation Identified in a Patient With Phenotypic Manifestations Concerning for GIST-Plus Syndrome: A Case Report and Review of Literature.
Clinical characteristics of pancreatic and biliary tract cancers in Lynch syndrome: A retrospective analysis from the Finnish National Lynch Syndrome Research Registry.
Prognostic and Predictive Biomarkers in Familial Breast Cancer.
Identification of individuals at high-risk for pancreatic cancer using a digital patient-input tool combining family cancer history screening and new-onset diabetes.
A systematic review and meta-analysis of germline BRCA mutations in pancreatic cancer patients identifies global and racial disparities in access to genetic testing.

Ecancermedicalscience. 2022 ;16 1487

Li-Fraumeni-associated pancreatic neuroendocrine tumour and XAF1 p.Glu134Ter risk modifier variant.

Rachel P Riechelmann, Diogo C Soares, Carla Dias, Dirce M Carraro, Giovana T Torrezan.

  Studies have demonstrated that up to 17% of patients with pancreatic neuroendocrine tumours (pNETs) present pathogenic germline variants (PGVs) in several different genes, irrespective of family cancer history. Li-Fraumeni syndrome (LFS) is an autosomal dominant cancer predisposition syndrome related to PGVs in the TP53 gene. A previous case of a pNET associated with LFS (c.1009C > T, p.R337C) has been reported. Here we report the first case of a patient with pNET and TP53 p.R337H and XAF1 p.E134* germline variants, expanding the knowledge of LFS and germline mutations in neuroendocrine tumours.

Keywords:  Li–Fraumeni; neuroendocrine tumour; pancreas neoplasm

DOI:  https://doi.org/10.3332/ecancer.2022.1487
J Med Genet. 2023 Feb 22. pii: jmg-2022-108854. [Epub ahead of print]

Germline pathogenic SMARCA4 variants in neuroblastoma.

Leora Witkowski, Kim E Nichols, Marjolijn Jongmans, Nienke van Engelen, Ronald R de Krijger, Jennifer Herrera-Mullar, Lieve Tytgat, Armita Bahrami, Helen Mar Fan, Aimee L Davidson, Thomas Robertson, Michael Anderson, Martin Hasselblatt, Sharon E Plon, William D Foulkes.

  Heterozygous germline pathogenic variants (GPVs) in SMARCA4, the gene encoding the ATP-dependent chromatin remodelling protein SMARCA4 (previously known as BRG1), predispose to several rare tumour types, including small cell carcinoma of the ovary, hypercalcaemic type, atypical teratoid and malignant rhabdoid tumour, and uterine sarcoma. The increase in germline testing of SMARCA4 in recent years has revealed putative GPVs affecting SMARCA4 in patients with other cancer types. Here we describe 11 patients with neuroblastoma (NBL), including 4 previously unreported cases, all of whom were found to harbour heterozygous germline variants in SMARCA4 Median age at diagnosis was 5 years (range 2 months-26 years); nine were male; and eight of nine cases had tumour location information in the adrenal gland. Eight of the germline variants were expected to result in loss of function of SMARCA4 (large deletion, truncating and canonical splice variants), while the remaining four were missense variants. Loss of heterozygosity of the wild-type SMARCA4 allele was found in all eight cases where somatic testing was performed, supporting the notion that SMARCA4 functions as a classic tumour suppressor. Altogether, these findings strongly suggest that NBL should be included in the spectrum of SMARCA4-associated tumours.

Keywords:  Genetic Predisposition to Disease; Genetic Testing; Germ-Line Mutation; Pediatrics; Sequence Analysis, DNA

DOI:  https://doi.org/10.1136/jmg-2022-108854
EJHaem. 2023 Feb;4(1): 145-152

Germline RUNX1 variants in paediatric patients in a French specialised centre.

Cécile Liu, Paola Ballerini, Guillaume Nguyen, Zoia Mincheva, Bruno Copin, Boutheina Bouslama, Guy Leverger, Arnaud Petit, Rémi Favier, Hélène Lapillonne, Hélène Boutroux.

