bims-lifras 2022-02-13 papers

bims-lifras

Biomed News

on Li-Fraumeni syndrome

Issue of 2022–02–13
nine papers selected by
Joanna Zawacka-Pankau, Karolinska Institutet

Increasing our knowledge of germline variants.
Hereditary oral squamous cell carcinoma associated with CDKN2A germline mutation: a case report.
KLK3 germline mutation I179T complements DNA repair genes for predicting prostate cancer progression.
Germline mutations of the adenomatous polyposis coli (APC) gene in Algerian familial adenomatous polyposis cohort: first report.
Germline variant testing in Serrated Polyposis Syndrome.
Lynch syndrome caused by a novel deletion of the promoter and exons 1-13 of MLH1 gene.
Retrospective assessment of barriers and access to genetic services for hereditary cancer syndromes in an integrated health care delivery system.
Unique ER PR expression pattern in breast cancers with CHEK2 mutation: a hormone receptor and HER2 analysis based on germline cancer predisposition genes.
The Mutational Landscape of Early-Onset Breast Cancer: A Next-Generation Sequencing Analysis.

Int Cancer Conf J. 2022 Jan;11(1): 1

Increasing our knowledge of germline variants.

Noriomi Matsumura.

DOI: https://doi.org/10.1007/s13691-021-00529-4
J Otolaryngol Head Neck Surg. 2022 Feb 05. 51(1): 5

Hereditary oral squamous cell carcinoma associated with CDKN2A germline mutation: a case report.

Ah-Reum Jeong, Kimberly Forbes, Ryan K Orosco, Ezra E W Cohen.

   BACKGROUND: Germline CDKN2A mutations are a well-known cause of familial atypical multiple mole melanoma (OMIM #155601) and melanoma-pancreatic cancer syndrome (OMIM #606719). Increased risk of head and neck squamous cell carcinoma (HNSCC), particularly oral squamous cell carcinoma (OSCC) in those with germline CDKN2A mutations, has been described. However, screening for HNSCC is not a routine practice in patients with CDKN2A germline mutations and these mutations are not a conventional test for HNSCC patients without obvious risk factors.
CASE PRESENTATION: We describe a female with no smoking history who developed oral squamous cell carcinoma at age 39 and had a complex clinical course of recurrent multifocal squamous cell carcinoma (SCC) and carcinoma in situ of the oral cavity and oropharynx. Detailed family history demonstrated that her mother was diagnosed with OSCC and melanoma in her 40 s, and her maternal grandfather was diagnosed with metastatic melanoma in his 40 s. Genetic testing of the patient and her mother revealed CDKN2A c.301G>T mutation. She was referred to genetic counseling as well as to dermatology, gastroenterology, and neurology for cancer surveillance. She was treated with resections and has no evidence of disease 3 years after diagnosis.
CONCLUSIONS: We report a family with a CDKN2A c.301 G>T mutation who also have significant history of OSCC, adding to the growing body of literature suggesting increased risk of HNSCC, particularly OSCC, in CDKN2A germline mutation carriers. It is important to consider CDKN2A mutation testing in familial HNSCC and young patients without obvious risk factors. Moreover, surveillance for HNSCC should be routine practice in those with a CDKN2A germline mutation.

Keywords:  CDKN2A germline mutation; Case report; Familial atypical multiple moles melanoma; Head and neck squamous cell cancer; Oral squamous cell cancer

DOI:  https://doi.org/10.1186/s40463-022-00556-y
Prostate Cancer Prostatic Dis. 2022 Feb 11.

KLK3 germline mutation I179T complements DNA repair genes for predicting prostate cancer progression.

Jianfeng Xu, Zhuqing Shi, Jun Wei, Rong Na, W Kyle Resurreccion, Chi-Hsiung Wang, Chris Sample, Misop Han, S Lilly Zheng, Kathleen A Cooney, Brian T Helfand, William B Isaacs.

