Given the increased risks associated with Lynch syndrome for gynecologic, colon and other cancers, physicians at the UCSF Gynecologic Oncology Center now approach testing, surveillance and treatment based on each patient’s individual genetic risk. Lynch syndrome is an autosomal dominant condition of inherited cancer susceptibility caused by defects in the mismatch repair (MMR) system. As outlined in the American College of Obstetricians and Gynecologists’ Practice Bulletin, the most common genes associated with Lynch syndrome are MLH1, MSH2, MSH6 and PMS2.
“While these genes have frequently been studied together as ‘Lynch genes,’ we are also discovering more about their different clinical manifestations,” said Practice Bulletin contributor Lee-may Chen, MD, gynecologic cancer surgeon and director of UCSF’s Division of Gynecologic Oncology. “Not all presentations of Lynch syndrome genes are the same. Our understanding of cancer risk is evolving and affects provider-patient decision-making in the practice of gynecologic oncology.”
Recent clinical cases reinforce the value of precision medicine in treating gynecologic cancers associated with Lynch syndrome.
Early detection and treatment of Stage 1A endometrial carcinoma based on family history
An asymptomatic 38-year-old woman visited the UCSF Cancer Genetics and Prevention Program for risk assessment due to a family history of colon cancer. Her sister was diagnosed with colon cancer at age 25 and their father at age 49. He subsequently died of the disease. The patient’s paternal aunt and uncle were also diagnosed with colon cancer at young ages before succumbing to the disease. The patient is screened annually for colorectal cancer.
The patient tested positive for a pathogenic variant in the MSH2 gene, which indicates:
- a 40 to 60% lifetime risk of colorectal cancer;
- a 40 to 60% lifetime risk of endometrial cancer; and
- a 10 to 20% lifetime risk of ovarian cancer.
The patient and the UCSF gynecologic oncology team discussed surveillance and chemoprevention with oral contraceptives or IUD. Through surveillance, an endometrial biopsy identified atypical endometrial hyperplasia, and the patient underwent a laparoscopic hysterectomy and bilateral salpingo-oophorectomy. She was diagnosed with stage IA grade 1 endometrial carcinoma. She was the first person in her family whose cancer was detected early, and remains cancer-free 17 years later.
Precision risk-reducing surgery for 44-year-old woman with pathogenic variant in the PMS2 gene
A 44-year-old woman whose mother was diagnosed with colon cancer at age 41 was found to carry a pathogenic variant in the PMS2 gene through testing at the UCSF Cancer Genetics and Prevention Program. This indicates:
- a 12 to 20% lifetime risk of colorectal cancer;
- a 13 to 24% lifetime risk of endometrial cancer; and
- a 2 to 3% lifetime risk of ovarian cancer.
Genetic counseling aided her decision to pursue risk-reducing hysterectomy and salpingectomy but not oophorectomy due to her premenopausal status and relatively low risk for ovarian cancer. To address her colorectal cancer risk, the patient undergoes an annual colonoscopy.
Lynch syndrome diagnoses led to genetic testing for family members
A 71-year-old woman with postmenopausal bleeding was diagnosed with endometrial cancer. She underwent a robotic-assisted total laparoscopic hysterectomy, a bilateral salpingo-oophorectomy, and sentinel lymph node mapping and biopsy. She was found to have a stage IA grade 1 endometrial carcinoma, which was absent for the MSH6 protein. Genetic testing revealed that she carried a pathogenic germline variant in the MSH6 gene, signifying Lynch syndrome. Discovery of this variant led her medical team to recommend genetic testing for her son so he could take steps to manage any elevated cancer risk.
In another case, a 51-year-old woman with abnormal bleeding was diagnosed with endometrial cancer. She underwent a robotic-assisted total laparoscopic hysterectomy, bilateral salpingo-oophorectomy, and sentinel lymph node mapping and biopsy, revealing a stage IIIC grade 1 endometrial carcinoma. Her tumor was sequenced through the UCSF 500 Cancer Gene Panel Test, which sequences the full coding region of more than 500 cancer genes. She was found to have a hypermutated tumor, including a tumor mutation in the MSH2 gene. In addition, germline genetic testing revealed a pathogenic variant in her MSH2 gene. Genetic testing for Lynch syndrome was recommended for her brother and mother.
“All of our Gynecologic Oncology Center patients with newly diagnosed ovarian or endometrial cancer undergo genetic evaluation,” Chen explained. “The gastrointestinal cancer team also screens all patients with colorectal cancer for Lynch syndrome. Yet the cancer risks may be quite different depending on which gene runs in the family.”
“Patients at high risk for cancer have treatment options available based on the pathogenic variants,” continued Chen. “Patients can choose surveillance versus risk-reducing surgery based on individual genetic risk. Affected patients with Lynch syndrome or other hereditary cancers can also help identify unaffected at-risk family members who may benefit from colonoscopy screening or appropriate risk-reducing gynecologic surgery. It's a privilege to be able to participate in these genetic discoveries and help people and their families.”
UCSF Medical Center is ranked as the best hospital in Northern California for cancer care by U.S. News & World Report’s 2021-2022 Best Hospitals survey.
Cancer research and treatment take place within the UCSF Helen Diller Family Comprehensive Cancer Center.
To learn more
UCSF Gynecologic Oncology Center
Phone: (415) 353-9600 | Fax: (415) 353-7657
