bims-lifras 2021-08-22 papers

Hered Cancer Clin Pract. 2021 Aug 16. 19(1): 33

Significant detection of new germline pathogenic variants in Australian Pancreatic Cancer Screening Program participants.

Krithika Murali, Tanya M Dwarte, Mehrdad Nikfarjam, Katherine M Tucker, Rhys B Vaughan, Marios Efthymiou, Allison Collins, Allan D Spigelman, Lucinda Salmon, Amber L Johns, David B Williams, Martin B Delatycki, Thomas John, Alina Stoita.

BACKGROUND: The Australian Pancreatic Cancer Screening Program (APCSP) offers endoscopic ultrasound surveillance for individuals at increased risk of pancreatic ductal adenocarcinoma (PDAC) with all participants requiring assessment by a Familial Cancer Service before or after study enrolment.
METHODS: Individuals aged 40-80 years (or 10 years younger than the earliest PDAC diagnosis) were eligible for APCSP study entry if they had 1) ≥ two blood relatives with PDAC (at least one of first-degree association); 2) a clinical or genetic diagnosis of Hereditary Pancreatitis or Peutz-Jeghers syndrome irrespective of PDAC family history; or 3) a known PDAC predisposition germline pathogenic variant (BRCA2, PALB2, CDKN2A, or Lynch syndrome) with ≥one PDAC-affected first- or second-degree relative. Retrospective medical record review was conducted for APCSP participants enrolled at the participating Australian hospitals from January 2011 to December 2019. We audited the genetic investigations offered by multiple Familial Cancer Services who assessed APCSP participants according to national guidelines, local clinical protocol and/or the availability of external research-funded testing, and the subsequent findings. Descriptive statistical analysis was performed using Microsoft Excel.
RESULTS: Of 189 kindreds (285 participants), 50 kindreds (71 participants) had a known germline pathogenic variant at enrolment (BRCA2 n = 35, PALB2 n = 6, CDKN2A n = 3, STK11 n = 3, PRSS1 n = 2, MLH1 n = 1). Forty-eight of 136 (35%) kindreds with no known germline pathogenic variant were offered mutation analysis; 89% was clinic-funded, with increasing self-funded testing since 2016. The relatively low rates of genetic testing performed reflects initial strict criteria for clinic-funded genetic testing. New germline pathogenic variants were detected in five kindreds (10.4%) after study enrolment (BRCA2 n = 3 kindreds, PALB2 n = 1, CDKN2A n = 1). Of note, only eight kindreds were reassessed by a Familial Cancer Service since enrolment, with a further 21 kindreds identified as being suitable for reassessment.
CONCLUSION: Germline pathogenic variants associated with PDAC were seen in 29.1% of our high-risk cohort (55/189 kindreds; 82/285 participants). Importantly, 10.4% of kindreds offered genetic testing were newly identified as having germline pathogenic variants, with majority being BRCA2. As genetic testing standards evolve rapidly in PDAC, 5-yearly reassessment of high-risk individuals by Familial Cancer Services is warranted.

Keywords: Cancer screening; Genetic testing; Genetics; Hereditary Cancer syndromes; Pancreatic cancer; Pathogenic variant

DOI: https://doi.org/10.1186/s13053-021-00190-1

Clin Transl Gastroenterol. 2021 Aug 16. 12(8): e00397

Integrating Tumor Sequencing Into Clinical Practice for Patients With Mismatch Repair-Deficient Lynch Syndrome Spectrum Cancers.

INTRODUCTION: Uninformative germline genetic testing presents a challenge to clinical management for patients suspected to have Lynch syndrome, a cancer predisposition syndrome caused by germline variants in the mismatch repair (MMR) genes or EPCAM.
METHODS: Among a consecutive series of MMR-deficient Lynch syndrome spectrum cancers identified through immunohistochemistry-based tumor screening, we investigated the clinical utility of tumor sequencing for the molecular diagnosis and management of suspected Lynch syndrome families. MLH1-deficient colorectal cancers were prescreened for BRAF V600E before referral for genetic counseling. Microsatellite instability, MLH1 promoter hypermethylation, and somatic and germline genetic variants in the MMR genes were assessed according to an established clinical protocol.
RESULTS: Eighty-four individuals with primarily colorectal (62%) and endometrial (31%) cancers received tumor-normal sequencing as part of routine clinical genetic assessment. Overall, 27% received a molecular diagnosis of Lynch syndrome. Most of the MLH1-deficient tumors were more likely of sporadic origin, mediated by MLH1 promoter hypermethylation in 54% and double somatic genetic alterations in MLH1 (17%). MSH2-deficient, MSH6-deficient, and/or PMS2-deficient tumors could be attributed to pathogenic germline variants in 37% and double somatic events in 28%. Notably, tumor sequencing could explain 49% of cases without causal germline variants, somatic MLH1 promoter hypermethylation, or somatic variants in BRAF.
DISCUSSION: Our findings support the integration of tumor sequencing into current Lynch syndrome screening programs to improve clinical management for individuals whose germline testing is uninformative.