BACKGROUND: Germline mutations in DNA repair genes and KLK3 have been associated with adverse prostate cancer (PCa) outcomes in separate studies but never jointly. The objective of this study is to simultaneously assess these two types of germline mutations.
METHODS: Germline rare pathogenic mutations (RPMs) in 9 commonly tested DNA repair genes and KLK3 variants were tested for their associations with PCa progression in two PCa cohorts: (1) hospital-based PCa patients treated with radical surgery at the Johns Hopkins Hospital (JHH, N = 1943), and (2) population-based PCa patients in the UK Biobank (UKB, N = 10,224). Progression was defined as metastasis and/or PCa-specific death (JHH) and PCa-specific death (UKB). RPMs of DNA repair genes were annotated using the American College of Medical Genetics recommendations. Known KLK3 variants were genotyped. Associations were tested using a logistic regression model adjusting for genetic background (top ten principal components).
RESULTS: In the JHH, 3.2% (59/1,843) of patients had RPMs in 9 DNA repair genes; odds ratio (OR, 95% confidence interval) for progression was 2.99 (1.6-5.34), P < 0.001. In comparison, KLK3 I179T mutation was more common; 9.7% (189/1,943) carried the mutation, OR = 1.6 (1.05-2.37), P = 0.02. Similar results were found in the UKB. Both types of mutations remained statistically significant in multivariable analyses. In the combined cohort, compared to patients without any mutations (RPMs-/KLK3-), RPMs-/KLK3+ patients had modestly increased risk for progression [OR = 1.54 (1.15-2.02), P = 0.003], and RPMs+/KLK3+ patients had greatly increased risk for progression [OR = 5.41 (2.04-12.99), P < 0.001]. Importantly, associations of mutations with PCa progression were found in patients with clinically defined low- or intermediate risk for disease progression.
CONCLUSIONS: Two different cohorts consistently demonstrate that KLK3 I179T and RPMs of nine commonly tested DNA repair genes are complementary for predicting PCa progression. These results are highly relevant to PCa germline testing and provide critical information for KLK3 I179T to be considered in guidelines.

DOI: https://doi.org/10.1038/s41391-021-00466-6
Mol Biol Rep. 2022 Feb 10.

Germline mutations of the adenomatous polyposis coli (APC) gene in Algerian familial adenomatous polyposis cohort: first report.

Feriel Khider, Farid Cherbal, Asma-Lamia Boumehdi, Karim Layaida, Hassen Mahfouf, Ferhat Zebboudj, Mustapha Maaoui.

   BACKGROUND: Familial adenomatous polyposis (known also as classical or severe FAP) is a rare autosomal dominant colorectal cancer predisposition syndrome, characterized by the presence of hundreds to thousands of adenomatous polyps in the colon and rectum from an early age. In the absence of prophylactic surgery, colorectal cancer (CRC) is the inevitable consequence of FAP. The vast majority of FAP is caused by germline mutations in the adenomatous polyposis coli (APC) tumor suppressor gene (5q21). To date, most of the germline mutations in classical FAP result in truncation of the APC protein and 60% are mainly located within exon 15.
MATERIAL AND METHODS: In this first nationwide study, we investigated the clinical and genetic features of 52 unrelated Algerian FAP families. We screened by PCR-direct sequencing the entire exon 15 of APC gene in 50 families and two families have been analyzed by NGS using a cancer panel of 30 hereditary cancer genes.
RESULTS: Among 52 FAP index cases, 36 had 100 or more than 100 polyps, 37 had strong family history of FAP, 5 developed desmoids tumors, 15 had extra colonic manifestations and 21 had colorectal cancer. We detected 13 distinct germline mutations in 17 FAP families. Interestingly, 4 novel APC germline pathogenic variants never described before have been identified in our study.
CONCLUSIONS: The accumulating knowledge about the prevalence and nature of APC variants in Algerian population will contribute in the near future to the implementation of genetic testing and counseling for FAP patients.

