TITLE

ABSTRACT

Lynch syndrome (LS) is an autosomal dominant inherited disease caused by a germline mutation
in mismatch repair genes, also known as hereditary nonpolyposis colorectal cancer (HNPCC)
syndrome. At the genetic level, it’s caused by a defective mismatch repair (MMR) system
because of the presence of germline defects. In 1990 the International Collaborative Group on
Hereditary Nonpolyposis Colorectal Cancer established Amsterdam I criteria (3-2-1 mnemonic)
for HNPCC. The Revised Bethesda Guideline was developed to include evaluation of MSI
and/or IHC to better identify individuals who deserve genetic testing to investigate for LS.
Barriers to implementation of a hereditary cancer identification process in a developing nation,
there is a disparity in skills and knowledge among the health care providers regarding the
availability of modern scientific tools, and recognition of the benefits of genetic testing for
gynecological cancers. A forty-two years old woman with a chief complaint of recurrent
abnormal uterine bleeding and changes in bowel habit. She had a family history of colorectal
cancer, breast cancer, and ovarian cancer. Ultrasonography (USG) and office hysteroscopy (OH)
was done and tissue was sent for histopathology study. Diagnosis of HNPCC with suspected
Lynch Syndrome was used according to Amsterdam II criteria. Surgery was planned with
planned laparoscopic hysterectomy with bilateral salphingo-oophorectomy. Genetic testing was
planned for the diagnosis of Lynch syndrome, but refusal was met. Indonesian Society of
Gynecologic Oncology (INASGO) is planning to make a national hereditary gynecology cancer
management guideline in Indonesia.

Background

Case presentation

Conclusions

KEYWORD

BACKGROUND
Lynch syndrome (LS) is an autosomal dominant inherited disease caused by a germline mutation

in mismatch repair genes, also known as hereditary nonpolyposis colorectal cancer (HNPCC)

syndrome. At the genetic level, it’s caused by a defective mismatch repair (MMR) system

because of the presence of germline defects in a minimum of one in all the MMR genes: MLH1,

MSH2, MSH6, PMS2, EPCAM. Defects in the mismatch repair genes cause variations in the

size of nucleotide repeats throughout the genome. The phenomenon is known as microsatellite

instability (MSI) and is the molecular hallmark of DNA mismatch repair defects.

In 1990 the International Collaborative Group on Hereditary Nonpolyposis Colorectal Cancer

established Amsterdam I criteria (3-2-1 mnemonic) for HNPCC. Afterward, they were revised to

Amsterdam II criteria, to incorporate some extracolonic tumors as qualifying criteria for LS. The

Bethesda criteria, which were established in 1997 and revised in 2004, outline criteria to assist

physicians in identifying patients with LS. The Revised Bethesda Guideline was developed to

include evaluation of MSI and/or IHC to better identify individuals who deserve genetic testing

to investigate for LS. Tissue testing (Immunohistochemistry [IHC]) or MSI analysis has emerged

as a practical first step in the evaluation of women thought to be at risk for having LS.

Barriers to implementation of a hereditary cancer identification process in a developing nation,

there is a disparity in skills and knowledge among the health care providers regarding the

availability of modern scientific tools, and recognition of the benefits of genetic testing for

gynecological cancers. In Asia, disparities in access to genetic counseling and genetic testing are

largely attributable to the lack of access to appropriately trained laboratory and healthcare

professionals, and lack of funding for laboratory and clinical services, which ends up in

particularly large disparities when combined with a limited regulatory framework for genetic
testing laboratory accreditation and prevention of genetic discrimination and Asian socio-cultural

beliefs of families and genetics

CASE PRESENTATION

A forty-two years old woman with a chief complaint of recurrent abnormal uterine bleeding and

changes in bowel habit. She had a family history of colorectal cancer, breast cancer, and ovarian

cancer. Ultrasonography (USG) and office hysteroscopy (OH) was done and tissue was sent for

histopathology study. Diagnosis of suspected endometrial cancer was done.

Histopathology study reported atypical endometrial hyperplasia with parts that changed into a

well-differentiated adenocarcinoma. Magnetic Resonance Imaging (MRI) was done for further

investigation.
Uterine MRI result showed an irregular heterogeneous mass with infiltration less than half of the

myometrium. The abdominal MRI result showed a circular mass at the distal segment of the

ascending colon without infiltration to the extraluminal, 28.75mm from the hepatic flexure.

Diagnosis of HNPCC with suspected Lynch Syndrome was used according to Amsterdam II

criteria. Joint operation with the digestive surgeon was planned with planned laparoscopic

hysterectomy with bilateral salphingo-oophorectomy and continued with laparoscopic right

hemicolectomy with end-to-end anastomosis. Surgically removed tissues were sent to

histopathology for further study.

Histopathology study of the uterus and bilateral adnexa reported well-differentiated endometrioid

endometrium, no lymphovascular invasion was found, tumor invasion was less than half of

myometrial thickness, and no infiltration of the tumor to the cervix, adnexa, and bilateral

parametrium. Histopathology study of the colon reported adenocarcinoma of the colon with

moderate differentiation, pT3N0. No lymphovascular invasion was found, no metastatic tumor

on the lymphatic gland.

