Don't BRCA my heart
Risk reducing oophorectomy is recommended at age 40-45
BRCA2
A 35-year-old woman presents with a recent diagnosis of colorectal carcinoma. Next-generation sequencing results show high microsatellite instability (MSI-H) and a mutation in the MLH1 gene with a variant allele frequency of 47%.
Which of the following should be included in counseling this patient?
Referral to genetic counseling and testing for germline mutations in mismatch repair genes.
Of the genes associated with paragangliomas and pheochromocytomas, this one shows parent of origin effects
SDHD
A healthy 38-year-old woman presents to your clinic after genetic testing revealed a variant of uncertain significance (VUS) in BRCA2. Her mother died of metastatic breast cancer at age 38 and was not tested for BRCA alterations.
The patient has one brother, and her mother had two sisters, all of whom are alive and without cancer. She is the only family member who has undergone genetic testing. She asks about the significance of the result and your recommendations.
Which of the following should you recommend now?
Annual mammogram and MRI
A 48-year-old woman presents to your clinic with a recent diagnosis of cecal adenocarcinoma. She initially presented to the emergency department with abdominal pain, and abdominal CT scan identified a cecal mass. Further staging workup included a CT of the chest and pelvis, which showed no evidence of metastatic disease.
Colonoscopy identified no evidence of polyps but did show a partially obstructing cecal mass. Biopsy of the mass revealed adenocarcinoma. The patient underwent a right hemicolectomy; final pathology findings showed pT2pN1 disease.
Her family history is notable for an older brother diagnosed with colon cancer at age 60 years, a paternal grandfather who had colon cancer at age 58 years, and a paternal aunt with endometrial cancer at age 54 years.
What gene are you considering?
Lynch genes
A 52-year-old perimenopausal woman presents for genetic testing. She reports a family history of breast cancer in two sisters in their fifties, both negative for BRCA1/2 and Lynch syndrome; premenopausal breast cancer in a paternal aunt; and colon cancer in her mother and two maternal uncles in their sixties.
She has no abnormal breast biopsy history, and menarche occurred at 12 years. Age at first live birth was 25 years.
Which of the following should you recommend now?
Broader germline genetic testing
You are seeing a patient due to abnormal immunohistochemistry showing loss of MLH1/PMS2.The best next step...
Refer to diagram on slide 8/9
Triple negative
pancreatic
metastatic/high risk prostate cancer
male breast cancer
etc...
A 37-year-old woman presents after recently being diagnosed with breast cancer. She reports that her son was affected by adrenocortical carcinoma and osteosarcoma in early childhood. Her mother and an aunt were diagnosed with breast cancer around age 30. Additionally, her maternal uncle and grandfather both died of brain tumors, and another maternal uncle developed colon cancer in his 40s.
Which of the following genes is likely to demonstrate a germline mutation?
TP53
A 41-year-old woman recently diagnosed with invasive lobular breast cancer presents for genetic counseling on the advice of her oncologist. She has an unusually strong family history of cancers, and her oncology team was concerned about the young age of onset of her breast cancer diagnosis.
Her detailed family history includes a sister and maternal aunt diagnosed with breast cancer. She also has a maternal uncle who died at a very young age from gastric cancer. Her maternal grandfather may have also died from "cancer in his belly," but she cannot recall exactly what type of cancer this was.
To her knowledge, she has no relatives who have had ovarian cancer or prostate cancer, and there is nothing else that the patient can think of that runs in her family.
Which of the following is the most likely pathogenic germline variant in this patient?
CDH1
A 35-year-old woman enrolled in a high-risk breast cancer screening program presents for discussion about endocrine therapy for breast cancer risk reduction. She has a known BRCA2 mutation and a paternal family history of breast cancer in two second-degree relatives before age 50 years with no other reported relevant family history.
Which of the following should you recommend now?
5 years of tamoxifen therapy for breast cancer risk reduction
A 48-year-old man presents with stage IIB invasive adenocarcinoma of the sigmoid colon. No relevant family history is reported. Universal mismatch repair immunohistochemistry was performed on a sigmoid colon biopsy specimen; screening for Lynch syndrome is normal/intact.
You discuss further germline testing with the patient.
Which of the following should you recommend now?
Germline genetic testing for Lynch syndrome and other colon cancer genes
Individuals with more than 10 tubular adenomas will have no family history of polyposis or colon cancer. This is because they could have..
De novo APC variant or bialleic MUTYH variants
A TP53 pathogenic variant is found in your 67-year-old patient diagnosed with triple negative breast cancer at 65 using a multi-gene panel with a variant allele frequency of 22%. Her family history is significant for her mother with an unknown primary at 42 and her maternal cousin who died of a brain cancer at 12. Recommended next steps?
Explanation: The variant allele frequency in an older person with a non-Li-Fraumeni cancer (TNBC in 60’s) is much more suggestive of a somatic variant contained to the lymphocytes than a germline variant.
Reference: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5976505/
The family history he provides you with is “patient’s maternal grandmother with endometrial cancer at 54 and maternal aunt with breast cancer at 43. The patient’s mother had thyroid nodules but she does not think they were malignant because she had a thyroidectomy and no additional follow-up". You suspect:
PTEN
A 47-year-old woman recently diagnosed with stage IIA (T2N0M0) breast cancer is seen in the oncology clinic to discuss her management plan. Molecular marker testing is negative for estrogen receptor (ER), progesterone receptor (PR), and HER2. She will begin neoadjuvant treatment with chemotherapy next week.
