bims-lifras 2024-04-21 papers

Issue of 2024–04–21
six papers selected by
Joanna Zawacka, Karolinska Institutet

Br J Haematol. 2024 Apr 19.

Germline assessment for alloHSCT candidates over 50 years: A 'Fast-Track' screening in myeloid neoplasms.

GESMD centres

Patients aged 50 or above diagnosed with myeloid neoplasms (MNs) are typically not candidates for germline testing. However, approximately 8% carry pathogenic germline variants. Allogeneic haematopoietic stem cell transplantation (alloHSCT) remains an option for those aged over 50; neglecting germline testing could mask the risk for relative donor cell-derived MN. We propose a germline-augmented somatic panel (GASP), combining MN predisposition genes with a myeloid somatic panel for timely germline variant identification when initial testing is not indicated. Out of our 133 whole-exome-sequenced MN cases aged over 50 years, 9% had pathogenic/likely variants. GASP detected 92%, compared to 50% with somatic-only panel. Our study highlights the relevance of germline screening in MN, particularly for alloHSCT candidates without established germline-testing recommendations.

Keywords: HSC transplantation; genetic testing; germline predisposition; myeloid neoplasms

DOI: https://doi.org/10.1111/bjh.19460

Pathology. 2024 Mar 29. pii: S0031-3025(24)00094-1. [Epub ahead of print]

Germline potential should not be overlooked for cancer variants identified in tumour-only somatic mutation testing.

Mohammad Al-Shinnag, Pak Leng Cheong, Annabel Goodwin, Ronald Trent, Bing Yu.

DNA sequencing of tumour tissue has become the standard care for many solid cancers because of the option to detect somatic variants that have significant therapeutic, diagnostic and prognostic implications. Variants found within the tumour may be either somatic or germline in origin. Somatic cancer gene panels are developed to detect acquired (somatic) variants that are relevant for therapeutic or molecular characterisation of the tumour, expanding gene panels now include genes which may also inform patient management such as cancer predisposition syndromes (CPS) genes. Identifying germline cancer predisposition variants can alter cancer management, the risk of developing new primary cancers and risk for cancer in at-risk family members. This paper discusses the clinical, technical and ethical challenges related to identifying and reporting potential germline pathogenic variants that are detected on tumour sequencing. It also highlights the existence of the eviQ national guidelines for CPS with advice on germline confirmation of somatic findings to pathology laboratories in Australia.

Keywords: Somatic mutation testing; germline pathogenic variants; somatic variants; tumour-only sequencing

DOI: https://doi.org/10.1016/j.pathol.2024.03.001

bioRxiv. 2024 Apr 05. pii: 2024.04.03.588009. [Epub ahead of print]

Distinct genomic and immunologic tumor evolution in germline TP53- driven breast cancers.

Pathogenic germline TP53 alterations cause Li-Fraumeni Syndrome (LFS), and breast cancer is the most common cancer in LFS females. We performed first of its kind multimodal analysis of LFS breast cancer (LFS-BC) compared to sporadic premenopausal BC. Nearly all LFS-BC underwent biallelic loss of TP53 with no recurrent oncogenic variants except ERBB2 (HER2) amplification. Compared to sporadic BC, in situ and invasive LFS-BC exhibited a high burden of short amplified aneuploid segments (SAAS). Pro-apoptotic p53 target genes BAX and TP53I3 failed to be up-regulated in LFS-BC as was seen in sporadic BC compared to normal breast tissue. LFS-BC had lower CD8+ T-cell infiltration compared to sporadic BC yet higher levels of proliferating cytotoxic T-cells. Within LFS-BC, progression from in situ to invasive BC was marked by an increase in chromosomal instability with a decrease in proliferating cytotoxic T-cells. Our study uncovers critical events in mutant p53-driven tumorigenesis in breast tissue.

DOI: https://doi.org/10.1101/2024.04.03.588009

medRxiv. 2024 Apr 07. pii: 2024.04.05.24305402. [Epub ahead of print]

Real-world evaluation of deep learning algorithms to classify functional pathogenic germline variants.

Ryan D Chow, Ravi B Parikh, Katherine L Nathanson.

