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Tut3 Genetics B - Cancer Genetics

Case 1

  1. List at least four genes which, when high risk variants are inherited, are associated with increased risk of breast cancer. brca1 and brac 2 p51 ppdl1

  2. Mrs. S. has a 31-year-old daughter who is concerned about her risk of developing breast cancer. Draw a pedigree summarising the self-reported history of cancer in the woman’s family.

There is cancer but not a common certain type

  1. Based on Mrs. S.’s history, do you think any further genetic testing is necessary? If so, who should be tested, and which genes would you test? If you think that testing is not required, explain why not.

As the HER2 (ERBB2) status is described as “equivocal” using immunohistochemistry, further testing using Fluorescent In Situ Hybridisation (FISH) was carried out to establish whether ERBB2 was amplified in the Mrs S’s tumour (see separate result print out). FISH is a molecular cytogenetic technique that can be used to determine the copy number of a gene using fluorescent probes.

Mrs. S.’s result shows that the ERBB2/D17Z1 ratio is 1.1 4. Based on the FISH result, what is the Her2 status of the Mrs. S.’s tumour?

  1. Given this result, would you advise that the Mrs. S. receives Herceptin/Trastuzumab as part of her treatment?

As Mrs. S. has oestrogen receptor positive breast cancer, her Oncologist recommends tamoxifen 20 mg OD for 5 years. Tamoxifen is a selective oestrogen receptor modulator which has been shown significantly reduce the risk of relapse of oestrogen receptor positive breast cancer. To help determine whether she will benefit from chemotherapy in addition to anti-oestrogen therapy, she elects to pay $4850 to have her tumour tested using the Oncotype. DX Breast Cancer Recurrence Score test. View the patient’s Oncotype DX result.

  1. How many genes are measured in the Oncotype DX test? How many of these are test genes and how many are reference genes?

  2. Which “risk of recurrence” category does the patient fall into?

  3. Based on the Mrs S’s Oncotype DX test result, would you recommend that chemotherapy is included in her treatment regime? Why or why not?

  4. Had Mrs S had a recurrence score of 30, what would your recommendation have been?

Seven years after the patient’s initial diagnosis, she presents with shortness of breath, difficulty breathing and a constant dry cough. A PET-CT scan reveals a number of masses in her lungs. Biopsies are taken from some of the masses and this analysis reveals that they are breast cancer metastases that are derived from the primary breast tumour. Histopathology analysis also reveals that the metastatic tumour is Her2 positive.

In an attempt to identify additional therapies that might be effective in treating the metastatic tumours, mutational analysis of DNA from the metastatic biopsies is carried out. This link shows patient marketing information on testing from this service:

The report from this analysis includes the following:

Genomic Alterations Identified ERBB2 amplification CDK12 deletion exon 2 TP53 c824G>T PIK3CA H1047R CCND1 amplification

  1. Based on the analysis of the metastatic tumour, what course of treatment would you recommend for the Mrs. S.?
Genomic alterations

detected		FDA-approved

therapies (in

patient’s tumour

type)		FDA-Approved

Therapies (in

another tumor

type)		Potential Clinical

Trials
ERBB2 amplificationTrastuzumab

Ado-trastuzumab

emtansine

Lapatinib

Pertuzumab		NoneYes, see clinical

trials section
CDK12 deletion exon 2NoneNoneYes, see clinical

trials section
TP53 c824G>TNoneNoneNone
PIK3CA H1047REverolimusIpatasertibYes, see clinical

trials section
CCND1 amplificationPalbociclib

ribociclib		AbemaciclibYes, see clinical

trials section
  1. Suggest why Mrs. S’s metastatic tumour may have tested positive for ERBB2 amplification whereas the primary tumour tested negative?

Mrs S was treated with Trastuzamab for 12 months and entered a research study in which the tumour DNA was sequenced and levels of circulating tumour DNA were monitored to assess the effectiveness of treatment. The results of this monitoring are shown in the graph below.

  1. Suggest why Mrs S’s levels of circulating tumour DNA may be increasing after 12 months of treatment.

  2. Would you recommend that Mrs. S. continues to receive Trastuzumab?

  3. Are there any other therapies that may be worthwhile treating the Mrs S with?

Case 2 - Patient (Mr. J.): Clinical History and Examination

A 45-year-old male (Mr. J.) presents to a GP with complaints of abdominal pain, changes in bowel habits (loose stools alternating with constipation), and unintentional weight loss of approximately 5 kg over the past two months. Mr J has no significant medical history and does not take any medications regularly. He denies any recent travel or infectious exposures. Mr. J’s father was diagnosed with colorectal cancer at the age of 50 and passed away from the disease at 52. His paternal uncle also developed colorectal cancer at age 60 years of age and required surgery and chemotherapy. His paternal grandmother also had a history of endometrial cancer. Mr J’s three children aged 21, 18 and 16 and his sister (47) have no known health problems.

Diagnostic Workup:

  • Complete Blood Count (CBC): The CBC revealed mild normocytic anaemia and other blood parameters within the normal range.
  • Stool Occult Blood Test: Positive for occult blood.
  • Colonoscopy: The colonoscopy showed a large, ulcerated mass in the sigmoid colon, approximately 4 cm in diameter, causing partial luminal obstruction.
  • Biopsy: Histopathological examination of the biopsy confirmed adenocarcinoma.
  1. Draw a pedigree summarising the self-reported history of cancer in Mr J’s family.

Given Mr J’s family history and early-onset colorectal cancer, he was referred to a genetic counsellor who assessed the family history and recommended genetic testing for Lynch Syndrome. Testing revealed a mutation in the MLH1 gene (c.755C>A [p.Ser252Ter].

  1. Review the ClinVar entry for this variant (https://www.ncbi.nlm.nih.gov/clinvar/variation/17078/) and describe the likely effect of this genetic variant on the MLH1 protein. Is this variant associated with Lynch syndrome?

  2. Based on this result, would you recommend that any of Mr J’s whanau should be referred for genetic counselling? If so, which family members should be offered a referral?

Mr J underwent a surgical resection of the tumour, and a pathologic evaluation confirmed the

extent of tumour invasion and lymph node involvement. His tumour stage was assessed as

T3N2bM1b (Stage IVb). An explanation of colorectal cancer staging can be found here:

https://bowelcancernz.org.nz/about-bowel-cancer/treatment-options/staging-and-grading/ or

for more detail: https://www.cancerresearchuk.org/about-cancer/bowel-cancer/stages-types-

and-grades/TNM-staging. To obtain further information about his diagnosis,

Mr J also elected to have mutational analysis carried out on his tumour using a commercially

available service. The report received from this analysis included the following:

Genomic Alterations Identified

EGFR amplification, L858R

PIK3CA H1047Q

DNMT3A R736H

Genomic alterations detectedFDA-approved therapies (in patient’s

tumour type)		FDA-Approved Therapies (in

another tumor type)
EGFR L858RIRESSA® (gefitinib)

TAGRISSO® (osimertinib)

TARCEVA® (erlotinib)		None
PIK3CA - H1047QNoneAlpelisib

Everolimus

Temsirolimus

DNMT3A - R736H None NoneELM2 Genetics Module Tutorials 2025

Biomarker Findings

Tumor Mutational Burden - 11 Muts/Mb

Microsatellite status - Unstable

Tumor Fraction - 55%

  1. Based on these results, suggest one treatment that might benefit Mr J

  2. Is Mr J likely to benefit from immune checkpoint inhibitor therapy? Why or why not?

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Graph View