Genetic testing was planned for this patient, for the diagnosis of Lynch syndrome, but refusal

was met

DISCUSSION

Lynch syndrome is the most typical of all inherited cancer syndromes, related to substantially

elevated risk for colonic and extracolonic malignancies, earlier onset, and high rates of multiple

primary cancers. Lynch syndrome is related to the first onset of cancer and therefore the

development of multiple cancer types, particularly colon and endometrial cancer. A

compromised MMR system results in accelerated accumulation of somatic mutations, often

leading to carcinogenesis, the presence of a germline defect is a prerequisite for the diagnosis of

LS. However, acquired loss of the corresponding normal allele (wild-type) in somatic tissue

through genetic or epigenetic mechanisms is required to compromise the function of the

complete MMR complex for LS to manifest phenotypically, therefore is recessive at a cellular

level but inherited as a Mendelian dominant. MLH1, MSH2, MSH6, and PMS2 are genes that

produce MMR proteins. estimated that 80-90% of LS is attributable to deleterious mutations in

MLH1 and MSH2. The defect in MMR genes could be due to the presence of a germline

mutation (LS) or secondary to hypermethylation of the MLH1 promoter (somatic

change/sporadic colorectal cancer). Loss of MLH1 protein is typical because of somatic events

(acquired mutation or hypermethylation) causing inactivation of MLH1 gene, whereas loss of

MSH2 protein is more likely because of a germline mutation of the MSH2 gene. Because the

loss of MLH1 protein expression could also be due to hypermethylation of MLH1 gene promoter

in sporadic colorectal cancer (CRC) it is imperative to check for the presence of BRAF gene

mutation which responsible for MLH1 gene promoter hypermethylation whenever MLH1 protein

is lost or underexpressed in CRC to distinguish between sporadic CRC from LS.

General guidelines that may alert health care providers of the presence of a hereditary cancer

syndrome include early age of onset of malignancy, presence of multiple and/or bilateral primary

cancers, multiple affected family members. Society of Gynecologic Oncologists Education

Committee recently published guidelines to help practicing clinicians determine which patients

may have a chance of having Lynch syndrome. Diagnosing individuals with Lynch syndrome is

important for several reasons, the significant lifetime risk of developing a second primary

malignancy and family members of affected individuals can be tested.

The Revised Bethesda Guideline was developed to include evaluation of MSI and/or IHC to

better identify individuals who deserve genetic testing to investigate for LS

Although LS implies the presence of a germline mutation in one of the MMR genes,

immunohistochemistry (IHC) of the tumor specimen often identifies concurrent loss or partial

production of two MMR genes protein and cannot distinguish between the loss of protein

expression due to germline mutation vs somatic hypermethylation. HNPCC is a clinical

diagnosis for patients and/or families that meet Amsterdam I or II criteria. Whereas the diagnosis

of LS requires the presence of a genetically confirmed mutation in one of the MMR genes known

to be implicated in LS. Genetic testing can definitively diagnose individuals with LS; however,

some families meet clinical criteria for LS for whom a specific mutation cannot be identified.

Genetic testing is expensive and is not reasonable to test all patients with endometrial cancer.

A detailed algorithm for genetic testing in clinical affected and at-risk member of the family is

described in a very recently published consensus statement on genetic evaluation and

management of LS by the US Multi-Society Task Force on Colorectal Cancer

 Genet

ic testing costs and the absence of their adoption into national healthcare systems are the major

economic barriers for approaching genetic services. Lack of legal frameworks against genetic

discrimination and a lack of public awareness of cancer risk assessment Asian BRCA

(ABRACA) Consortium established in October 2011 has members from 14 Asian Countries

(Korea, Japan, Malaysia, Singapore, Hongkong, China, Indonesia, Thailand, Philippines, India,

Bangladesh, Pakistan, Taiwan & Vietnam).

Present status of accessibility to genetic counseling and genetic testing in 14 Asian countries are

genetic counseling and genetic testing do not always correspond similarly to other healthcare

resources which usually correspond directly to World Bank economic stratification or

organization of healthcare delivery, availability, and payment, genetic testing is largely funded

through research and charitable funding. In Thailand, Indonesia, Philippines, Vietnam,

Bangladesh, and three centers in China, genetic testing has largely stopped at the top of the
research studies, additionally to economic factor, the healthcare system, legal system, and

cultural issues should all be considered in the assessment of disparities. Funding and financial

resources are the major issues that limit the accessibility to genetic counseling and testing and

lastly, cultural factors play an important part in deciding on the uptake of genetic testing in Asia.

In Asia, disparities in access to genetic counseling and genetic testing are largely attributable to

the lack of access to appropriately trained laboratory and healthcare professionals, and lack of

funding for laboratory and clinical services, which leads to particularly large disparities when

combined with a limited regulatory framework for genetic testing laboratory accreditation and

prevention of genetic discrimination and Asian socio-cultural beliefs of families and genetics.

Training programs for a genetic counselor are also needed in other countries to address their

genetic counseling service needs, particularly in recognition of the multicultural, multi-religious,

and multilingual settings in Asia.

In developing countries, the priorities, policies, and protocols are more focused on treating

patients who are already diagnosed with cancer and need treating physicians. Developed

countries have demonstrated that it is cost-effective to include the identification of mutation

carriers as a standard of care.

Indonesian Society of Gynecologic Oncology (INASGO) is planning to make a national

hereditary gynecology cancer management guideline in Indonesia. Our planning to increase

awareness of hereditary gynecology cancer are with a public symposium to raise public

awareness, routine gynecological examination at the risky population, early diagnosis based on

symptoms, genetic counseling to educate people about hereditary gynecology cancer.

Predictive genetic testing for hereditary cancer involves a genetic counselor to aid the people in

their understanding and decision making.

CONCLUSIONS

LIST OF ABBREVIATIONS

HNPCC: Hereditary Non-Polyposis Colorectal Cancer

LS: Lynch Syndrome

MMR: Mismatch Repair Gene

CRC: Colorectal Cancer

IHC: Immunohistochemistry

MRI: Magnetic Resonance Imaging

USG: Ultrasonography

OH: Office Hysteroscopy

INASGO: Indonesian Society of Gynecologic Oncology

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