Keywords:  APC; Algerian patients; Cancer panel; Colorectal cancer; FAP; Genetic testing; NGS

DOI:  https://doi.org/10.1007/s11033-022-07228-0
J Gastroenterol Hepatol. 2022 Feb 06.

Germline variant testing in Serrated Polyposis Syndrome.

Aisling Murphy, Joyce Solomons, Peter Risby, Jessica Gabriel, Tina Bedenham, Michael Johnson, Nathan Atkinson, Adam A Bailey, Elizabeth Bird-Lieberman, Simon J Leedham, James E East, Sujata Biswas.

   BACKGROUND: Serrated Polyposis Syndrome (SPS) is now known to be the commonest polyposis syndrome. Previous analyses for germline variants have shown no consistent positive findings. To exclude other polyposis syndromes, 2019 BSG guidelines advise gene panel testing if: the patient is under 50 years, there are multiple affected individuals within a family, or there is dysplasia within any of the polyps.
METHODS: A database of SPS patients was established at the Oxford University Hospitals NHS Foundation Trust. Patients were referred for genetic assessment based on personal and family history and patient preference. The majority were tested for a hereditary colorectal cancer panel including MUTYH, APC, PTEN, SMAD4, BMPR1A, STK11, NTLH1, POLD1, POLE, GREM1 (40kb duplication), PMS2 and Lynch syndrome mismatch repair genes.
RESULTS: 173 patients were diagnosed with SPS based on WHO 2019 criteria between February 2010 and December 2020. The mean age of diagnosis was 54.2 ± 16.8 years. 73 patients underwent genetic testing and 15/73 (20.5%) were found to have germline variants, of which 7/73 (9.6%) had a pathogenic variant (MUTYH n=2, SMAD4 n=1, CHEK2 n=2, POLD1 n=1 and RNF43 n=1). Only 60% (9/15) of these patients would have been recommended for gene panel testing according to current BSG guidelines.
CONCLUSIONS: 20.5% of SPS patients tested were affected by heterozygous germline variants, including previously unreported associations with CHEK2 and POLD1. This led to a change in management in 7 patients (9.6%). Current recommendations may miss SPS associated with germline variants, which is more common than previously anticipated.

Keywords:  Colon; Genetics; Polyposis

DOI:  https://doi.org/10.1111/jgh.15791
Cancer Genet. 2022 Jan 29. pii: S2210-7762(22)00005-9. [Epub ahead of print]262-263 91-94

Lynch syndrome caused by a novel deletion of the promoter and exons 1-13 of MLH1 gene.

Jialing Huang, Victoria Stinnett, Liqun Jiang, Supin Chen, Fausto Rodriguez, Christopher D Gocke, Ying S Zou.

  Lynch syndrome (LS) is the most common hereditary cancer syndrome involving multiple organ systems. The mutation patterns of the involved major DNA mismatch repair (MMR) genes, namely MLH1, MSH2, MSH6, and PMS2, have not been fully elucidated. Herein, we report a case of LS caused by a novel large deletion in the promoter and exons 1-13 of MLH1 gene. A 30 year-old male was admitted for dull abdominal pain for 5 months with family history significant for dominant familial colon cancer. Abdominal computed tomography (CT) revealed masses in colon, lung and liver. His-plasma CA19-9 was 1250 units/ml and CEA 133 ng/ml. Targeted liver biopsy showed metastatic adenocarcinoma. Immunocytochemically, the tumor cells were positive for CK20 and CDX2, and displayed loss of MLH1 and PMS2 expression but with intact MSH2 and MSH6 proteins. Next-generation sequencing of the liver metastasis demonstrated copy loss of MLH1 gene spanning exons 1 to 13. Further SNP array detected copy neutral loss of heterozygosity (CN-LOH) expanding the short arm of chromosome 3p21.3 to 3pter regions and a 219 kb deletion involving the promoter and first 13 exons of MLH1 gene (arr[GRCh37] 3p22.2(36,856,328_37075457)x1). Germline sequencing using a blood sample confirmed the deletion of the MLH gene including the promoter and this first 13 exons (NG_007109.2(NM_000249.3:c.(?_-198)_(1558+1_1559-1)del). In summary, we identified a novel MLH1 mutation pattern of partial deletion and CN-LOH causing LS.

