Clinicopathological Features of Patients with the  BRCA1  c.5339T>C (p.Leu1780Pro) Variant

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Abstract

Purpose

Recent studies revealed the BRCA1 c.5339T>C, p.Leu1780Pro variant (L1780P) is highly suggested as a likely pathogenic. The aim of this study was to evaluate clinicopathologic features of L1780P with breast cancer (BC) using multicenter data from Korea to reinforce the evidence as a pathogenic mutation and to compare L1780P and other BRCA1/2 mutations using Korean Hereditary Breast Cancer (KOHBRA) study data.

Materials and Methods

The data of 54 BC patients with L1780P variant from 10 institutions were collected and the clinicopathologic characteristics of the patients were reviewed. The hereditary breast and/or ovarian cancer–related characteristics of the L1780P variant were compared to those of BC patients in the KOHBRA study.

Results

The median age of all patients was 38 years, and 75.9% of cases showed triple-negative breast cancer. Comparison of cases with L1780P to carriers from the KOHBRA study revealed that the L1780P patients group was more likely to have family history (FHx) of ovarian cancer (OC) (24.1% vs. 19.6% vs. 11.2%, p < 0.001 and p=0.001) and a personal history of OC (16.7% vs. 2.9% vs. 1.3%, p=0.003 and p=0.001) without significant difference in FHx of BC and bilateral BC. The cumulative risk of contralateral BC at 10 years after diagnosis was 31.9%, while the cumulative risk of OC at 50 years of age was 20.0%. Patients with L1780P showed similar features with BRCA1 carriers and showed higher penetrance of OC than patients with other BRCA1 mutations.

Conclusion

L1780P should be considered as a pathogenic mutation. Risk-reducing salpingo-oophorectomy is highly recommended for women with L1780P.

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Most cited references 23

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Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations

Timothy R Rebbeck, Tara M Friebel, Eitan Friedman … (2018)

The prevalence and spectrum of germline mutations in BRCA1 and BRCA2 have been reported in single populations, with the majority of reports focused on Caucasians in Europe and North America. The Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) has assembled data on 18,435 families with BRCA1 mutations and 11,351 families with BRCA2 mutations ascertained from 69 centers in 49 countries on 6 continents. This study comprehensively describes the characteristics of the 1,650 unique BRCA1 and 1,731 unique BRCA2 deleterious (disease-associated) mutations identified in the CIMBA database. We observed substantial variation in mutation type and frequency by geographical region and race/ethnicity. In addition to known founder mutations, mutations of relatively high frequency were identified in specific racial/ethnic or geographic groups that may reflect founder mutations and which could be used in targeted (panel) first pass genotyping for specific populations. Knowledge of the population-specific mutational spectrum in BRCA1 and BRCA2 could inform efficient strategies for genetic testing and may justify a more broad-based oncogenetic testing in some populations.

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Founder mutations in BRCA1 and BRCA2 genes.

R Ferla, V Calò, S Cascio … (2007)

BRCA1 and BRCA2 germline mutations contribute to a significant number of familial and hereditary breast and/or ovarian cancers. The proportion of high-risk families with breast and/or ovarian cancer cases due to mutations in these tumor suppressor genes varies widely among populations. In some population, a wide spectrum of different mutations in both genes are present, whereas in other groups specific mutations in BRCA1 and BRCA2 have been reported with high frequency. Most of these mutations are prevalent in restricted populations as consequence of a founder effect. The comparison of haplotypes between families with the same mutation can distinguish whether high-frequency alleles derive from an older or more recent single mutational event or whether they have arisen independently more than once. Here, we review some of the most well-known and significant examples of founder mutations in BRCA genes found in European and non-European populations. In conclusion, the identification of the ethnic group of families undergoing genetic counseling enables the geneticist and oncologist to make more specific choices, leading to simplify the clinical approach to genetic testing carried out on members of high-risk families. Futhermore, the high frequency of founder mutations, allowing to analyze a large number of cases, might provide accurate information regarding their penetrance.

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Comprehensive analysis of missense variations in the BRCT domain of BRCA1 by structural and functional assays.