  Familial platelet disorder with associated myeloid malignancy (FPD-MM; OMIM 601399) is related to germline RUNX1 mutation. The pathogenicity of RUNX1 variants was initially linked to FPD-MM phenotype, but the discovery of new variants through the expansion of genetic explorations in leukaemia is questioning this assertion. In this study, we add 10 families with germline RUNX1 variant explored at Armand Trousseau Hospital for leukaemia diagnosis or thrombocytopenia, to the 259 described so far. Detailed description of their personal and family history of haematological pathologies allows identifying three phenotypes related to germline RUNX1 variants: thrombocytopenia and/or malignant haematological disease with family history of haematological diseases, thrombocytopenia with no family history of haematological diseases and acute lymphoblastic leukaemia (ALL) with no family history of haematological diseases. In the latter phenotype, ALL characteristics involving RUNX1 suggest the implication of germline variants in the onset of the malignancy.

Keywords:  RUNX1; genetic predisposition to disease; haematologic diseases

DOI:  https://doi.org/10.1002/jha2.594
Genes (Basel). 2023 Jan 19. pii: 262. [Epub ahead of print]14(2):

Functional Analyses of Rare Germline Missense BRCA1 Variants Located within and outside Protein Domains with Known Functions.

Henrikke Nilsen Hovland, Eunice Kabanyana Mchaina, Hildegunn Høberg-Vetti, Sarah Louise Ariansen, Wenche Sjursen, Marijke Van Ghelue, Bjørn Ivar Haukanes, Per Morten Knappskog, Ingvild Aukrust, Elisabet Ognedal.

  The BRCA1 protein is implicated in numerous important cellular processes to prevent genomic instability and tumorigenesis, and pathogenic germline variants predispose carriers to hereditary breast and ovarian cancer (HBOC). Most functional studies of missense variants in BRCA1 focus on variants located within the Really Interesting New Gene (RING), coiled-coil and BRCA1 C-terminal (BRCT) domains, and several missense variants in these regions have been shown to be pathogenic. However, the majority of these studies focus on domain specific assays, and have been performed using isolated protein domains and not the full-length BRCA1 protein. Furthermore, it has been suggested that BRCA1 missense variants located outside domains with known function are of no functional importance, and could be classified as (likely) benign. However, very little is known about the role of the regions outside the well-established domains of BRCA1, and only a few functional studies of missense variants located within these regions have been published. In this study, we have, therefore, functionally evaluated the effect of 14 rare BRCA1 missense variants considered to be of uncertain clinical significance, of which 13 are located outside the well-established domains and one within the RING domain. In order to investigate the hypothesis stating that most BRCA1 variants located outside the known protein domains are benign and of no functional importance, multiple protein assays including protein expression and stability, subcellular localisation and protein interactions have been performed, utilising the full-length protein to better mimic the native state of the protein. Two variants located outside the known domains (p.Met297Val and p.Asp1152Asn) and one variant within the RING domain (p.Leu52Phe) were found to make the BRCA1 protein more prone to proteasome-mediated degradation. In addition, two variants (p.Leu1439Phe and p.Gly890Arg) also located outside known domains were found to have reduced protein stability compared to the wild type protein. These findings indicate that variants located outside the RING, BRCT and coiled-coiled domains could also affect the BRCA1 protein function. For the nine remaining variants, no significant effects on BRCA1 protein functions were observed. Based on this, a reclassification of seven variants from VUS to likely benign could be suggested.

Keywords:  BRCA1; VUS; breast; functional assays; hereditary cancer; ovarian; variants of uncertain significance

DOI:  https://doi.org/10.3390/genes14020262
J Am Board Fam Med. 2023 Feb 17. pii: jabfm.2022.220288R1. [Epub ahead of print]

Primary Care Implications of the Expanded National Guidelines for Germline Testing of Patients Previously Diagnosed with Colorectal Cancer.

Steven Sorscher.