Keywords:  Lynch syndrome; MLH1 gene; SNP array; gene deletion; next-generation sequencing

DOI:  https://doi.org/10.1016/j.cancergen.2022.01.005
Hered Cancer Clin Pract. 2022 Feb 10. 20(1): 7

Retrospective assessment of barriers and access to genetic services for hereditary cancer syndromes in an integrated health care delivery system.

Kristin R Muessig, Jamilyn M Zepp, Erin Keast, Elizabeth E Shuster, Ana A Reyes, Briana Arnold, Chalinya Ingphakorn, Marian J Gilmore, Tia L Kauffman, Jessica Ezzell Hunter, Sarah Knerr, Heather S Feigelson, Katrina A B Goddard.

   BACKGROUND: A critical step in access to genetic testing for hereditary cancer syndromes is referral for genetic counseling to assess personal and family risk. Individuals meeting testing guidelines have the greatest need to be evaluated. However, referrals to genetics are underutilized in US patients with hereditary cancer syndromes, especially within traditionally underserved populations, including racial and ethnic minorities, low-income, and non-English speaking patients.
METHODS: We studied existing processes for referral to genetic evaluation and testing for hereditary cancer risk to identify areas of potential improvement in delivering these services, especially for traditionally underserved patients. We conducted a retrospective review of 820 referrals to the Kaiser Permanente Northwest (KPNW) genetics department containing diagnosis codes for hereditary cancer risk. We classified referrals as high- or low-quality based on whether sufficient information was provided to determine if patients met national practice guidelines for testing. Through chart abstraction, we also assessed consistency with practice guidelines, whether the referral resulted in a visit to the genetics department for evaluation, and clinical characteristics of patients receiving genetic testing.
RESULTS: Most referrals (n = 514, 63%) contained sufficient information to assess the appropriateness of referral; of those, 92% met practice guidelines for genetic testing. Half of referred patients (50%) were not offered genetic evaluation; only 31% received genetic testing. We identified several barriers to receiving genetic evaluation and testing, the biggest barrier being completion of a family history form sent to patients following the referral. Those with a referral consistent with testing guidelines, were more likely to receive genetic testing than those without (39% vs. 29%, respectively; p = 0.0058). Traditionally underserved patients were underrepresented in those receiving genetic evaluation and testing relative to the overall adult KPNW population.
CONCLUSIONS: Process improvements are needed to increase access to genetic services to diagnose hereditary cancer syndromes prior to development of cancer.

Keywords:  Genetic evaluation; Genetic referrals; Genetic testing; Hereditary breast and ovarian cancer; Lynch syndrome

DOI:  https://doi.org/10.1186/s13053-022-00213-5
Breast Cancer Res. 2022 Feb 08. 24(1): 11

Unique ER PR expression pattern in breast cancers with CHEK2 mutation: a hormone receptor and HER2 analysis based on germline cancer predisposition genes.

Grace Wei, Mingxiang Teng, Marilin Rosa, Xia Wang.