S Lee, David D. Hau, Desmond Foo … (2010)

Genetic screening of the breast and ovarian cancer susceptibility gene BRCA1 has uncovered a large number of variants of uncertain clinical significance. Here, we use biochemical and cell-based transcriptional assays to assess the structural and functional defects associated with a large set of 117 distinct BRCA1 missense variants within the essential BRCT domain of the BRCA1 protein that have been documented in individuals with a family history of breast or ovarian cancer. In the first method, we used limited proteolysis to assess the protein folding stability of each of the mutants compared with the wild-type. In the second method, we used a phosphopeptide pull-down assay to assess the ability of each of the variants to specifically interact with a peptide containing a pSer-X-X-Phe motif, a known functional target of the BRCA1 BRCT domain. Finally, we used transcriptional assays to assess the ability of each BRCT variant to act as a transcriptional activation domain in human cells. Through a correlation of the assay results with available family history and clinical data, we define limits to predict the disease risk associated with each variant. Forty-two of the variants show little effect on function and are likely to represent variants with little or no clinical significance; 50 display a clear functional effect and are likely to represent pathogenic variants; and the remaining 25 variants display intermediate activities. The excellent agreement between the structure/function effects of these mutations and available clinical data supports the notion that functional and structure information can be useful in the development of models to assess cancer risk.

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Author and article information

Journal

Journal ID (nlm-ta): Cancer Res Treat

Journal ID (iso-abbrev): Cancer Res Treat

Journal ID (publisher-id): CRT

Title: Cancer Research and Treatment : Official Journal of Korean Cancer Association

Publisher: Korean Cancer Association

ISSN (Print): 1598-2998

ISSN (Electronic): 2005-9256

Publication date (Print): July 2020

Publication date (Electronic): 28 January 2020

Volume: 52

Issue: 3

Pages: 680-688

Affiliations

[1 ]Department of Surgery, Yonsei University College of Medicine, Seoul, Korea

[2 ]Department of Surgery, Samsung Comprehensive Cancer Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

[3 ]Cancer Prevention Center, Yonsei Cancer Center, Seoul, Korea

[4 ]Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea

[5 ]Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea

[6 ]Center for Breast Cancer, National Cancer Center, Goyang, Korea

[7 ]Department of Surgery, Seoul National University College of Medicine, Seoul, Korea

[8 ]Breast Care Center, Seoul National University Bundang Hospital, Seongnam, Korea

[9 ]Department of Surgery, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea

[10 ]Department of Surgery, Dankook University College of Medicine, Cheonan, Korea

[11 ]Department of Surgery, School of Medicine, Kyungpook National University, Daegu, Korea

[12 ]Division of Breast and Endocrine Surgery, Department of Surgery, Korea University Anam Hospital, Korea University College of Medicine, Seoul, Korea

[13 ]Department of Surgery, Breast Care Center, Daerim St. Mary's Hospital, Seoul, Korea

Author notes

Correspondence: Sung-Won Kim, MD, PhD Department of Surgery, Breast Care Center, Daerim St. Mary's Hospital, 657 Siheung-daero, Yeongdeungpo-gu, Seoul 07442, Korea Tel: 82-2-829-9000 Fax: 82-2-3410-6982 E-mail: brcakorea@ 123456gmail.com

Co-correspondence: Jeong Eon Lee, MD, PhD Division of Breast Surgery, Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Korea Tel: 82-2-3410-3479 Fax: 82-2-3410-6982 E-mail: paojlus@ 123456hanmail.net

[*]

Hyung Seok Park and Jai Min Ryu contributed equally to this work.

Article

Publisher ID: crt-2019-351

DOI: 10.4143/crt.2019.351

PMC ID: 7373877

PubMed ID: 32019279

SO-VID: 0969be1e-5f2c-4bde-a218-7f7794b35056

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Clinicopathological Features of Patients with the BRCA1 c.5339T>C (p.Leu1780Pro) Variant

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Abstract

Purpose

Materials and Methods

Results

Conclusion

Related collections

Karger: Oncology

Most cited references 23

Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations

Founder mutations in BRCA1 and BRCA2 genes.

Comprehensive analysis of missense variations in the BRCT domain of BRCA1 by structural and functional assays.

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