  Colorectal cancer (CRC) is among the most common cancers diagnosed in the United States. Most patients are cured, have completed their routine surveillance in oncology clinics, and are being followed by primary care clinicians (PCCs). Those providers are tasked with discussing with these patients genetic testing for inherited cancer-predisposing genes that are called PGVs.Recently, the National Comprehensive Cancer Network (NCCN) Hereditary/Familial High-Risk Assessment: Colorectal Guidelines expert panel updated their recommendations for genetic testing. It is now recommended that all patients diagnosed with CRC before age 50 be tested and patients diagnosed at age 50 or older be considered for multigene panel testing (MGPT) for inherited cancer-predisposing PGVs.Here, I discuss the basis for the NCCN expanded genetic testing recommendations and highlight the salient controversies related to genetic testing. I also review the literature that suggests that PCCs identified more training as the measure needed before they are comfortable having complex discussions related to genetic testing with their patients.

Keywords:  Colorectal Cancer; Genetic Testing; Germline Mutation; Primary Health Care; Risk Assessment

DOI:  https://doi.org/10.3122/jabfm.2022.220288R1
Cureus. 2023 Jan;15(1): e33975

Germline Testing of Mismatch Repair Genes Is Needed in the Initial Evaluation of Patients With Muir-Torre Syndrome-Associated Cutaneous Sebaceous Neoplasms: A Case Series.

Philip R Cohen, Razelle Kurzrock.

  Muir-Torre syndrome, a subtype of Lynch syndrome, is characterized by a germline mutation of one or more mismatch repair genes such as MutL Homolog 1 (MLH1), MutS Homolog 2 (MSH2), MutS Homolog 6 (MSH6), and PMS1 Homolog 2, mismatch repair system component (PMS2) resulting in microsatellite instability and at least one malignancy and a minimum of one syndrome-associated sebaceous neoplasm such as a sebaceous adenoma, epithelioma, or carcinoma. The syndrome has an autosomal dominant mode of inheritance detectable with germline sequencing of normal body elements such as blood, saliva, or normal skin for a mismatch repair gene mutation. Sebaceous neoplasms can occur before, concurrent with, or following Muir-Torre syndrome-related cancer. Immunohistochemistry, microsatellite instability testing, and next-generation sequencing of tumor tissue can evaluate malignancies such as colorectal and endometrial cancer and sebaceous neoplasms for somatic mismatch repair gene defects. However, these tests cannot differentiate somatic (acquired) versus germline alterations, and immunohistochemistry and microsatellite stability assessment can produce false negatives. Finally, the Mayo Muir-Torre syndrome risk score algorithm cannot always reliably determine which patient with a new sebaceous neoplasm should have germline testing. We report three men who presented with a Muir-Torre syndrome-associated sebaceous neoplasm: a 67-year-old male with no personal or family history of cancer who presented with a chest sebaceous carcinoma with MSH2 and MSH6 gene expression loss on immunohistochemistry and a Mayo Muir-Torre syndrome risk score of 0 who declined germline testing; a 74-year-old male with Janus kinase 2 (JAK2)-related myelodysplastic syndrome, yet no history of a Lynch syndrome-associated cancer, who developed a sebaceous epithelioma on his leg with PMS2 gene expression loss by immunohistochemistry and, although Mayo Muir-Torre syndrome risk score was only 1 (suggests no likelihood of a Lynch syndrome germline mismatch repair gene mutation), germline testing demonstrated a PMS2 alteration; and a 59-year-old male with a germline-confirmed MLH1-associated Lynch syndrome and a prior colon carcinoma, who developed a sebaceous adenoma on his nostril that unexpectedly demonstrated preservation of normal MLH1 staining (reflecting a false negative) by immunohistochemistry. In summary, these cases are consistent with the literature suggesting that tumor immunohistochemistry and microsatellite stability testing can miss germline alterations. Hence, we recommend that the initial evaluation of a patient with even a single new Muir-Torre syndrome-associated sebaceous neoplasm should include germline mismatch repair gene mutation testing. Finding a mismatch repair gene germline mutation should prompt genetic counseling, initial and future cancer screening recommendations, and germline testing of family members.

