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Table of Contents
Year : 2020  |  Volume : 3  |  Issue : 2  |  Page : 81-83

A twisted tale of a family with multiple malignancies: Mystery solved

1 Laboratory and Transfusion Services, New Delhi, India
2 Molecular Diagnostics, Rajiv Gandhi Cancer Institute and Research Centre, New Delhi, India

Date of Submission02-Nov-2020
Date of Acceptance05-Nov-2020
Date of Web Publication31-Dec-2020

Correspondence Address:
Dr. Shrinidhi Nathany
Molecular Diagnostics, Rajiv Gandhi Cancer Institute and Research Centre, New Delhi.
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jco.jco_37_20

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How to cite this article:
Mehta A, Nathany S. A twisted tale of a family with multiple malignancies: Mystery solved. J Curr Oncol 2020;3:81-3

How to cite this URL:
Mehta A, Nathany S. A twisted tale of a family with multiple malignancies: Mystery solved. J Curr Oncol [serial online] 2020 [cited 2022 Nov 30];3:81-3. Available from: http://www.https://journalofcurrentoncology.org//text.asp?2020/3/2/81/305854

  Case History Top

In 2012, a 42-year-old female presented with a lump in her right breast that was suspicious of malignancy on mammography (BIRADS 4 category lesion). Histologically, the lump was diagnosed as a micropapillary carcinoma and the tumor cells were immunonegative for ER, PR and positive for Mammaglobin and CK7. The Her2 status on FISH revealed an amplified status. The patient underwent right-sided quandrantectomy with axillary lymph node dissection and was treated with adjuvant chemotherapy and trastuzumab. In August 2020, she presented with a thigh mass that was histologically confirmed as a pleomorphic undifferentiated sarcoma with myxoid areas. She underwent wide local excision for the same.

Q1. Based on the above history, do you think the second malignancy is a part of

  • A. An inherited cancer syndrome

  • B. Two sporadic cancers

  • C. Therapy-related sarcoma after treatment for breast carcinoma

Answer 1. The answer is option A: An inherited cancer syndrome. This patient presented with a carcinoma breast at an early age, which was hormone receptor negative but Her2 positive. Traditionally, Her2-positive breast malignancies have been described to be sporadic and not associated with a hereditary breast ovarian carcinoma syndrome. However, the same has been reported in 63–83%[1] cases of Li Fraumeni syndrome.[2] It is not two sporadic cancers (Option B) because of the early onset of breast carcinoma and the second malignancy occurring after eight years of onset of the first malignancy. It is unlikely to be a therapy-related process, as the incidence of a therapy-related sarcoma is very low after breast cancer adjuvant chemotherapy.

On seeking detailed family history of the patient, it was found that her mother and four siblings have succumbed to cancer at early ages. All the five deceased family members had some malignancy, the details of which were not available. The pedigree of the family is shown in [Figure 1] next for your reference.
Figure 1: Pedigree chart of the patient. Arrow shows the patient in question

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Q2. From the family history of multiple affected members, and a personal history of two malignancies of the patient in question, which syndrome would you think of?

  • A. Cowden syndrome

  • B. Neurofibromatosis

  • C. Li Fraumeni syndrome

  • D. Lynch syndrome

Answer 2. The answer is option C: Li Fraumeni syndrome. As per the pedigree chart provided and a personal history, it is clear that this is an inherited cancer predisposition syndrome. It is evident that the ongoing process is autosomal dominant in nature with high penetrance, as a total of six family members are affected. The presentation of this patient with an early onset of Her2-positive breast carcinoma followed by a soft tissue sarcoma is highly likely of a Li Fraumeni syndrome, as this combination of a carcinoma and sarcoma is more common in the same.