   PURPOSE: Estrogen-receptor (ER) and progesterone-receptor (PR) expression levels in breast cancer, which have been principally compared via binomial descriptors, can vary widely across tumors. We sought to characterize ER and PR expression levels using semi-quantitative analyses of receptor staining in germline pathogenic variant (PV) carriers of cancer predisposition genes.
METHODS: We conducted a retrospective chart review of patients who underwent germline genetic testing for cancer predisposition genes at a tertiary cancer center genetics clinic. We performed comparisons of semi-quantitative ER and PR percentage staining levels across carriers and non-carriers of cancer predisposition genes.
RESULTS: Breast cancers from BRCA1 PV carriers expressed significantly lower ER (15.2% vs 78.2%, p < 0.001) and lower PR (6.8% vs 41.1%, p < 0.001) staining compared to non-PV carriers. Similarly, breast cancers of BRCA2 (66.7% vs 78.2%, p = 0.005) and TP53 (50.6% vs 78.2%, p = 0.015) PV tumors also displayed moderate decreases in ER staining. Conversely, CHEK2 tumors displayed higher ER (93.1% vs 78.2%, p = 0.005) and PR (72% vs 48.8%, p = 0.001) staining when compared to non-PV carriers. We observed a wide range of dispersion across the ER and PR staining levels of the carriers and noncarriers. ER and PR ranges of dispersion of CHEK2 tumors were uniquely narrower than all other groups.
CONCLUSION: The findings of our study suggest that precise expression levels of ER and PR in breast cancers can vary widely. These differences are further augmented when comparing expression staining across PV and non-PV carriers, suggesting potentially unique tumorigenesis and progression pathways influenced by germline cancer predisposition genes.

Keywords:  Breast cancer; ER; Germline cancer predisposition gene; HER2; Hormone receptor expression; PR; Tumorigenesis

DOI:  https://doi.org/10.1186/s13058-022-01507-1
Front Oncol. 2021 ;11 797505

The Mutational Landscape of Early-Onset Breast Cancer: A Next-Generation Sequencing Analysis.

Angeliki Andrikopoulou, Spyridoula Chatzinikolaou, Ilias Kyriopoulos, Garyfalia Bletsa, Maria Kaparelou, Michalis Liontos, Meletios-Athanasios Dimopoulos, Flora Zagouri.

   Background: Around 5%-7% of breast cancer cases are diagnosed in women younger than 40, making it the leading cause of female cancer in the 25- to 39-year-old age group. Unfortunately, young age at diagnosis is linked to a more aggressive tumor biology and a worse clinical outcome. The identification of the mutational landscape of breast cancer in this age group could optimize the management.
Methods: We performed NGS analysis in paraffin blocks and blood samples of 32 young patients with breast cancer [<40 years] and 90 older patients during the period 2019 through 2021. All patients were treated in a single institution at the Oncology Department of "Alexandra" Hospital, Medical School, University of Athens, Greece.
Results: Breast tumors were characterized more frequently by HER2 overexpression [25% vs 18.9%], higher ki67 levels [75% vs 61%] and lower differentiation [71.9% vs 60%] in the younger group. PIK3CA [6/20; 30%] and TP53 [6/20; 30%] were the most frequent pathogenic somatic mutations identified in young patients, while one case of BRCA2 somatic mutation [1/20; 5%] and one case of PTEN somatic mutation [1/20; 5%] were also identified. PIK3CA mutations [16/50; 32%] and TP53 mutations [20/50; 40%] were the most common somatic mutations identified in older patients, however other somatic mutations were also reported (ATM, AKT, CHEK2, NRAS, CDKN2A, PTEN, NF1, RB1, FGFR1, ERBB2). As for germline mutations, CHEK2 [3/25; 12%] was the most common pathogenic germline mutation in younger patients followed by BRCA1 [2/25; 8%]. Of note, CHEK2 germline mutations were identified less frequently in older patients [2/61; 3%] among others [BRCA1 (2/61; 3%), ATM (2/61; 3%), APC (1/61; 1,6%) and BRCA2 (1/61; 1,6%)].
Conclusion: We here report the mutational profile identified via NGS in patients with early-onset breast cancer compared to their older counterparts. Although the sample size is small and no statistically significant differences were detected, we highlight the need of genetic testing to most patients in this subgroup.

Keywords:  NGS; breast cancer; early-onset; genetic testing; young women

DOI:  https://doi.org/10.3389/fonc.2021.797505