Keywords:  adenoma; carcinoma; epithelioma; germline; microsatellite instability; mismatch repair; muir-torre syndrome; neoplasm; sebaceous; somatic

DOI:  https://doi.org/10.7759/cureus.33975
Sci Rep. 2023 Feb 20. 13(1): 2959

Identification of germline cancer predisposition variants in pediatric sarcoma patients from somatic tumor testing.

Piedad Alba-Pavón, Lide Alaña, Miriam Gutierrez-Jimeno, Susana García-Obregón, Teresa Imízcoz, Elena Panizo, Paula González-Urdiales, Aizpea Echebarria-Barona, Ricardo Lopez Almaraz, Laura Zaldumbide, Itziar Astigarraga, Ana Patiño-García, Olatz Villate.

Genetic predisposition is an important risk factor for cancer in children and adolescents but detailed associations of individual genetic mutations to childhood cancer are still under intense investigation. Among pediatric cancers, sarcomas can arise in the setting of cancer predisposition syndromes. The association of sarcomas with these syndromes is often missed, due to the rarity and heterogeneity of sarcomas and the limited search of cancer genetic syndromes. This study included 43 pediatric and young adult patients with different sarcoma subtypes. Tumor profiling was undertaken using the Oncomine Childhood Cancer Research Assay (Thermo Fisher Scientific). Sequencing results were reviewed for potential germline alterations in clinically relevant genes associated with cancer predisposition syndromes. Jongmans´ criteria were taken into consideration for the patient selection. Fifteen patients were selected as having potential pathogenic germline variants due to tumor sequencing that identified variants in the following genes: CDKN2A, NF1, NF2, RB1, SMARCA4, SMARCB1 and TP53. The variants found in NF1 and CDKN2A in two different patients were detected in the germline, confirming the diagnosis of a cancer predisposition syndrome. We have shown that the results of somatic testing can be used to identify those at risk of an underlying cancer predisposition syndrome.

DOI: https://doi.org/10.1038/s41598-023-29982-2
Hum Genomics. 2023 Feb 23. 17(1): 13

Analysis of clinical and genomic profiles of therapy-related myeloid neoplasm in Korea.

Jiwon Yun, Hyojin Song, Sung-Min Kim, Soonok Kim, Seok Ryun Kwon, Young Eun Lee, Dajeong Jeong, Jae Hyeon Park, Sunghoon Kwon, Hongseok Yun, Dong Soon Lee.

  BACKGROUND: Therapy-related myeloid neoplasm (T-MN) rarely occurs among cancer survivors, and was characterized by poor prognosis. T-MN has germline predisposition in a considerable proportion. Here, clinical characteristics and germline/somatic variant profiles in T-MN patients were investigated, and the findings were compared with those of previous studies.METHODS: A review of medical records, cytogenetic study, targeted sequencing by next-generation sequencing, and survival analysis were performed on 53 patients with T-MN at a single institution in Korea.
RESULTS: The patients were relatively younger compared to T-MN patients in other studies. Our T-MN patients showed a high frequency of complex karyotypes, -5/del(5q), and -7/del(7q), which was similar to the Japanese study group but higher than the Australian study group. The most common primary disease was non-Hodgkin lymphoma, followed by breast cancer. The detailed distributions of primary diseases were different across study groups. Seven patients (13.2%) harbored deleterious presumed/potential germline variants in cancer predisposition genes (CPG) such as BRIP1, CEBPA, DDX41, FANCM, NBN, NF1, and RUNX1. In the somatic variant profile, TP53 was the most frequently mutated gene, which was consistent with the previous studies about T-MN. However, the somatic variant frequency in our study group was lower than in other studies. Adverse factors for overall survival were male sex, older age, history of previous radiotherapy, previous longer cytotoxic therapy, and -5/del(5q).
CONCLUSION: The findings of our study corroborate important information about T-MN patients. As well as a considerable predisposition to CPG, the clinical characteristics and somatic variant profile showed distinctive patterns. Germline variant testing should be recommended for T-MN patients. If the T-MN patients harbor pathogenic germline variants, the family members for stem cell donation should be screened for carrier status through germline variant testing to avoid donor-derived myeloid neoplasm. For the prediction of the prognosis in T-MN patients, sex, age, past treatment history, and cytogenetic findings can be considered.