Deep learning models for variant pathogenicity prediction can recapitulate expert-curated annotations, but their performance remains unexplored on actual disease phenotypes in a real-world setting. Here, we apply three state-of-the-art pathogenicity prediction models to classify hereditary breast cancer gene variants in the UK Biobank. Predicted pathogenic variants in BRCA1, BRCA2 and PALB2 , but not ATM and CHEK2 , were associated with increased breast cancer risk. We explored gene-specific score thresholds for variant pathogenicity, finding that they could improve model performance. However, when specifically tasked with classifying variants of uncertain significance, the deep learning models were generally of limited clinical utility.

DOI: https://doi.org/10.1101/2024.04.05.24305402

Cancer Prev Res (Phila). 2024 Apr 18. OF1-OF8

Germline and Somatic Fumarate Hydratase Testing in Atypical Uterine Leiomyomata.

Lindsay M Kipnis, Katelyn M Breen, Diane R Koeller, Alison Schwartz Levine, Zelei Yang, Hyeji Jun, Nabihah Tayob, Samantha M Stokes, Connor P Hayes, Arezou A Ghazani, Sarah J Hill, Huma Q Rana.

PREVENTION RELEVANCE: Women diagnosed with fumarate hydratase (FH)-deficient uterine leiomyomata are at increased risk of renal cancer. This work suggests a more standardized pathology-genetic counseling referral pathway for these patients, and that research on underlying causes of FH-deficient uterine leiomyomata in the absence of germline FH pathogenic/likely pathogenic variants is needed.

DOI: https://doi.org/10.1158/1940-6207.CAPR-23-0535

Int J Clin Oncol. 2024 Apr 14.

Incidence and molecular characteristics of deficient mismatch repair conditions across nine different tumors and identification of germline variants involved in Lynch-like syndrome.

Tetsuya Ito, Tatsuro Yamaguchi, Kensuke Kumamoto, Okihide Suzuki, Noriyasu Chika, Satoru Kawakami, Tomonori Nagai, Tsukasa Igawa, Kenji Fujiyoshi, Yoshito Akagi, Tomio Arai, Kiwamu Akagi, Hidetaka Eguchi, Yasushi Okazaki, Hideyuki Ishida.

BACKGROUND: Based on molecular characteristics, deficient DNA mismatch repair (dMMR) solid tumors are largely divided into three categories: somatically MLH1-hypermethylated tumors, Lynch syndrome (LS)-associated tumors, and Lynch-like syndrome (LLS)-associated tumors. The incidence of each of these conditions and the corresponding pathogenic genes related to LLS remain elusive.
METHODS: We identified dMMR tumors in 3609 tumors from 9 different solid organs, including colorectal cancer, gastric cancer, small-bowel cancer, endometrial cancer, ovarian cancer, upper urinary tract cancer, urinary bladder cancer, prostate cancer, and sebaceous tumor, and comprehensively summarized the characterization of dMMR tumors. Characterization of dMMR tumors were performed as loss of at least one of MMR proteins (MLH1, MSH2, MSH6, and PMS2), by immunohistochemistry, followed by MLH1 promotor methylation analysis and genetic testing for MMR genes where appropriate. Somatic variant analysis of MMR genes and whole exome sequencing (WES) were performed in patients with LLS.
RESULTS: In total, the incidence of dMMR tumors was 5.9% (24/3609). The incidence of dMMR tumors and the proportion of the three categorized dMMR tumors varied considerably with different tumor types. One to three likely pathogenic/pathogenic somatic MMR gene variants were detected in 15 out of the 16 available LLS tumors. One patient each from 12 patients who gave consent to WES demonstrated non-MMR germline variants affect function (POLQ or BRCA1).
CONCLUSIONS: Our data regarding the LS to LLS ratio would be useful for genetic counseling in patients who are suspected to have LS, though the genetic backgrounds for the pathogenesis of LLS need further investigation.

Keywords: Deficient DNA mismatch repair (dMMR); Lynch-like syndrome; dMMR tumors

DOI: https://doi.org/10.1007/s10147-024-02518-y