She states that a distant relative also had breast cancer in her 60s and another family member was diagnosed with colorectal cancer at an unknown age, both on her father's side. She is meeting with a genetic counselor to discuss germline testing.
Which of the following tests should you order now?
Next-generation sequencing for a targeted panel covering multiple high-penetrance cancer susceptibility genes.
A 30-year-old man with a known germline APC mutation presents to the clinic seeking advice for additional testing related to familial adenomatous polyposis (FAP). He underwent a total colectomy for polyps at age 27 and has not seen a doctor since then.
He is married and plans to have children. He does not smoke or vape and reports drinking socially a few times a month. At today's visit, he has no symptoms.
Which of the following is the most appropriate next step?
48-year-old male patient presents to your genetics clinic because he has recently been diagnosed with a pancreatic neuroendocrine tumor. In reviewing his personal history, you learn that he was diagnosed with hyperparathyroidism when he was 22 years old. Aside from a distant cousin with breast cancer, he does not have a strong family history of cancer. When asked about other non-cancerous findings in his family, he reports that he father had a benign tumor near his brain that caused him to lactate and the patient’ts younger brother has a history of kidney stones. Based on this information, which of the conditions listed below is most likely for this patient and his family?
MEN1
A 55-year-old woman with a history of sunburns and type 2 diabetes mellitus presents for routine clinical examination, which reveals an abnormal pigmented lesion on the right upper arm. Lesion biopsy shows malignant melanoma: 1-mm Breslow depth, nonulcerated, no mitoses.
She then undergoes wide local excision with clear margins; lymphoscintigraphy-led sentinel lymph node biopsy shows no melanoma involvement. Tumor testing is positive for a BRAF V600K mutation.
Her family history includes cutaneous melanoma in her father and paternal grandfather, breast cancer in her sister, and prostate cancer in her paternal uncle.
Which of the following should you recommend now?
Germline mutation testing
A 45-year-old man presents with a history of two unique, previously resected, early-stage melanoma primaries. He reports a family history of skin cancer in his father, unknown type in his fifties, and his brother had melanoma at 38 years. He meets with a genetic counselor and undergoes panel testing for germline mutations.
A truncating mutation is found in the CDKN2A gene. He is referred for close dermatologic follow-up and cascade testing for his relatives.
Which of the following tests should you order now?
Pancreatic cancer screening with MRCP and endoscopic ultrasonogram
A 36-year-old woman presents to your high-risk clinic with a strong family history of breast cancer. Her mother was diagnosed with breast cancer at age 42 years, her maternal aunt had breast cancer at age 50, and her maternal grandmother had breast cancer in her 60s. She has reliable information that there is no history of cancer throughout her paternal lineage, and she is not of Ashkenazi Jewish background.
Her mother had germline genetic testing within the last year with a large panel of cancer genes, showing a variant of uncertain significance (VUS, class 3) in BRCA2 but no other germline changes.
You run an approved breast cancer risk model, which gives her a lifetime risk of breast cancer of 33.5%. She is requesting testing for the VUS so she can make decisions about management of her breast and ovarian cancer risks.
Which of the following should you recommend now?
Manage according to high risk protocols
A 70-year-old woman follows up in the oncology clinic for metastatic colon cancer. Two years ago, she was diagnosed with cancer in the ascending colon on routine colonoscopy. She had surgical resection of a stage IIIA disease, followed by 3 months of chemotherapy with capecitabine and oxaliplatin at her local hospital.
Immunohistochemistry testing done at the time showed loss of mismatch repair (MMR) protein expression, but no further testing was done. You request genomic sequencing and start her on treatment with pembrolizumab. She presents today to review results of CT scans completed after 3 months of treatment. CT showed response to treatment, but she is worried about hereditary Lynch syndrome after doing some research. She asks if her children and grandchildren should pursue genetic testing.
After reviewing her sequencing results, you inform her that there is no need for further evaluation for Lynch syndrome and that this was more likely a sporadic MMR deficiency.
Which of the following genetic alterations found on sequencing most likely informed your statement?
BRAF V600E mutation
When you have a suspicion of a germline component you should...
Refer to genetic counseling!
A 45-year-old woman is seen at the 3-year mark with stage II hormone receptor-positive, HER2-negative breast cancer, managed with lumpectomy, radiation, and hormone blockers. She has no evidence of disease on cancer surveillance and is doing well.
She shares that her father was recently diagnosed with prostate cancer, and he had a prior history of follicular thyroid cancer. Her paternal aunt has also recently been diagnosed with endometrial cancer. She reports to her oncologist that she initially declined genetic counseling, but is now interested. Panel genetic testing reveals a pathogenic variant in PTEN.
Along with screening for breast and endometrial cancers, which of the following would you recommend screening for?
Thyroid and renal cancer
A 33-year-old man with no significant medical history is diagnosed with acute myeloid leukemia (AML) after presenting with easy bruising and bleeding. He has a family history of thrombocytopenia in several first-degree relatives. He also has a sibling with myelodysplastic syndrome (MDS) at age 25.
You suspect a germline predisposing disorder.
A germline variant in which gene is most likely to be associated with this patient's presentation?
RUNX1