Keywords:  Germline predisposition; Next-generation sequencing; Somatic mutation; Therapy-related myeloid neoplasm

DOI:  https://doi.org/10.1186/s40246-023-00458-8
Clin J Gastroenterol. 2023 Feb 17.

A case of unresectable intrahepatic cholangiocarcinoma with a germline BRCA1 mutation.

Yumiko Yamashita, Yasutaka Ishii, Masahiro Serikawa, Wataru Okamoto, Tomofumi Tsuboi, Yumiko Tatsukawa, Shinya Nakamura, Tetsuro Hirano, Juri Ikemoto, Shiro Oka.

  Intrahepatic cholangiocarcinoma (ICC) is a malignant liver tumor with poor prognosis. Various mutations in cancer-predisposing genes have been reported in ICC, and germline BRCA1/2 mutations, which are the causative genes for hereditary breast and ovarian cancer syndrome (HBOC), have been reported in many patients with ICC. Here, we report a case of unresectable ICC with a germline BRCA1 mutation. A 73-year-old man was found to have a mass in the left lobe of the liver on abdominal ultrasonography during a medical check-up and was referred to our institution. Contrast-enhanced computed tomography revealed a 30-mm mass with a delayed enhancement pattern, tumor invasion into the major blood vessels, and enlarged regional lymph nodes. Ultrasound-guided percutaneous tumor biopsy revealed a well-differentiated adenocarcinoma, and the patient was diagnosed with clinical Stage IIIB ICC. Systemic chemotherapy with gemcitabine and cisplatin was initiated because of the unresectable nature of the disease. Regarding family history, his eldest daughter was diagnosed with HBOC with a germline BRCA1 mutation at the time of breast cancer surgery, and she developed pancreatic cancer seven years later. The patient underwent BRCA1 single-site analysis and was diagnosed with HBOC with a germline BRCA1 mutation.

Keywords:  BRCA1; Hereditary breast and ovarian cancer syndrome; Intrahepatic cholangiocarcinoma

DOI:  https://doi.org/10.1007/s12328-023-01772-3
Int J Surg Pathol. 2023 Feb 19. 10668969231152588

A Rare PDGFRA Exon 15 Germline Mutation Identified in a Patient With Phenotypic Manifestations Concerning for GIST-Plus Syndrome: A Case Report and Review of Literature.

Chiyun Wang, Rhonda K Yantiss, Michael D Lieberman, Francesca Tubito-Massarano, Lihui Qin, Anna Yemelyanova, James P Solomon, Erika Hissong.

  Molecular alterations in PDGFRA are well-described as drivers of sporadic gastrointestinal stromal tumors (GISTs) and inflammatory fibroid polyps (IFPs). However, a small number of families with germline PDGFRA mutations in exons 12, 14, and 18 have been reported, forming the basis of an autosomal dominant inherited disorder with incomplete penetrance and variable expressivity, now referred to as PDGFRA-mutant syndrome or GIST-plus syndrome. Phenotypic manifestations of this rare syndrome include multiple gastrointestinal GISTS, IFPs, fibrous tumors, and other variable features. Herein, we report the case of a 58-year-old female who presented with a gastric GIST and numerous small intestinal IFPs, found to harbor a previously undescribed germline PDGFRA exon 15 p.G680R mutation. Somatic tumor testing was performed on the GIST, a duodenal IFP, and an ileal IFP utilizing a targeted next-generation sequencing panel, revealing additional and distinct secondary PDGFRA exon 12 somatic mutations in each of the 3 tumors. Our findings raise important considerations regarding mechanisms of tumor development in patients with underlying germline PDGFRA alterations and highlight the potential utility of expanding currently available germline and somatic testing panels to include exons outside the typical hotspot regions.

Keywords:  GIST-plus syndrome; PDGFRA; gastrointestinal stromal tumor; inflammatory fibroid polyp; tumor predisposition syndrome

DOI:  https://doi.org/10.1177/10668969231152588
Front Oncol. 2023 ;13 1123901

Clinical characteristics of pancreatic and biliary tract cancers in Lynch syndrome: A retrospective analysis from the Finnish National Lynch Syndrome Research Registry.

