bims-lifras 2022-05-01 papers

Cancer Epidemiol Biomarkers Prev. 2022 Apr 27. pii: cebp.EPI-21-1287-A.2021. [Epub ahead of print]

Germline Pathogenic Variants Impact Clinicopathology of Advanced Lung Cancer.

BACKGROUND: The genetic factors that modulate risk for developing lung cancer have not been fully defined. Here, we sought to determine the prevalence and clinical significance of germline pathogenic/likely pathogenic variants (PV) in patients with advanced lung cancer.
METHODS: We studied clinical and tumor characteristics of germline PV in 5118 patients who underwent prospective genomic profiling using paired tumor-normal tissue samples in 468 cancer genes.
RESULTS: Germline PV in high/moderate penetrance genes were observed in 222 (4.3%) patients; of these, 193 patients had PV in DNA damage repair (DDR) pathway genes including BRCA2 (n=54), CHEK2 (n=30) and ATM (n=26) that showed high rate of biallelic inactivation in tumors. BRCA2 heterozygotes with lung adenocarcinoma were more likely to be never smokers and had improved survival compared to non-carriers. Fourteen patients with germline PV in lung cancer predisposing genes (TP53, EGFR, BAP1 and MEN1) were diagnosed at younger age compared to non-carriers, and of tumor suppressors, 75% demonstrated bi-allelic inactivation in tumors. Significantly higher proportion of germline PV in high/moderate penetrance genes were detected in high-risk patients who had either a family history of any cancer, multiple primary tumors or early age at diagnosis compared to unselected patients (10.5% vs 4.1%; p-value=1.7e-04).
CONCLUSIONS: These data underscore the biological and clinical importance of germline mutations in highly penetrant DDR genes as a risk factor for lung cancer.
IMPACT: The family members of lung cancer patients harboring PV in cancer predisposing genes should be referred for genetic counseling and may benefit from proactive surveillance.

DOI: https://doi.org/10.1158/1055-9965.EPI-21-1287

Cold Spring Harb Mol Case Stud. 2022 Apr;pii: a006203. [Epub ahead of print]8(3):

Pathogenic ATM and BAP1 germline mutations in a case of early-onset, familial sarcomatoid renal cancer.

Hannah N Bell, Chandan Kumar-Sinha, Rahul Mannan, Dana Zakalik, Yuping Zhang, Rohit Mehra, Deepa Jagtap, Saravana M Dhanasekaran, Ulka Vaishampayan.

Metastatic renal cell carcinoma (RCC) remains an incurable malignancy, despite recent advances in systemic therapies. Genetic syndromes associated with kidney cancer account for only 5%-8% of all diagnosed kidney malignancies, and genetic predispositions to kidney cancer predisposition are still being studied. Genomic testing for kidney cancer is useful for disease molecular subtyping but provides minimal therapeutic information. Understanding how aberrations drive RCC development and how their contextual influences, such as chromosome loss, genome instability, and DNA methylation changes, may alter therapeutic response is of importance. We report the case of a 36-yr-old female with aggressive, metastatic RCC and a significant family history of cancer, including RCC. This patient harbors a novel, pathogenic, germline ATM mutation along with a rare germline variant of unknown significance in the BAP1 gene. In addition, somatic loss of heterozygosity (LOH) in BAP1 and ATM genes, somatic mutation and LOH in the VHL gene, copy losses in Chromosomes 9p and 14, and genome instability are also noted in the tumor, potentially dictating this patient's aggressive clinical course. Further investigation is warranted to evaluate the association of ATM and BAP1 germline mutations with increased risk of RCC and if these mutations should lead to enhanced and early screening.

Keywords: clear cell renal cell carcinoma

DOI: https://doi.org/10.1101/mcs.a006203

AJOB Empir Bioeth. 2022 Apr 26. 1-14

Managing Pandora's Box: Familial Expectations around the Return of (Future) Germline Results.

Liza-Marie Johnson, Belinda N Mandrell, Chen Li, Zhaohua Lu, Jami Gattuso, Lynn W Harrison, Motomi Mori, Annastasia A Ouma, Michele Pritchard, Katianne M Howard Sharp, Kim E Nichols.

BACKGROUND: Pediatric oncology patients are increasingly being offered germline testing to diagnose underlying cancer predispositions. Meanwhile, as understanding of variant pathogenicity evolves, planned reanalysis of genomic results has been suggested. Little is known regarding the types of genomic information that parents and their adolescent children with cancer prefer to receive at the time of testing or their expectations around the future return of genomic results.
METHODS: Parents and adolescent children with cancer eligible for genomic testing for cancer predisposition were surveyed regarding their attitudes and expectations for receiving current and future germline results (ClinicalTrials.gov Identifier: NCT02530658).
RESULTS: All parents (100%) desired to learn about results for treatable or preventable conditions, with 92.4% wanting results even when there is no treatment or prevention. Parents expressed less interest in receiving uncertain results for themselves (88.3%) than for their children (95.3%). Most parents (95.9%) and adolescents (87.9%) believed that providers have a responsibility to share new or updated germline results indefinitely or at any point during follow-up care. Fewer parents (67.5%) indicated that they would want results if their child was deceased: 10.3% would not want to be contacted, 19.3% were uncertain.
CONCLUSIONS: Expectations for return of new or updated genomic results are high among pediatric oncology families, although up to one third of parents have reservations about receiving such information in the event of their child's death. These results underscore the importance of high-quality pre-and post-test counseling, conducted by individuals trained in consenting around genomic testing to elicit family preferences and align expectations around the return of germline results.

Keywords: Germline genomic testing; bioethics; cancer predisposition; pediatric oncology; pediatrics; return of results

DOI: https://doi.org/10.1080/23294515.2022.2063994