bims-lifras 2022-02-27 papers

Genes (Basel). 2022 Feb 09. pii: 321. [Epub ahead of print]13(2):

Pancreatic Cancer with Mutation in BRCA1/2, MLH1, and APC Genes: Phenotype Correlation and Detection of a Novel Germline BRCA2 Mutation.

Maria Teresa Vietri, Giovanna D'Elia, Gemma Caliendo, Luisa Albanese, Giuseppe Signoriello, Claudio Napoli, Anna Maria Molinari.

Pancreatic ductal adenocarcinoma (PDAC) is the seventh leading cause of cancer death worldwide; most of cases are sporadic, however about 5% to 10% report a hereditary predisposition. Several hereditary syndromes have been associated with familial pancreatic cancer (FPC) onset, including hereditary breast and ovarian cancer syndrome (HBOC), Lynch syndrome (LS), Familial atypical multiple mole melanoma (FAMMM), Familial adenomatous polyposis (FAP), Li-Fraumeni syndrome (LFS), Peutz-Jeghers syndrome (PJS), and Hereditary pancreatitis (HP).The aim of this study was to determine the mutational status of a cohort of 56 HBOC families, 7 LS families, 3 FAP and FAMMM families, and 1 LFS family with at least one case of PDAC. Mutation analysis of BRCA1/2, ATM, CHEK2, PALB2, RAD51C, RAD51D, NBN, CDH1, TP53, MLH1, MSH2, MSH6, and PMS2 genes, showedmutation in BRCA1/2, MLH1, and APC genes. We founda high mutation rate in patients belong HBOC and LS families, with a percentage of 28.6% in both syndromes and prevalence in HBOC of BRCA2 mutations with one case of double mutation in BRCA2 gene. In FAP family, we found a pathogenic mutation in APC gene in 1/3 families. We observed an early onset of PDAC and a lower survival in PDAC patients belonging to mutated families, while no evidence of possible pancreatic cancer cluster regions was found. Moreover, we identified a novel BRCA2 germline mutation, c.5511delT (p.Phe1837LeufsX3), not reported in any database, that segregated with disease in HBOC patients. Mutational analysis was extended to family membersof mutated patients, both healthy and cancer affected, which revealed 23 unaffected family members that inherited the proband's mutation. Although correlative by its nature, the presence of a BRCA mutation in PDAC patients may have benefits in terms of optimized treatment and longer outcome.

Keywords: BRCA genes; MMR genes; familial adenomatous polyposis; hereditary breast and ovarian cancer syndrome; hereditary nonpolyposis colon cancer syndrome; pancreatic ductal adenocarcinoma

DOI: https://doi.org/10.3390/genes13020321

Sci Rep. 2022 02 21. 12(1): 2507

Half of germline pathogenic and likely pathogenic variants found on panel tests do not fulfil NHS testing criteria.

Tala Andoni, Jennifer Wiggins, Rachel Robinson, Ruth Charlton, Michael Sandberg, Rosalind Eeles.

Genetic testing for cancer predisposition has been curtailed by the cost of sequencing, and testing has been restricted by eligibility criteria. As the cost of sequencing decreases, the question of expanding multi-gene cancer panels to a broader population arises. We evaluated how many additional actionable genetic variants are returned by unrestricted panel testing in the private sector compared to those which would be returned by adhering to current NHS eligibility criteria. We reviewed 152 patients referred for multi-gene cancer panels in the private sector between 2014 and 2016. Genetic counselling and disclosure of all results was standard of care provided by the Consultant. Every panel conducted was compared to current eligibility criteria. A germline pathogenic / likely pathogenic variant (P/LP), in a gene relevant to the personal or family history of cancer, was detected in 15 patients (detection rate of 10%). 46.7% of those found to have the P/LP variants (7 of 15), or 4.6% of the entire set (7 of 152), did not fulfil NHS eligibility criteria. 46.7% of P/LP variants in this study would have been missed by national testing guidelines, all of which were actionable. However, patients who do not fulfil eligibility criteria have a higher Variant of Uncertain Significance (VUS) burden. We demonstrated that the current England NHS threshold for genetic testing is missing pathogenic variants which would alter management in 4.6%, nearly 1 in 20 individuals. However, the clinical service burden that would ensue is a detection of VUS of 34%.