Kristina Zalevskaja, Jukka-Pekka Mecklin, Toni T Seppälä.

  Introduction: Patients with Lynch syndrome (LS) have an increased lifetime risk of pancreatic cancer (PC) and biliary tract cancer (BTC). These cancers have a notoriously pessimistic prognosis due to late diagnosis and limited therapeutic options. There are limited data based on small cohorts reviewing PC and BTC in LS patients.Methods: In this retrospective study of the Lynch Syndrome Registry of Finland (LSRFi), records of genetically verified LS patients diagnosed with PC or BTC between 1982 and 2020 were analyzed.
Results: Thirty-nine patients were included: tumor(s) were in the pancreas in 26 patients, in the biliary tract in 10, and in the ampulla of Vater in three. A pathogenic germline variant was found in MLH1 in 33 of 39 patients. Twenty-six patients with 28 tumors located in the pancreas were identified: 23 pancreatic ductal adenocarcinomas (PDACs) and five neuroendocrine tumors (NETs). The median age at diagnosis of PC was 64 years (range of 38-81). In PC, the 5-year overall survival (OS) rate was 20%, and in PDAC, it was 13.6%. Ten patients with BTC were diagnosed: two intrahepatic, five perihilar, two distal extrahepatic cholangiocarcinomas, and one gallbladder carcinoma. Eight patients were male, and the median age at diagnosis was 54 years (range of 34-82). The 5-year OS rate for BTC was 30%. Metachronous tumors were diagnosed in 28 patients (70%). Colorectal cancer was the most common metachronous tumor, diagnosed in 20 patients (51%), and diagnosed prior to PC or BTC in all cases. Curative surgery was attempted on 17 of 39 patients. For 30 patients (91%), the cause of death was PC or BTC; two patients died from another LS-associated cancer, and one died from a stroke.
Conclusion: Although the survival of LS patients with PC or BTC is better than in sporadic cancers, it is still poor and may be reflected by the relatively higher surgical resectability accounted for by the earlier age of onset. More studies on analyses of the molecular and immune profile, screening, and management of LS-associated pancreaticobiliary cancers are warranted.

Keywords:  Lynch syndrome (LS); biliary tract cancer; hereditary nonpolyposis colon cancer (HNPCC); microsatellite instability (MSI); pancreatic cancer

DOI:  https://doi.org/10.3389/fonc.2023.1123901
Cancers (Basel). 2023 Feb 20. pii: 1346. [Epub ahead of print]15(4):

Prognostic and Predictive Biomarkers in Familial Breast Cancer.

Siddhartha Deb, Anannya Chakrabarti, Stephen B Fox.

  Large numbers of breast cancers arise within a familial context, either with known inherited germline mutations largely within DNA repair genes, or with a strong family history of breast and/or ovarian cancer, with unknown genetic underlying mechanisms. These cancers appear to be different to sporadic cases, with earlier age of onset, increased multifocality and with association with specific breast cancer histological and phenotypic subtypes. Furthermore, tumours showing homologous recombination deficiency, due to loss of BRCA1, BRCA2, PALB2 and CHEK2 function, have been shown to be especially sensitive to platinum-based chemotherapeutics and PARP inhibition. While there is extensive research and data accrued on risk stratification and genetic predisposition, there are few data pertaining to relevant prognostic and predictive biomarkers within this breast cancer subgroup. The following is a review of such biomarkers in male and female familial breast cancer, although the data for the former are particularly sparse.

Keywords:  BRCA1; BRCA2; biomarker; familial breast cancer; prognostic and predictive

DOI:  https://doi.org/10.3390/cancers15041346
Prev Med Rep. 2023 Feb;31 102110

Identification of individuals at high-risk for pancreatic cancer using a digital patient-input tool combining family cancer history screening and new-onset diabetes.

Derk C F Klatte, Kristin E Clift, Sarah K Mantia, Lindsey Millares, Sanne A M Hoogenboom, Richard J Presutti, Michael B Wallace.