DOI: https://doi.org/10.14309/ctg.0000000000000397

Cancer Discov. 2021 Aug 20.

Distinct Mutational Processes Influence Germline DNA Mutations.

Nine distinct mutational processes underlie human germline mutations.

DOI: https://doi.org/10.1158/2159-8290.CD-RW2021-121

Elife. 2021 Aug 18. pii: e68699. [Epub ahead of print]10

Multi-syndrome, multi-gene risk modeling for individuals with a family history of cancer with the novel R package PanelPRO.

Gavin Lee, Jane W Liang, Qing Zhang, Theodore Huang, Christine Choirat, Giovanni Parmigani, Danielle Braun.

Identifying individuals who are at high risk of cancer due to inherited germline mutations is critical for effective implementation of personalized prevention strategies. Most existing models focus on a few specific syndromes; however recent evidence from multi-gene panel testing shows that many syndromes are overlapping, motivating the development of models that incorporate family history on several cancers and predict mutations for a comprehensive panel of genes. We present PanelPRO, a new, open-source R package providing a fast, flexible back-end for multi-gene, multi-cancer risk modeling with pedigree data. It includes a customizable database with default parameter values estimated from published studies and allows users to select any combinations of genes and cancers for their models, including well-established single syndrome BayesMendel models (BRCAPRO and MMRPRO). This leads to more accurate risk predictions and ultimately has a high impact on prevention strategies for cancer and clinical decision making. The package is available for download for research purposes at https://projects.iq.harvard.edu/bayesmendel/panelpro.

Keywords: cancer biology; genetics; genomics; none

DOI: https://doi.org/10.7554/eLife.68699

Pharmacogenomics. 2021 Aug 19.

Molecular pathogenesis of hereditary lung cancer: a literature review.

Souraya Rammal, Hampig Raphael Kourie, Nadine Jalkh, Cybel Mehawej, Eliane Chouery, Elissar Moujaess, Georges Dabar.

Among all cancer types, pulmonary cancer has the highest mortality rate. Tobacco consumption remains the major risk factor for the development of lung cancer. However, many studies revealed a correlation between inherited genetic variants and predisposition to lung cancer, especially in nonsmokers. To date, genetic testing for the detection of germline mutations is not yet recommended in patients with lung cancer and testing is focused on somatic alterations given their implication in the treatment choice. Understanding the impact of genetic predisposition on the occurrence of lung cancer is essential to enable the introduction of accurate guidelines and recommendations that might reduce mortality. In this review paper, we describe familial lung cancer, and expose germline mutations that are linked to this type of cancer. We also report pathogenic genetic variants linked to syndromes associated with lung cancer.

Keywords: familial lung cancer; germline mutation; heredity; pulmonary cancer

DOI: https://doi.org/10.2217/pgs-2020-0150

Am J Ophthalmol Case Rep. 2021 Sep;23 101189

Germline ATM mutation and somatic PIK3CA and BCOR mutations found in an infant with aggressive orbital embryonal rhabdomyosarcoma.

Pimkwan Jaru-Ampornpan, Chottiwat Tansirisithikul, Manachaya Prukajorn, Somponnat Sampattavanich, Manop Pithukpakorn.

Purpose: To report a case of aggressive infantile orbital embryonal rhabdomyosarcoma harboring germline ATM mutation and 2 somatic mutations as revealed by next-generation sequencing and the potential application for personalized therapy.
Observations: A 7-month-old male developed a rapidly progressive left proptosis over 6 weeks due to a large medial orbital mass. Biopsy revealed embryonal rhabdomyosarcoma. After the first cycle of chemotherapy, re-imaging showed interval tumor enlargement with intracranial extension. Craniotomy, combined with orbital exenteration, was performed. Tumor specimens and blood samples were sent for 596 gene DNA sequencing panels with RNA-sequencing focused on actionable mutations as well as gene fusion detection. Sequencing revealed 3 clinically relevant mutations: a germline ATM loss-of-function (LOF) mutation, a somatic PIK3CA gain-of-function mutation, and a somatic BCOR LOF mutation. No chromosomal translocation was detected. Workup for metastasis was positive for bone marrow involvement. Despite standard high-dose adjuvant chemotherapy in combination with radiation therapy, the patient died 10 months later with metastatic diseases.
Conclusions and importance: This case highlights an aggressive form of embryonal rhabdomyosarcoma in an infantile orbit. The presence of germline mutation may explain the increased chemo-resistance and adverse prognosis, and may be used as the target for genomic-directed therapy.

Keywords: ATM mutation; Embryonal; Infantile; Orbit; Rhabdomyosarcoma

DOI: https://doi.org/10.1016/j.ajoc.2021.101189