DOI: https://doi.org/10.1038/s41598-022-06376-4

Dis Colon Rectum. 2022 Feb 21.

Germline Cancer Risk Profiles of Young-Onset Colorectal Cancer Patients: Findings from a Prospective Universal Germline Testing and Tele-Genetics Program.

Y Nancy You, Julie Moskowitz, George J Chang, Maureen Mork, Miguel Rodriguez-Bigas, Brian K Bednarski, Craig Messick, Matthew Tillman, John Skibber, Sa Nguyen, Scott Kopetz, Eduardo Vilar.

BACKGROUND: Colorectal cancer is being increasingly diagnosed under age 50. An inheritable cancer predisposition has been reported in 22% of the young-onset cases. Assessment of germline risk is critical for personalized cancer care.
OBJECTIVE: To implement universal germline cancer risk assessment and testing, and to define the germline cancer risk profiles of patients presenting with young-onset disease.
DESIGN: A prospective cohort study.
SETTING: A tertiary-referral academic medical center.
PATIENTS: Newly diagnosed patients presenting to surgical clinics between September 2019 and February 2021 were treated on a standardized care pathway including universal germline risk assessment.
INTERVENTION: Patients received education material on young-onset disease, genetic testing, and insurance coverage, followed by genetic counseling (either remotely by tele-genetics or in-person). Consenting patients were assessed on a 47-gene common hereditary cancers panel.
MAIN OUTCOME MEASURE: Proportion of patients with identifiable germline cancer predisposition.
RESULTS: Among 500 colorectal cancer patients, 185(37%) were aged 50 or younger (median: 44). A family history was absent in the majority (123, 67%), and 15 tumors (8.1%) were deoxyribonucleic acid mismatch-repair-deficient. Germline testing was completed in 130 patients (70%); the remainder were pending (7%), deceased (1%), or declined (22%). Pathogenic germline mutations were identified in 25 (of 130, 19%) patients: 12 in mismatch repair genes and 13 in other genes. A variant of uncertain significance was found in 23 (18%) patients. Importantly, a pathogenic germline mutation was identified in 12% of the patients without a family history (versus 32% with; p = 0.015) and in 13% of those with mismatch-repair-proficient colorectal cancers (versus 71% if deficient; p < 0.001).
LIMITATIOND: Implemented at single tertiary academic institution.
CONCLUSION: One in five patients with young-onset disease harbored germline cancer predisposition. This detection rate, coupled with a high level of interest and acceptance from patients and feasibility of implementation, support universal germline cancer risk assessment in this patient population. See Video Abstract at http://links.lww.com/DCR/B925.

DOI: https://doi.org/10.1097/DCR.0000000000002347

Cancers (Basel). 2022 Feb 16. pii: 1004. [Epub ahead of print]14(4):

Clinical Management of Prostate Cancer in High-Risk Genetic Mutation Carriers.

Roderick Clark, Jaime Herrera-Caceres, Miran Kenk, Neil Fleshner.

BACKGROUND: Prostate cancer is a leading cause of death. Approximately one in eight men who are diagnosed with prostate cancer will die of it. Since there is a large difference in mortality between low- and high-risk prostate cancers, it is critical to identify individuals who are at high-risk for disease progression and death. Germline genetic differences are increasingly recognized as contributing to risk of lethal prostate cancer. The objective of this paper is to review prostate cancer management options for men with high-risk germline mutations.
METHODS: We performed a review of the literature to identify articles regarding management of prostate cancer in individuals with high-risk germline genetic mutations.
RESULTS: We identified numerous publications regarding the management of prostate cancer among high-risk germline carriers, but the overall quality of the evidence is low.
CONCLUSIONS: We performed a review of the literature and compiled clinical considerations for the management of individuals with high-risk germline mutations when they develop prostate cancer. The quality of the evidence is low, and there is an immediate need for further research and the development of consensus guidelines to guide clinical practice for these individuals.

Keywords: clinical management; germline genetic mutations; prostate cancer

DOI: https://doi.org/10.3390/cancers14041004