  Capturing family history might be a valuable tool for identification of individuals at increased risk of pancreatic cancer, which would allow enrollment into pancreatic surveillance programs. In addition, weight loss and concurrent new-onset diabetes may be utilized as an early marker for pancreatic cancer. This study evaluates the yield of combining family history and the Enriching New-Onset Diabetes for Pancreatic Cancer (ENDPAC) model to identify individuals who could benefit from pancreatic surveillance. A novel questionnaire and digital input tool was created that combined questions on family cancer history and criteria of the ENDPAC model. Individuals meeting ENDPAC criteria were enrolled directly in the high-risk pancreatic clinic. Individuals who met the criteria for a significant family history of cancer were offered referral to a genetic counselor. The questionnaire was completed by 453 patients. Of those, 25.8% (117/453) had significant familial risk factors. Eighteen individuals (15.4%) completed genetic testing previously, of whom five had a pathogenic variant. Thirty-four (29.9%) out of 117 individuals with a strong family history - flagged by the questionnaire - underwent genetic testing. Four (11.8%) of these patients harbored a pathogenic variant. Additionally, through cascade family testing, two siblings were found to carry pathogenic variants. Four (0.9%) of the 453 patients matched ENDPAC criteria. Two were diagnosed with pancreatic cancer and the others were enrolled in the surveillance program. In conclusion, identification of high-risk individuals for pancreatic cancer can be achieved by combining family history screening and the ENDPAC model to facilitate referral to genetic counseling and high-risk clinics.

Keywords:  Family history; Genetic counseling; Genetic testing; Hereditary pancreatic cancer

DOI:  https://doi.org/10.1016/j.pmedr.2023.102110
ESMO Open. 2023 Feb 21. pii: S2059-7029(23)00101-1. [Epub ahead of print]8(2): 100881

A systematic review and meta-analysis of germline BRCA mutations in pancreatic cancer patients identifies global and racial disparities in access to genetic testing.

S Paiella, D Azzolina, D Gregori, G Malleo, T Golan, D M Simeone, M B Davis, P G Vacca, A Crovetto, C Bassi, R Salvia, A V Biankin, R Casolino.

  BACKGROUND: Germline BRCA1 and BRCA2 mutations (gBRCAm) can inform pancreatic cancer (PC) risk and treatment but most of the available information is derived from white patients. The ethnic and geographic variability of gBRCAm prevalence and of germline BRCA (gBRCA) testing uptake in PC globally is largely unknown.MATERIALS AND METHODS: We carried out a systematic review and prevalence meta-analysis of gBRCA testing and gBRCAm prevalence in PC patients stratified by ethnicity. The main outcome was the distribution of gBRCA testing uptake across diverse populations worldwide. Secondary outcomes included: geographic distribution of gBRCA testing uptake, temporal analysis of gBRCA testing uptake in ethnic groups, and pooled proportion of gBRCAm stratified by ethnicity. The study is listed under PROSPERO registration number #CRD42022311769.
RESULTS: A total of 51 studies with 16 621 patients were included. Twelve of the studies (23.5%) enrolled white patients only, 10 Asians only (19.6%), and 29 (56.9%) included mixed populations. The pooled prevalence of white, Asian, African American, and Hispanic patients tested per study was 88.7%, 34.8%, 3.6%, and 5.2%, respectively. The majority of included studies were from high-income countries (HICs) (64; 91.2%). Temporal analysis showed a significant increase only in white and Asians patients tested from 2000 to present (P < 0.001). The pooled prevalence of gBRCAm was: 3.3% in white, 1.7% in Asian, and negligible (<0.3%) in African American and Hispanic patients.
CONCLUSIONS: Data on gBRCA testing and gBRCAm in PC derive mostly from white patients and from HICs. This limits the interpretation of gBRCAm for treating PC across diverse populations and implies substantial global and racial disparities in access to BRCA testing in PC.

Keywords:  BRCA; disparities; germline testing; pancreatic cancer

DOI:  https://doi.org/10.1016/j.esmoop.2023.100881