It is not a Neurofibromatosis (Option B), as there is no history or features suggestive of any skin or subcutaneous nodules, or any neurologic tumors. Option A (Cowden syndrome) is also ruled out, as this comprises mainly colorectal carcinoma, glioblastoma, and skin adnexal neoplasms. It cannot be a Lynch syndrome (Option D), as the same is associated mainly with tumors of a colorectal origin. [Table 1] highlights the different hereditary cancer predisposition syndromes and their phenotypic manifestations.
Table 1: Differential syndromic diagnoses considered in this case

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Li Fraumeni syndrome is an autosomal dominant process associated with germline alterations in the TP53 gene, which is a tumor suppressor gene and is also known as the “guardian of the genome.” It maps to chromosome 17p,[3] and it is involved in cell cycle checks and DNA repair mechanisms. More than 250 pathogenic germline mutations [Figure 2] have been reported in this gene, spanning almost the entire coding region, but they are mainly clustered in exons 5–8.[2]
Figure 2: Codon-wise distribution of pathogenic Germline mutations reported in the TP53 gene; adopted from https://p53.iarc.fr/TP53GermlineMutations.aspx

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  Criteria to Diagnose Li Fraumeni Syndrome, Including Chompret Criteria Top

  • a. An individual with Li Fraumeni Syndrome (LFS)-spectrum tumor (soft tissue or osteosarcomas, brain tumors, premenopausal breast cancers, leukemia, adrenocortical carcinoma (ACCs), and lung bronchoalveolar carcinomas, except breast cancer), 46 years of age, and at least one first- or second-degree relative with an LFS tumor before 56 years of age or with multiple tumors at any age.


  • b. Proband with multiple tumors (except multiple breast cancers), the first of which occurs before the age of 46 years, with at least two belonging to the LFS spectrum.


  • c. Proband with an ACC or choroid plexus carcinoma regardless of family history.


  • d. Breast cancer before 31 years of age.

Q3. Which is the best method available today to test for mutations in the Tp53 gene?

  1. Real-time PCR

  2. Sanger sequencing

  3. Next-generation sequencing

  4. FISH

TP53, located on chromosome 17p, is a tumor suppressor gene, and it is a large gene with more than 30 coding exons. To ensure accurate detection of a potential variant in this gene, the entire gene has to be sequenced. Owing to the large size, PCR or Sanger sequencing will be cumbersome and will require multiple primer sets; hence, next-generation sequencing-based assay is the best possible way to test for the same. Large deletions/ duplications may also occur in Germline, hence a multiplex ligation probe assay may also be needed to detect the same.

This patient underwent an NGS assay on blood to look for Germline mutations in any hereditary cancer genes. The panel consists of 33 genes implicated in hereditary predisposition of cancers, along with genes implicated in homologous repair deficiency.

The NGS revealed a mutation in the TP53 gene, annotated as: chr17:7578283G>T; c.566C>A; p.Ala189Asp at a variant allele fraction of 44.11%. This was predicted as pathogenic by ACMG guidelines,[4] and it showed both somatic and Germline counts in the IARC TP53 Database.[3]

Q4. This patient has been proven as having Li Fraumeni syndrome. What would you do next?

  • A. No further testing required

  • B. Test her children only for Germline TP53

  • C. Test her children and remaining siblings for Germline TP53

  • D. Test her children, alive sibling for Germline variant, and tissue of deceased sibling to establish co-segregation

  Conclusion Top

Historically, a young woman with an early onset of hormone receptor negative breast carcinoma is considered as a candidate for Germline testing for BRCA1/BRCA2 genes. However, the Her2 positivity, in this case, was the crux. This unique combination of a breast carcinoma and a pleomorphic sarcoma with a highly suggestive family history made Li-Fraumeni syndrome more likely. This unique article highlights an important algorithm depicted next.

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Conflicts of interest

There are no conflicts of interest.

  References Top

Rath MG, Masciari S, Gelman R, Miron A, Miron P, Foley K, et al. Prevalence of germline TP53 mutations in HER2+ breast cancer patients. Breast Cancer Res Treat 2013;139:193-8.  Back to cited text no. 1
Mehta A, Gupta G Li–Fraumeni syndrome : A lesser known and investigated “Cancer Predisposition Syndrome.” J Curr Oncol2020;2:1-5.  Back to cited text no. 2
Bouaoun L, Sonkin D, Ardin M, Hollstein M, Byrnes G, Zavadil J, et al. TP53 variations in human cancers: New lessons from the IARC TP53 database and genomics data. Hum Mutat2016;37:865-76.  Back to cited text no. 3
Kopanos C, Tsiolkas V, Kouris A, Chapple CE, Albarca Aguilera M, Meyer R, et al. Varsome: The human genomic variant search engine. Bioinformatics 2019;35:1978-80.  Back to cited text no. 4


  [Figure 1], [Figure 2]

  [Table 1]


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